Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

Traumatic brain injury (TBI) affects more than 2 million people in the United States each year.¹ TBI can trigger a cascade of secondary injury mechanisms, such as inflammation, hypoxic/ischemic injury, excito­toxicity, and oxidative stress,² that could contribute to cognitive and behavioral changes. Although neuropsychiatric symptoms might not be obvious after a TBI, they have a high prevalence in these patients, can last long term, and may be difficult to treat.³ Despite research advances in understanding the biological basis of TBI and identifying potential therapeutic targets, treatment options for individuals with TBI remain limited.

As a result, clinicians have turned to alternative treatments for TBI, including nutraceuticals. In this article, we will:

• provide an overview of nutraceuticals used in treating TBI, first exploring outcomes soon after TBI, then concentrating on neuropsychiatric outcomes
• evaluate the existing evidence, including recommended dietary allowances (Table 1)^4,5 and side effects (Table 2)
• review recommendations for their clinical use.

Pharmacologic approaches are limited

Nutraceuticals have gained attention for managing TBI-associated neuropsychiatric disorders because of the limited evidence supporting current approaches. Existing strategies encompass pharmacologic and non-pharmacologic interventions, psychoeducation, supportive and behavioral psychotherapies, and cognitive rehabilitation.⁶

Many pharmacologic options exist for specific neurobehavioral symptoms, but the evidence for their use is based on small studies, case reports, and knowledge extrapolated from their use in idiopathic psychiatric disorders.^7,8 No FDA-approved drugs have been effective for treating neuro­psychiatric disturbances after a TBI. Off-label use of antidepressants, anticonvulsants, dopaminergic agents, and cholinesterase inhibitors in TBI has been associated with inadequate clinical response and/or intolerable side effects.^9,10

What are nutraceuticals?

DeFelice¹¹ introduced the term “nutraceutical” to refer to “any substance that is a food or part of a food and provides medical or health benefits, including the prevention and treatment of disease.” The term has been expanded to include dietary supplements, such as vitamins, minerals, amino acids, herbal or other botanicals, and food products that provide health benefits beyond what they normally provide in food form. The FDA does not regulate the marketing or manufacturing of nutraceuticals; therefore, their bioavailability and metabolism can vary.

Despite their widespread use, the evidence supporting the efficacy of nutraceuticals for patients with TBI is limited. Their effects might vary by population and depend on dose, timing, TBI severity, and whether taken alone or in combination with other nutraceutical or pharmaceutical agents. Fourteen randomized controlled trials (RCTs) have addressed the use of nutraceuticals in TBI (Table 3), but further research is needed to clarify for which conditions they provide maximum benefit.

Nutraceuticals and their potential use in TBI

Zinc is considered essential for optimal CNS functioning. Patients with TBI might be at risk for zinc deficiency, which has been associated with increased cell death and behavioral deficits.^12,13 A randomized, prospective, double-blinded controlled trial examined the effects of supplemental zinc administration (12 mg for 15 days) compared with standard zinc therapy (2.5 mg for 15 days) over 1 month in 68 adults with acute severe closed head injury.¹⁴ The supplemental zinc group showed improved visceral protein levels, lower mortality, and more favorable neurologic recovery based on higher adjusted mean Glasgow Coma Scale score on day 28 and mean motor score on days 15 and 21.

Rodent studies have shown that zinc supplementation could reduce deficits in spatial learning and memory and depression-like behaviors and help decrease stress and anxiety,¹² although no human clinical trials have been conducted. Despite the potential neuroprotective effects of zinc supplementation, evidence exists that endogenous zinc release and accumulation following TBI can trigger cellular changes that result in neuronal death.¹³

Vitamins C and E. Oxidative damage is believed to play a significant role in secondary injury in TBI, so research has focused on the role of antioxidants, such as vitamins C and E, to promote post-TBI recovery.¹⁵ One RCT¹⁶ of 100 adults with acute severe head injury reported that vitamin E administration was associated with reduced mortality and lower Glasgow Outcome Scale (GOS) scores, and vitamin C was associated with stabilized or reduced perilesional edema/infarct on CT scan.

Vitamin D. An animal study reported that vitamin D supplementation can help reduce inflammation, oxidative stress, and cell death in TBI, and that vitamin D deficiency has been associated with increased inflammation and behavioral deficits.¹⁷ Further evidence suggests that vitamin D may have a synergistic effect when used in combination with the hormone progesterone. A RCT of 60 patients with severe TBI reported that 60% of those who received progesterone plus vitamin D had GOS scores of 4 (good recovery) or 5 (moderate disability) vs 45% receiving progesterone alone or 25% receiving placebo.¹⁸

Magnesium, one of the most widely used nutraceuticals, is considered essential for CNS functioning, including the regulation of N-methyl-d-aspartate receptors and calcium influx. After a TBI, magnesium deficiency can result in increased oxidative stress and cell death and has been associated with greater neurologic impairment. Animal studies have provided some evidence of the potential neuroprotective effects of magnesium, but human trials have found mixed evidence. One small human study reported a correlation between magnesium balance and oxidative stress in TBI patients.¹⁹

A RCT evaluated the safety and efficacy of magnesium supplementation in 60 patients with severe closed TBI, with one-half randomized to standard care and the other also receiving magnesium sulfate (MgSO₄; initiation dose of 4 g IV and 10 g IM, continuation dose of 5 g IM every 4 hours for 24 hours).²⁰ After 3 months, more patients in the MgSO₄ group had higher GOS scores than controls (73.3% vs 40%), lower 1-month mortality rates (13.3% vs 43.3%), and lower rates of intraoperative brain swelling (29.4% vs 73.3%).

However, a larger RCT of 499 patients with moderate or severe TBI randomized to high-dose (1.25 to 2.5 mmol/L) or low-dose (1.0 to 1.85 mmol/L) IV MgSO₄ or placebo provided conflicting results.²¹ Participants received MgSO₄ 8 hours after injury and continued for 5 days. After 6 months, patients in the high-dose MgSO₄ and placebo groups had similar composite primary outcome measures (eg, seizures, neuropsychological measures, functional status measures), although the high-dose group had a higher mortality rate than the placebo group. Patients who received low-dose MgSO₄ showed worse outcomes than those assigned to placebo.

Amino acids. Branched-chain amino acids (BCAAs), including valine, isoleucine, and leucine, are essential in protein and neuro­transmitter synthesis. Reduced levels of endogenous BCAAs have been reported in patients with mild or severe TBI.²² Preclinical studies suggest that BCAAs can improve hippocampal-dependent cognitive functioning following TBI.²³

Two RCTs of BCAAs have been conducted in humans. One study randomized 40 men with severe TBI to IV BCAAs or placebo.²⁴ After 15 days, the BCAA group showed greater improvement in Disability Rating Scale scores. The study also found that supplementation increased total BCAA levels without negatively affecting plasma levels of neurotransmitter precursors tyrosine and tryptophan. A second study found that 41 patients in a vegetative or minimally conscious state who received BCAA supplementation for 15 days had higher Disability Rating Scale scores than those receiving placebo.²⁵

Probiotics and glutamine. Probiotics are non-pathogenic microorganisms that have been shown to modulate the host’s immune system.²⁶ TBI is associated with immunological changes, including a shift from T-helper type 1 (TH1) cells to T-helper type 2 (TH2) cells that increase susceptibility to infection.²⁷

A RCT of 52 patients with severe TBI suggested a correlation between probiotic administration-modulated cytokine levels and TH1/TH2 balance.²⁸ A 3-times daily probiotic mix of Bifidobacterium longum, Lactobacillus bulgaricus, and Streptococcus thermophilus for 21 days led to shorter average ICU stays (6.8 vs 10.7 days, P = .034) and a decrease in nosocomial infections (34.6% vs 57.7%, P = .095) vs placebo, although the latter difference was not statistically significant.²⁸

A prospective RCT of 20 patients with brain injury²⁹ found a similar impact of early enteral nutrition supplemented with Lactobacillus johnsonii and glutamine, 30 g, vs a standard enteral nutrition formula. The treatment group experienced fewer nosocomial infections (50% vs 100%, P = .03), shorter ICU stays (10 vs 22 days, P < .01), and fewer days on mechanical ventilation (7 vs 14, P = .04). Despite these studies, evidence for the use of glutamine in patients with TBI is scarce and inconclusive.

N-acetylcysteine (NAC) comes from the amino acid L-cysteine. NAC is an effective scavenger of free radicals and improves cerebral microcirculatory blood flow and tissue oxygenation.³⁰ A randomized, double-blind, placebo-controlled study of oral NAC supplementation in 81 active duty service members with mild TBI found NAC had a significant effect on outcomes.³¹ Oral NAC supplementation led to improved neuropsychological test results, number of mild TBI symptoms, complete symptom resolution by day 7 of treatment compared with placebo, and NAC was well tolerated. Lack of replication studies and generalizability of findings to civilian, moderate, or chronic TBI populations are key limitations of this study.

Proposed mechanisms for the neuro­protective benefit of NAC include its antioxidant and inflammatory activation of cysteine/glutamate exchange, metabotropic glutamate receptor modulation, and glutathione synthesis.³² NAC has poor blood–brain permeability, but the vascular disruption seen in acute TBI might facilitate its delivery to affected neural sites.³¹ As such, the benefits of NAC in subacute or chronic TBI are questionable.

Neuropsychiatric outcomes of nutraceuticals

Enzogenol. This flavonoid-rich extract from the bark of the Monterey pine tree (Pinus radiata), known by the trade name Enzogenol, reportedly has antioxidant and anti-inflammatory properties that may counter oxidative damage and neuro­inflammation following TBI. A phase II trial randomized participants to Enzogenol, 1,000 mg/d, or placebo for 6 weeks, then all participants received Enzogenol for 6 weeks followed by placebo for 4 weeks.³³ Enzogenol was well tolerated with few side effects.

Compared with placebo, participants receiving Enzogenol showed no significant change in mood, as measured by the Hospital Anxiety and Depression Scale, and greater improvement in overall cognition as assessed by the Cognitive Failures Questionnaire. However, measures of working memory (digit span, arithmetic, and letter–number sequencing subtests of the Wechsler Adult Intelligence Scale) and episodic memory (California Verbal Learning Test) showed no benefit from Enzogenol.

Citicoline (CDP-choline) is an endogenous compound widely available as a nutraceutical that has been approved for TBI therapy in 59 countries.³⁴ Animal studies indicate that it could possess neuroprotective properties. Proposed mechanisms for such effects have included stabilizing cell membranes, reducing inflammation, reducing the presence of free radicals, or stimulating production of acetylcholine.^35,36 A study in rats found that CDP-choline was associated with increased levels of acetylcholine in the hippocampus and neocortex, which may help reduce neuro­behavioral deficits.³⁷

A study of 14 adults with mild to moderate closed head injury³⁸ found that patients who received CDP-choline showed a greater reduction in post-concussion symptoms and improvement in recognition memory than controls who received placebo. However, the Citicoline Brain Injury Treatment Trial, a large randomized trial of 1,213 adults with complicated mild, moderate, or severe TBI, reported that CDP-choline did not improve functional and cognitive status.³⁹

Physostigmine and lecithin. The cholinergic system is a key modulatory neurotransmitter system of the brain that mediates conscious awareness, attention, learning, and working memory.⁴⁰ A double-blind, placebo-controlled study of 16 patients with moderate to severe closed head injury provided inconsistent evidence for the efficacy of physostigmine and lecithin in the treatment of memory and attention disturbances.⁴¹The results showed no differences between the physostigmine–lecithin combination vs lecithin alone, although sustained attention on the Continuous Performance Test was more efficient with physostigmine than placebo when the drug condition occurred first in the crossover design. The lack of encouraging data and concerns about its cardiovascular and proconvulsant properties in patients with TBI may explain the dearth of studies with physostigmine.

Cerebrolysin. A peptide preparation produced from purified pig brain proteins, known by the trade name Cerebrolysin, is popular in Asia and Europe for its nootropic properties. Cerebrolysin may activate cerebral mechanisms related to attention and memory processes,⁴² and some data have shown efficacy in improving cognitive symptoms and daily activities in patients with Alzheimer’s disease⁴³ and TBI.⁴⁴

A blinded 12-week study of 32 participants with acute mild TBI reported that those randomized to Cerebrolysin showed improvement in cognitive functioning vs the placebo group.⁴⁵ The authors concluded that Cerebrolysin provides an advantage for patients with mild TBI and brain contusion if treatment starts within 24 hours of mild TBI onset. Cerebrolysin was well tolerated. Major limitations of this study were small sample size, lack of information regarding comorbid neuropsychiatric conditions and treatments, and short treatment duration.

A recent Cochrane review of 6 RCTs with 1,501 participants found no clinical benefit of Cerebrolysin for treating acute ischemic stroke, and found moderate-quality evidence of an increase with non-fatal serious adverse events but not in total serious adverse events.⁴⁶ We do not recommend Cerebrolysin use in patients with TBI at this time until additional efficacy and safety data are available.

Nutraceuticals used in other populations

Other nutraceuticals with preclinical evidence of possible benefit in TBI but lacking evidence from human clinical trials include omega-3 fatty acids,⁴⁷ curcumin,⁴⁸ and resveratrol,⁴⁹ providing further proof that results from experimental studies do not necessarily extend to clinical trials.⁵⁰

Studies of nutraceuticals in other neuro­logical and psychiatric populations have yielded some promising results. Significant interest has focused on the association between vitamin D deficiency, dementia, and neurodegenerative conditions such as Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease.⁵¹ The role of vitamin D in regulation of calcium-mediated neuronal excitotoxicity and oxidative stress and in the induction of synaptic structural proteins, neurotrophic factors, and deficient neuro­transmitters makes it an attractive candidate as a neuroprotective agent.⁵²

RCTs of nutraceuticals also have reported positive findings for a variety of mood and anxiety disorders, such as St. John’s wort, S-adenosylmethionine, omega-3 fatty acids for major depression⁵³ and bipolar depression,⁵⁴ and kava for generalized anxiety disorder.⁵⁵ More research, however, is needed in these areas.

The use of nonpharmacologic agents in TBI often relies on similar neuropsychiatric symptom profiles of idiopathic psychiatric disorders. Attention-deficit/hyperactivity disorder (ADHD) closely resembles TBI, but systemic reviews of studies of zinc, magnesium, and polyunsaturated fatty acids supplementation in ADHD provide no evidence of therapeutic benefit.^56-58

Educate patients in role of nutraceuticals

Despite lack of FDA oversight and limited empirical support, nutraceuticals continue to be widely marketed and used for their putative health benefits⁵⁹ and have gained increased attention among clinicians.⁶⁰ Because nutritional deficiency may make the brain less able than other organs to recover from injury,⁶¹ supplementation is an option, especially in individuals who could be at greater risk of TBI (eg, athletes and military personnel).

Lacking robust scientific evidence to support the use of nutraceuticals either for enhancing TBI recovery or treating neuropsychiatric disturbances, clinicians must educate patients that these agents are not completely benign and can have significant side effects and drug interactions.^62,63 Nutraceuticals may contain multiple ingredients, some of which can be toxic, particularly at higher doses. Many patients may not volunteer information about their nutraceutical use to their health care providers,⁶⁴ so we must ask them about that and inform them of the potential for adverse events and drug interactions.

GLU is now recognized as the most abundant neurotransmitter in the brain, and its excitatory properties are vital for brain structure and function. Importantly, it also is the precursor of γ-aminobutyric acid, the ubiquitous inhibitory neurotransmitter in the brain. GLU is one of the first molecules produced during fetal life and plays a critical role in brain development and in organ development because it is a building block for protein synthesis and for manufacturing muscle and other body tissue. Therefore, aberrations in GLU activity can have a major impact on neurodevelopment—the underpinning of most psychiatric disorders due to genetic and environmental factors—and the general health of the brain and body.

GLU is derived from glutamic acid, which is not considered an essential amino acid because it is synthesized in the body via the citric acid cycle. It is readily available from many food items, including cheese, soy, and tomatoes. Monosodium GLU² is used as a food additive to enhance flavor (Chinese food, anyone?). Incidentally, GLU represents >50% of all amino acids in breast milk, which underscores its importance for a baby’s brain and body development.

GLU’s many brain receptors

Amazingly, although it has been long known that GLU is present in all body tissues, the role of GLU in the CNS and brain was not recognized until the 1980s. This was several decades after the discovery of other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, which are less widely distributed in the CNS. Over the past 30 years, advances in psychiatric research have elucidated the numerous effects of GLU and its receptors on neuropsychiatric disorders. Multiple receptors of GLU have been discovered, including 16 ion channel receptors (7 for N-methyl-D-aspartate [NMDA], 5 for kainate, and 4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), as well as 8 metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The NMDA receptor ion channel allows both sodium and calcium when opened (not just sodium as with AMPA and kainate). This is important because calcium is associated with cognition and neuroplasticity, both of which are impaired in schizophrenia and other major psychiatric disorders, implicating NMDA receptor dysfunction in those disorders.

GLU and neurodegeneration

An excess of GLU activity can be neuro­toxic and can lead to brain damage.³ Therefore, it is not surprising that excess GLU activity has been found in many neurodegenerative disorders (Table). Similar to other neurologic disorders that are considered neurodegenerative, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease, major psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, also are neurodegenerative if left untreated or if multiple relapses recur because of treatment discontinuation (Table). Several neuroimaging studies have documented brain tissue loss in psychotic and mood disorders after repeated episodes. Therefore, targeting GLU in psychotic and mood disorders is legitimately a “hot” research area in psychiatry.

GLU models of psychiatric neurobiology

Advances in biological psychiatry have moved GLU to the forefront of the neuro­biology and pathophysiology of the most serious psychiatric disorders. Overactivity or underactivity of the GLU NMDA receptor has emerged as scientifically plausible mechanisms underlying psychotic and mood disorders. The GLU hypothesis of schizophrenia⁴ grew out of the observation that phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger than ketamine), can trigger in healthy individuals a severe psychosis indistinguishable from schizophrenia, with positive and negative symptoms, cognitive impairment, thought disorder, catatonia, and agitation. Similarly, the recently discovered paraneoplastic encephalitis caused by an ovarian teratoma that secretes antibodies to the NMDA receptor produces acute psychosis, seizures, delirium, dyskinesia, headache, bizarre behavior, confusion, paranoia, auditory and visual hallucinations, and cognitive deficits.⁵ This demonstrates how the GLU NMDA receptor and its 7 subunits are intimately associated with various psychotic symptoms when genetic or non-genetic factors (antagonists or antibodies) drastically reduce its activity.

On the other hand, there is an impressive body of evidence that, unlike the hypofunction of NMDA receptors in schizophrenia, there appears to be increased activity of NMDA receptors in both unipolar and bipolar depression.⁶ Several NMDA antagonists have been shown in controlled clinical trials to be highly effective in rapidly reversing severe, chronic depression that did not respond to standard antidepressants.⁷ A number of NMDA antagonists have been reported to rapidly reverse—within a few hours—severe and chronic depression when administered intravenously (ketamine, rapastinel, scopolamine), intranasally (S-ketamine), or via inhalation (nitrous oxide). NMDA antagonists also show promise in other serious psychiatric disorders such as obsessive-compulsive disorder.⁸ Riluzole and memantine reduce GLU activity and both are FDA-approved for treating neurodegenerative disorders, such as ALS and AD, respectively.^9,10 Therefore, antagonism of GLU is considered neuro­protective and can be therapeutically beneficial in managing neurodegenerative brain disorders.

GLU and the future of psychopharmacology

Based on the wealth of data generated over the past 2 decades regarding the central role of GLU receptors (NMDA, AMPA, kainate, and others) in brain health and disease, modulating GLU pathways is rapidly emerging as a key target for drug development for neuropsychiatric disorders. This approach could help with some medical comorbidities, such as diabetes¹¹ and pain,¹² that co-occur frequently with schizophrenia and depression. GLU has been implicated in diabetes via toxicity that destroys pancreatic beta cells.¹¹ It is possible that novel drug development in the future could exploit GLU signaling and pathways to concurrently repair disorders of the brain and body, such as schizophrenia with comorbid diabetes or depression with comorbid pain. It is worth noting that glucose dysregulation has been shown to exist at the onset of schizophrenia before treatment is started.¹³ This might be related to GLU toxicity occurring simultaneously in the body and the brain. Also worth noting is that ketamine, an NMDA antagonist which has emerged as an ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may help mitigate the pain symptoms that often accompany major depression.

It is logical to conclude that GLU pathways show exciting prospects for therapeutic advances for the brain, body, and mind. This merits intensive scientific effort for novel drug development in neuropsychiatric disorder that may parsimoniously rectify co-occurring GLU-related diseases of the brain, body, and mind.

GLU is now recognized as the most abundant neurotransmitter in the brain, and its excitatory properties are vital for brain structure and function. Importantly, it also is the precursor of γ-aminobutyric acid, the ubiquitous inhibitory neurotransmitter in the brain. GLU is one of the first molecules produced during fetal life and plays a critical role in brain development and in organ development because it is a building block for protein synthesis and for manufacturing muscle and other body tissue. Therefore, aberrations in GLU activity can have a major impact on neurodevelopment—the underpinning of most psychiatric disorders due to genetic and environmental factors—and the general health of the brain and body.

GLU is derived from glutamic acid, which is not considered an essential amino acid because it is synthesized in the body via the citric acid cycle. It is readily available from many food items, including cheese, soy, and tomatoes. Monosodium GLU² is used as a food additive to enhance flavor (Chinese food, anyone?). Incidentally, GLU represents >50% of all amino acids in breast milk, which underscores its importance for a baby’s brain and body development.

GLU’s many brain receptors

Amazingly, although it has been long known that GLU is present in all body tissues, the role of GLU in the CNS and brain was not recognized until the 1980s. This was several decades after the discovery of other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, which are less widely distributed in the CNS. Over the past 30 years, advances in psychiatric research have elucidated the numerous effects of GLU and its receptors on neuropsychiatric disorders. Multiple receptors of GLU have been discovered, including 16 ion channel receptors (7 for N-methyl-D-aspartate [NMDA], 5 for kainate, and 4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), as well as 8 metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The NMDA receptor ion channel allows both sodium and calcium when opened (not just sodium as with AMPA and kainate). This is important because calcium is associated with cognition and neuroplasticity, both of which are impaired in schizophrenia and other major psychiatric disorders, implicating NMDA receptor dysfunction in those disorders.

GLU and neurodegeneration

An excess of GLU activity can be neuro­toxic and can lead to brain damage.³ Therefore, it is not surprising that excess GLU activity has been found in many neurodegenerative disorders (Table). Similar to other neurologic disorders that are considered neurodegenerative, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease, major psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, also are neurodegenerative if left untreated or if multiple relapses recur because of treatment discontinuation (Table). Several neuroimaging studies have documented brain tissue loss in psychotic and mood disorders after repeated episodes. Therefore, targeting GLU in psychotic and mood disorders is legitimately a “hot” research area in psychiatry.

GLU models of psychiatric neurobiology

Advances in biological psychiatry have moved GLU to the forefront of the neuro­biology and pathophysiology of the most serious psychiatric disorders. Overactivity or underactivity of the GLU NMDA receptor has emerged as scientifically plausible mechanisms underlying psychotic and mood disorders. The GLU hypothesis of schizophrenia⁴ grew out of the observation that phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger than ketamine), can trigger in healthy individuals a severe psychosis indistinguishable from schizophrenia, with positive and negative symptoms, cognitive impairment, thought disorder, catatonia, and agitation. Similarly, the recently discovered paraneoplastic encephalitis caused by an ovarian teratoma that secretes antibodies to the NMDA receptor produces acute psychosis, seizures, delirium, dyskinesia, headache, bizarre behavior, confusion, paranoia, auditory and visual hallucinations, and cognitive deficits.⁵ This demonstrates how the GLU NMDA receptor and its 7 subunits are intimately associated with various psychotic symptoms when genetic or non-genetic factors (antagonists or antibodies) drastically reduce its activity.

On the other hand, there is an impressive body of evidence that, unlike the hypofunction of NMDA receptors in schizophrenia, there appears to be increased activity of NMDA receptors in both unipolar and bipolar depression.⁶ Several NMDA antagonists have been shown in controlled clinical trials to be highly effective in rapidly reversing severe, chronic depression that did not respond to standard antidepressants.⁷ A number of NMDA antagonists have been reported to rapidly reverse—within a few hours—severe and chronic depression when administered intravenously (ketamine, rapastinel, scopolamine), intranasally (S-ketamine), or via inhalation (nitrous oxide). NMDA antagonists also show promise in other serious psychiatric disorders such as obsessive-compulsive disorder.⁸ Riluzole and memantine reduce GLU activity and both are FDA-approved for treating neurodegenerative disorders, such as ALS and AD, respectively.^9,10 Therefore, antagonism of GLU is considered neuro­protective and can be therapeutically beneficial in managing neurodegenerative brain disorders.

GLU and the future of psychopharmacology

Based on the wealth of data generated over the past 2 decades regarding the central role of GLU receptors (NMDA, AMPA, kainate, and others) in brain health and disease, modulating GLU pathways is rapidly emerging as a key target for drug development for neuropsychiatric disorders. This approach could help with some medical comorbidities, such as diabetes¹¹ and pain,¹² that co-occur frequently with schizophrenia and depression. GLU has been implicated in diabetes via toxicity that destroys pancreatic beta cells.¹¹ It is possible that novel drug development in the future could exploit GLU signaling and pathways to concurrently repair disorders of the brain and body, such as schizophrenia with comorbid diabetes or depression with comorbid pain. It is worth noting that glucose dysregulation has been shown to exist at the onset of schizophrenia before treatment is started.¹³ This might be related to GLU toxicity occurring simultaneously in the body and the brain. Also worth noting is that ketamine, an NMDA antagonist which has emerged as an ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may help mitigate the pain symptoms that often accompany major depression.

It is logical to conclude that GLU pathways show exciting prospects for therapeutic advances for the brain, body, and mind. This merits intensive scientific effort for novel drug development in neuropsychiatric disorder that may parsimoniously rectify co-occurring GLU-related diseases of the brain, body, and mind.

GLU is now recognized as the most abundant neurotransmitter in the brain, and its excitatory properties are vital for brain structure and function. Importantly, it also is the precursor of γ-aminobutyric acid, the ubiquitous inhibitory neurotransmitter in the brain. GLU is one of the first molecules produced during fetal life and plays a critical role in brain development and in organ development because it is a building block for protein synthesis and for manufacturing muscle and other body tissue. Therefore, aberrations in GLU activity can have a major impact on neurodevelopment—the underpinning of most psychiatric disorders due to genetic and environmental factors—and the general health of the brain and body.

GLU is derived from glutamic acid, which is not considered an essential amino acid because it is synthesized in the body via the citric acid cycle. It is readily available from many food items, including cheese, soy, and tomatoes. Monosodium GLU² is used as a food additive to enhance flavor (Chinese food, anyone?). Incidentally, GLU represents >50% of all amino acids in breast milk, which underscores its importance for a baby’s brain and body development.

GLU’s many brain receptors

Amazingly, although it has been long known that GLU is present in all body tissues, the role of GLU in the CNS and brain was not recognized until the 1980s. This was several decades after the discovery of other neurotransmitters, such as acetylcholine, norepinephrine, and serotonin, which are less widely distributed in the CNS. Over the past 30 years, advances in psychiatric research have elucidated the numerous effects of GLU and its receptors on neuropsychiatric disorders. Multiple receptors of GLU have been discovered, including 16 ion channel receptors (7 for N-methyl-D-aspartate [NMDA], 5 for kainate, and 4 for α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA]), as well as 8 metabotropic G protein-coupled receptors divided into groups 1, 2, and 3. The NMDA receptor ion channel allows both sodium and calcium when opened (not just sodium as with AMPA and kainate). This is important because calcium is associated with cognition and neuroplasticity, both of which are impaired in schizophrenia and other major psychiatric disorders, implicating NMDA receptor dysfunction in those disorders.

GLU and neurodegeneration

An excess of GLU activity can be neuro­toxic and can lead to brain damage.³ Therefore, it is not surprising that excess GLU activity has been found in many neurodegenerative disorders (Table). Similar to other neurologic disorders that are considered neurodegenerative, such as amyotrophic lateral sclerosis (ALS), multiple sclerosis, Alzheimer’s disease (AD), Huntington’s disease, and Parkinson’s disease, major psychiatric disorders, such as schizophrenia, depression, and bipolar disorder, also are neurodegenerative if left untreated or if multiple relapses recur because of treatment discontinuation (Table). Several neuroimaging studies have documented brain tissue loss in psychotic and mood disorders after repeated episodes. Therefore, targeting GLU in psychotic and mood disorders is legitimately a “hot” research area in psychiatry.

GLU models of psychiatric neurobiology

Advances in biological psychiatry have moved GLU to the forefront of the neuro­biology and pathophysiology of the most serious psychiatric disorders. Overactivity or underactivity of the GLU NMDA receptor has emerged as scientifically plausible mechanisms underlying psychotic and mood disorders. The GLU hypothesis of schizophrenia⁴ grew out of the observation that phencyclidine, a drug of abuse that is a potent NMDA antagonist (50-fold stronger than ketamine), can trigger in healthy individuals a severe psychosis indistinguishable from schizophrenia, with positive and negative symptoms, cognitive impairment, thought disorder, catatonia, and agitation. Similarly, the recently discovered paraneoplastic encephalitis caused by an ovarian teratoma that secretes antibodies to the NMDA receptor produces acute psychosis, seizures, delirium, dyskinesia, headache, bizarre behavior, confusion, paranoia, auditory and visual hallucinations, and cognitive deficits.⁵ This demonstrates how the GLU NMDA receptor and its 7 subunits are intimately associated with various psychotic symptoms when genetic or non-genetic factors (antagonists or antibodies) drastically reduce its activity.

On the other hand, there is an impressive body of evidence that, unlike the hypofunction of NMDA receptors in schizophrenia, there appears to be increased activity of NMDA receptors in both unipolar and bipolar depression.⁶ Several NMDA antagonists have been shown in controlled clinical trials to be highly effective in rapidly reversing severe, chronic depression that did not respond to standard antidepressants.⁷ A number of NMDA antagonists have been reported to rapidly reverse—within a few hours—severe and chronic depression when administered intravenously (ketamine, rapastinel, scopolamine), intranasally (S-ketamine), or via inhalation (nitrous oxide). NMDA antagonists also show promise in other serious psychiatric disorders such as obsessive-compulsive disorder.⁸ Riluzole and memantine reduce GLU activity and both are FDA-approved for treating neurodegenerative disorders, such as ALS and AD, respectively.^9,10 Therefore, antagonism of GLU is considered neuro­protective and can be therapeutically beneficial in managing neurodegenerative brain disorders.

GLU and the future of psychopharmacology

Based on the wealth of data generated over the past 2 decades regarding the central role of GLU receptors (NMDA, AMPA, kainate, and others) in brain health and disease, modulating GLU pathways is rapidly emerging as a key target for drug development for neuropsychiatric disorders. This approach could help with some medical comorbidities, such as diabetes¹¹ and pain,¹² that co-occur frequently with schizophrenia and depression. GLU has been implicated in diabetes via toxicity that destroys pancreatic beta cells.¹¹ It is possible that novel drug development in the future could exploit GLU signaling and pathways to concurrently repair disorders of the brain and body, such as schizophrenia with comorbid diabetes or depression with comorbid pain. It is worth noting that glucose dysregulation has been shown to exist at the onset of schizophrenia before treatment is started.¹³ This might be related to GLU toxicity occurring simultaneously in the body and the brain. Also worth noting is that ketamine, an NMDA antagonist which has emerged as an ultra-rapid acting antidepressant, is an anesthetic, suggesting that perhaps it may help mitigate the pain symptoms that often accompany major depression.

It is logical to conclude that GLU pathways show exciting prospects for therapeutic advances for the brain, body, and mind. This merits intensive scientific effort for novel drug development in neuropsychiatric disorder that may parsimoniously rectify co-occurring GLU-related diseases of the brain, body, and mind.

CASE Suicidal and paranoid

Ms. B, age 53, has a 30-year history of bipolar disorder, a 1-year history of hepatitis C virus (HCV), and previous inpatient psychiatric hospitalizations secondary to acute mania. She presents to our hospital describing her symptoms as the “worst depression ever” and reports suicidal ideation and paranoid thoughts of people watching and following her. Ms. B describes significant neurovegetative symptoms of depression, including poor sleep, poor appetite, low energy and concentration, and chronic feelings of hopelessness with thoughts of “ending it all.” Ms. B reports that her symptoms started 3 weeks ago, a few days after she started taking sofosbuvir and ribavirin for refractory HCV.

Ms. B’s medication regimen consisted of quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, for bipolar disorder, when she started taking sofosbuvir and ribavirin. Ms. B admits she stopped taking her psychotropic and antiviral medications after she noticed progressively worsening depression with intrusive suicidal thoughts, including ruminative thoughts of overdosing on them.

At evaluation, Ms. B is casually dressed, pleasant, with fair hygiene and poor eye contact. Her speech is decreased in rate, volume, and tone; mood is “devastated and depressed”; affect is labile and tearful. Her thought process reveals occasional thought blocking and her thought content includes suicidal ideations and paranoid thoughts. Her cognition is intact; insight and judgment are poor. During evaluation, Ms. B reveals a history of alcohol and marijuana use, but reports that she has not used either for the past 15 years. She further states that she had agreed to a trial of medication first for her liver disease and had deferred any discussion of liver transplant at the time of her diagnosis with HCV.

Laboratory tests reveal a normal complete blood count, creatinine, and electrolytes. However, liver functions were elevated, including aspartate aminotransferase (AST) of 107 U/L (reference range, 8 to 48 U/L) and alanine aminotransferase of 117 U/L (reference range, 7 to 55 U/L). Although increased, the levels of AST and ALT were slightly less than her levels pre-sofosbuvir–ribavirin trial, indicating some response to the medication.

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The authors’ observations

Approximately 170 million people worldwide suffer from chronic HCV infection, affecting 2.7 to 5.2 million people in the United States, with 350,000 deaths attributed to liver disease caused by HCV.¹

The standard treatment of HCV genotype 1, which represents 70% of all cases of chronic HCV in the United States, is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peg-interferon (IFN)–alpha-2a plus ribavirin, with the duration of therapy guided by the on-treatment response and the stage of hepatic fibrosis.¹

In 2013, the FDA approved sofosbuvir, a direct-acting antiviral drug for chronic HCV. It is a nucleotide analogue HCV NS5B polymerase inhibitor with similar in vitro activity against all HCV genotypes.¹ This medication is efficient when used with an antiviral regimen in adults with HCV with liver disease, cirrhosis, HIV coinfection, and hepatocellular carcinoma awaiting liver transplant.²

TREATMENT Medication restarted

Ms. B is admitted to the psychiatric unit for management of severe depression and suicidal thoughts, and quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, are restarted. The hepatology team is consulted for further evaluation and management of her liver disease.

She receives supportive psychotherapy, art therapy, and group therapy to develop better coping skills for her depression and suicidal thoughts and psychoeducation about her medical and psychiatric illness to understand the importance of treatment adherence for symptom improvement. Over the course of her hospital stay, Ms. B has subjective and objective improvements of her depressive symptoms.

The authors’ observations

Psychiatric adverse effects associated with IFN-α therapy in chronic HCV patients are the main cause of antiviral treatment discontinuation, resulting in a decreased rate of sustained viral response.³ Chronic HCV is a major health burden; therefore there is a need for treatment options that are more efficient, safer, simpler, more convenient, and preferably IFN-free.

Sofosbuvir has met many of these criteria and has been found to be safe and well tolerated when administered alone or with ribavirin. Sofosbuvir represents a major breakthrough in HCV care to achieve cures and prevent IFN-associated morbidity and mortality.^4,5

[polldaddy:9777328]

OUTCOME Refuses treatment

Ms. B is seen by the hepatology team who discuss the best treatment options for HCV, including ledipasvir/sofosbuvir, daclatasvir and ribavirin, and ombitasvir/paritaprevir/ritonavir plus dasabuvir. However, she refuses treatment for HCV stating, “I would rather have no depression with hepatitis C than feel depressed and suicidal while getting treatment for hepatitis C.”

Ms. B is discharged with referral to the outpatient psychiatry clinic and hepatology clinic for monitoring her liver function and restarting sofosbuvir and ribavirin for HCV once her mood symptoms improved.

The authors’ observations

A robust psychiatric evaluation is required before initiating the previously mentioned antiviral therapy to identify high-risk patients to prevent emergence or exacerbation of new psychiatric symptoms, including depression and mania, when treating with IFN-free or IFN-containing regimens. Collaborative care involving a hepatologist and psychiatrist is necessary for comprehensive monitoring of a patient’s psychiatric symptoms and management with medication and psychotherapy. This will limit psychiatric morbidity in patients receiving antiviral treatment with sofosbuvir and ribavirin.

It’s imperative to improve medication adherence for patients by adopting strategies, such as:

• identifying factors leading to noncompliance
• establishing a strong rapport with the patients
• providing psychoeducation about the illness, discussing the benefits and risks of medications and the importance of maintenance treatment
• simplifying medication regimen.⁶

More research on medication management of HCV in patients with comorbid psychiatric illness should be encouraged and focused on initiating and monitoring non-IFN treatment regimens for patients with HCV and preexisting bipolar disorder or other mood disorders.

CASE Suicidal and paranoid

Ms. B, age 53, has a 30-year history of bipolar disorder, a 1-year history of hepatitis C virus (HCV), and previous inpatient psychiatric hospitalizations secondary to acute mania. She presents to our hospital describing her symptoms as the “worst depression ever” and reports suicidal ideation and paranoid thoughts of people watching and following her. Ms. B describes significant neurovegetative symptoms of depression, including poor sleep, poor appetite, low energy and concentration, and chronic feelings of hopelessness with thoughts of “ending it all.” Ms. B reports that her symptoms started 3 weeks ago, a few days after she started taking sofosbuvir and ribavirin for refractory HCV.

Ms. B’s medication regimen consisted of quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, for bipolar disorder, when she started taking sofosbuvir and ribavirin. Ms. B admits she stopped taking her psychotropic and antiviral medications after she noticed progressively worsening depression with intrusive suicidal thoughts, including ruminative thoughts of overdosing on them.

At evaluation, Ms. B is casually dressed, pleasant, with fair hygiene and poor eye contact. Her speech is decreased in rate, volume, and tone; mood is “devastated and depressed”; affect is labile and tearful. Her thought process reveals occasional thought blocking and her thought content includes suicidal ideations and paranoid thoughts. Her cognition is intact; insight and judgment are poor. During evaluation, Ms. B reveals a history of alcohol and marijuana use, but reports that she has not used either for the past 15 years. She further states that she had agreed to a trial of medication first for her liver disease and had deferred any discussion of liver transplant at the time of her diagnosis with HCV.

Laboratory tests reveal a normal complete blood count, creatinine, and electrolytes. However, liver functions were elevated, including aspartate aminotransferase (AST) of 107 U/L (reference range, 8 to 48 U/L) and alanine aminotransferase of 117 U/L (reference range, 7 to 55 U/L). Although increased, the levels of AST and ALT were slightly less than her levels pre-sofosbuvir–ribavirin trial, indicating some response to the medication.

[polldaddy:9777325]

The authors’ observations

Approximately 170 million people worldwide suffer from chronic HCV infection, affecting 2.7 to 5.2 million people in the United States, with 350,000 deaths attributed to liver disease caused by HCV.¹

The standard treatment of HCV genotype 1, which represents 70% of all cases of chronic HCV in the United States, is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peg-interferon (IFN)–alpha-2a plus ribavirin, with the duration of therapy guided by the on-treatment response and the stage of hepatic fibrosis.¹

In 2013, the FDA approved sofosbuvir, a direct-acting antiviral drug for chronic HCV. It is a nucleotide analogue HCV NS5B polymerase inhibitor with similar in vitro activity against all HCV genotypes.¹ This medication is efficient when used with an antiviral regimen in adults with HCV with liver disease, cirrhosis, HIV coinfection, and hepatocellular carcinoma awaiting liver transplant.²

TREATMENT Medication restarted

Ms. B is admitted to the psychiatric unit for management of severe depression and suicidal thoughts, and quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, are restarted. The hepatology team is consulted for further evaluation and management of her liver disease.

She receives supportive psychotherapy, art therapy, and group therapy to develop better coping skills for her depression and suicidal thoughts and psychoeducation about her medical and psychiatric illness to understand the importance of treatment adherence for symptom improvement. Over the course of her hospital stay, Ms. B has subjective and objective improvements of her depressive symptoms.

The authors’ observations

Psychiatric adverse effects associated with IFN-α therapy in chronic HCV patients are the main cause of antiviral treatment discontinuation, resulting in a decreased rate of sustained viral response.³ Chronic HCV is a major health burden; therefore there is a need for treatment options that are more efficient, safer, simpler, more convenient, and preferably IFN-free.

Sofosbuvir has met many of these criteria and has been found to be safe and well tolerated when administered alone or with ribavirin. Sofosbuvir represents a major breakthrough in HCV care to achieve cures and prevent IFN-associated morbidity and mortality.^4,5

[polldaddy:9777328]

OUTCOME Refuses treatment

Ms. B is seen by the hepatology team who discuss the best treatment options for HCV, including ledipasvir/sofosbuvir, daclatasvir and ribavirin, and ombitasvir/paritaprevir/ritonavir plus dasabuvir. However, she refuses treatment for HCV stating, “I would rather have no depression with hepatitis C than feel depressed and suicidal while getting treatment for hepatitis C.”

Ms. B is discharged with referral to the outpatient psychiatry clinic and hepatology clinic for monitoring her liver function and restarting sofosbuvir and ribavirin for HCV once her mood symptoms improved.

The authors’ observations

A robust psychiatric evaluation is required before initiating the previously mentioned antiviral therapy to identify high-risk patients to prevent emergence or exacerbation of new psychiatric symptoms, including depression and mania, when treating with IFN-free or IFN-containing regimens. Collaborative care involving a hepatologist and psychiatrist is necessary for comprehensive monitoring of a patient’s psychiatric symptoms and management with medication and psychotherapy. This will limit psychiatric morbidity in patients receiving antiviral treatment with sofosbuvir and ribavirin.

It’s imperative to improve medication adherence for patients by adopting strategies, such as:

• identifying factors leading to noncompliance
• establishing a strong rapport with the patients
• providing psychoeducation about the illness, discussing the benefits and risks of medications and the importance of maintenance treatment
• simplifying medication regimen.⁶

More research on medication management of HCV in patients with comorbid psychiatric illness should be encouraged and focused on initiating and monitoring non-IFN treatment regimens for patients with HCV and preexisting bipolar disorder or other mood disorders.

CASE Suicidal and paranoid

Ms. B, age 53, has a 30-year history of bipolar disorder, a 1-year history of hepatitis C virus (HCV), and previous inpatient psychiatric hospitalizations secondary to acute mania. She presents to our hospital describing her symptoms as the “worst depression ever” and reports suicidal ideation and paranoid thoughts of people watching and following her. Ms. B describes significant neurovegetative symptoms of depression, including poor sleep, poor appetite, low energy and concentration, and chronic feelings of hopelessness with thoughts of “ending it all.” Ms. B reports that her symptoms started 3 weeks ago, a few days after she started taking sofosbuvir and ribavirin for refractory HCV.

Ms. B’s medication regimen consisted of quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, for bipolar disorder, when she started taking sofosbuvir and ribavirin. Ms. B admits she stopped taking her psychotropic and antiviral medications after she noticed progressively worsening depression with intrusive suicidal thoughts, including ruminative thoughts of overdosing on them.

At evaluation, Ms. B is casually dressed, pleasant, with fair hygiene and poor eye contact. Her speech is decreased in rate, volume, and tone; mood is “devastated and depressed”; affect is labile and tearful. Her thought process reveals occasional thought blocking and her thought content includes suicidal ideations and paranoid thoughts. Her cognition is intact; insight and judgment are poor. During evaluation, Ms. B reveals a history of alcohol and marijuana use, but reports that she has not used either for the past 15 years. She further states that she had agreed to a trial of medication first for her liver disease and had deferred any discussion of liver transplant at the time of her diagnosis with HCV.

Laboratory tests reveal a normal complete blood count, creatinine, and electrolytes. However, liver functions were elevated, including aspartate aminotransferase (AST) of 107 U/L (reference range, 8 to 48 U/L) and alanine aminotransferase of 117 U/L (reference range, 7 to 55 U/L). Although increased, the levels of AST and ALT were slightly less than her levels pre-sofosbuvir–ribavirin trial, indicating some response to the medication.

[polldaddy:9777325]

The authors’ observations

Approximately 170 million people worldwide suffer from chronic HCV infection, affecting 2.7 to 5.2 million people in the United States, with 350,000 deaths attributed to liver disease caused by HCV.¹

The standard treatment of HCV genotype 1, which represents 70% of all cases of chronic HCV in the United States, is 12 to 32 weeks of an oral protease inhibitor combined with 24 to 48 weeks of peg-interferon (IFN)–alpha-2a plus ribavirin, with the duration of therapy guided by the on-treatment response and the stage of hepatic fibrosis.¹

In 2013, the FDA approved sofosbuvir, a direct-acting antiviral drug for chronic HCV. It is a nucleotide analogue HCV NS5B polymerase inhibitor with similar in vitro activity against all HCV genotypes.¹ This medication is efficient when used with an antiviral regimen in adults with HCV with liver disease, cirrhosis, HIV coinfection, and hepatocellular carcinoma awaiting liver transplant.²

TREATMENT Medication restarted

Ms. B is admitted to the psychiatric unit for management of severe depression and suicidal thoughts, and quetiapine, 400 mg at bedtime, fluoxetine, 40 mg/d, and lamotrigine, 150 mg/d, are restarted. The hepatology team is consulted for further evaluation and management of her liver disease.

She receives supportive psychotherapy, art therapy, and group therapy to develop better coping skills for her depression and suicidal thoughts and psychoeducation about her medical and psychiatric illness to understand the importance of treatment adherence for symptom improvement. Over the course of her hospital stay, Ms. B has subjective and objective improvements of her depressive symptoms.

The authors’ observations

Psychiatric adverse effects associated with IFN-α therapy in chronic HCV patients are the main cause of antiviral treatment discontinuation, resulting in a decreased rate of sustained viral response.³ Chronic HCV is a major health burden; therefore there is a need for treatment options that are more efficient, safer, simpler, more convenient, and preferably IFN-free.

Sofosbuvir has met many of these criteria and has been found to be safe and well tolerated when administered alone or with ribavirin. Sofosbuvir represents a major breakthrough in HCV care to achieve cures and prevent IFN-associated morbidity and mortality.^4,5

[polldaddy:9777328]

OUTCOME Refuses treatment

Ms. B is seen by the hepatology team who discuss the best treatment options for HCV, including ledipasvir/sofosbuvir, daclatasvir and ribavirin, and ombitasvir/paritaprevir/ritonavir plus dasabuvir. However, she refuses treatment for HCV stating, “I would rather have no depression with hepatitis C than feel depressed and suicidal while getting treatment for hepatitis C.”

Ms. B is discharged with referral to the outpatient psychiatry clinic and hepatology clinic for monitoring her liver function and restarting sofosbuvir and ribavirin for HCV once her mood symptoms improved.

The authors’ observations

A robust psychiatric evaluation is required before initiating the previously mentioned antiviral therapy to identify high-risk patients to prevent emergence or exacerbation of new psychiatric symptoms, including depression and mania, when treating with IFN-free or IFN-containing regimens. Collaborative care involving a hepatologist and psychiatrist is necessary for comprehensive monitoring of a patient’s psychiatric symptoms and management with medication and psychotherapy. This will limit psychiatric morbidity in patients receiving antiviral treatment with sofosbuvir and ribavirin.

It’s imperative to improve medication adherence for patients by adopting strategies, such as:

• identifying factors leading to noncompliance
• establishing a strong rapport with the patients
• providing psychoeducation about the illness, discussing the benefits and risks of medications and the importance of maintenance treatment
• simplifying medication regimen.⁶

More research on medication management of HCV in patients with comorbid psychiatric illness should be encouraged and focused on initiating and monitoring non-IFN treatment regimens for patients with HCV and preexisting bipolar disorder or other mood disorders.

Eating disorders are thought to affect only the young. Although the mean age of presentation is 17 years for anorexia nervosa and 18 to 25 years for bulimia nervosa, many women >65 years suffer from these disorders.¹ Often, geriatric patients with a history of eating disorders during their youth that partially remitted have the same disorders re-emerge during their golden years. Because many practitioners think of eating disorders as a younger person’s illness, we could miss an opportunity to help these individuals when screening our geriatric patients.

DSM-5² categorizes feeding and eating disorders as:

• binge eating disorder
• anorexia nervosa
• bulimia nervosa
• other specified feeding and eating disorders
• pica
• avoidant/restrictive food intake disorder.

Binge eating disorder’s main feature is recurrent binge eating, which is the sense that one has lost control when consuming a larger amount of food within a discrete time period than what most people might eat in the same time period. Binge eating may include eating rapidly, feeling uncomfortably full, feeling embarrassment from the amount of food consumed, eating alone and/or feeling self-disgust. Because these patients lack compensatory behaviors, such as purging, they could be at risk of obesity.

Anorexia nervosa is defined as the restriction of energy intake relative to necessary energy requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health, as well as an intense fear of gaining weight or persistent behaviors interfering with weight gain.

Bulimia nervosa is repetitive loss of control when eating large amounts of food (more than most would eat in a period), with compensatory behaviors to prevent weight gain. It is possible that the value attached to youthful slenderness leads to dissatisfaction among older women as their bodies change; binging might provide a sense of control during a time of uncertainty.

Body mass index typically is highest at middle age and slowly declines. In part, this decline is caused by a reduction in energy intake because of modifications in eating habits and lowered appetite often seen during aging. Older women eat 30% fewer calories than younger women.^3,4 Social isolation, chronic disease, and depression also contribute to diminished food intake. It is important to remember that distorted body image can occur in older individuals as well. Anorexia nervosa has the highest fatality rate among psychiatric conditions,⁵ and geriatric patients could be at particularly high risk.

Assessment

Assess for eating disorders in a geriatric patient by exploring the patient’s perception of body image and ruling out underlying causes of weight loss and medical comorbidities. Take a detailed history, including:

• body image and disordered thinking about food
• abnormal behaviors or rituals surrounding food
• history of eating disorders, psychiatric illness, or hospitalization
• medical history
• current and past medications
• illicit drug use or addiction to prescription medications.

Collateral informants, such as partners and adult children of the patient, may yield important information. Because geriatric patients often take several medications, contacting the primary care physician is important in the integrated care of the patient.

A thorough physical and mental status examination will provide information about the patient’s physical appearance. For example, if the patient appears emaciated or weak, the content and process of thoughts related to food will help rule out other etiologies, such as psychosis, depressive disorders, or anxiety. Vital signs and a full physical examination are needed when caring for patients with an eating disorder, regardless of age, but particularly in medically fragile geriatric patients. Because osteoporosis and osteopenia are concerns for many older patients, it’s important to collaborate with the primary care physician early to help minimize bone loss.

Treatment

While ensuring medical stability of the patient, psychotherapy is the treatment of choice for eating disorders in geriatric patients. Moderate to severe binge eating disorder can be treated with lisdexamfetamine. For bulimia nervosa, consider a combination of SSRI and psychotherapy. There is no FDA-approved medication for treating anorexia nervosa; therefore identifying and treating underlying medical causes and/or psychiatric comorbidities can help improve prognosis. Despite this, 1 study showed 20% of geriatric patients with an eating disorder die of complications from eating disorders.⁶

Eating disorders are thought to affect only the young. Although the mean age of presentation is 17 years for anorexia nervosa and 18 to 25 years for bulimia nervosa, many women >65 years suffer from these disorders.¹ Often, geriatric patients with a history of eating disorders during their youth that partially remitted have the same disorders re-emerge during their golden years. Because many practitioners think of eating disorders as a younger person’s illness, we could miss an opportunity to help these individuals when screening our geriatric patients.

DSM-5² categorizes feeding and eating disorders as:

• binge eating disorder
• anorexia nervosa
• bulimia nervosa
• other specified feeding and eating disorders
• pica
• avoidant/restrictive food intake disorder.

Binge eating disorder’s main feature is recurrent binge eating, which is the sense that one has lost control when consuming a larger amount of food within a discrete time period than what most people might eat in the same time period. Binge eating may include eating rapidly, feeling uncomfortably full, feeling embarrassment from the amount of food consumed, eating alone and/or feeling self-disgust. Because these patients lack compensatory behaviors, such as purging, they could be at risk of obesity.

Anorexia nervosa is defined as the restriction of energy intake relative to necessary energy requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health, as well as an intense fear of gaining weight or persistent behaviors interfering with weight gain.

Bulimia nervosa is repetitive loss of control when eating large amounts of food (more than most would eat in a period), with compensatory behaviors to prevent weight gain. It is possible that the value attached to youthful slenderness leads to dissatisfaction among older women as their bodies change; binging might provide a sense of control during a time of uncertainty.

Body mass index typically is highest at middle age and slowly declines. In part, this decline is caused by a reduction in energy intake because of modifications in eating habits and lowered appetite often seen during aging. Older women eat 30% fewer calories than younger women.^3,4 Social isolation, chronic disease, and depression also contribute to diminished food intake. It is important to remember that distorted body image can occur in older individuals as well. Anorexia nervosa has the highest fatality rate among psychiatric conditions,⁵ and geriatric patients could be at particularly high risk.

Assessment

Assess for eating disorders in a geriatric patient by exploring the patient’s perception of body image and ruling out underlying causes of weight loss and medical comorbidities. Take a detailed history, including:

• body image and disordered thinking about food
• abnormal behaviors or rituals surrounding food
• history of eating disorders, psychiatric illness, or hospitalization
• medical history
• current and past medications
• illicit drug use or addiction to prescription medications.

Collateral informants, such as partners and adult children of the patient, may yield important information. Because geriatric patients often take several medications, contacting the primary care physician is important in the integrated care of the patient.

A thorough physical and mental status examination will provide information about the patient’s physical appearance. For example, if the patient appears emaciated or weak, the content and process of thoughts related to food will help rule out other etiologies, such as psychosis, depressive disorders, or anxiety. Vital signs and a full physical examination are needed when caring for patients with an eating disorder, regardless of age, but particularly in medically fragile geriatric patients. Because osteoporosis and osteopenia are concerns for many older patients, it’s important to collaborate with the primary care physician early to help minimize bone loss.

Treatment

While ensuring medical stability of the patient, psychotherapy is the treatment of choice for eating disorders in geriatric patients. Moderate to severe binge eating disorder can be treated with lisdexamfetamine. For bulimia nervosa, consider a combination of SSRI and psychotherapy. There is no FDA-approved medication for treating anorexia nervosa; therefore identifying and treating underlying medical causes and/or psychiatric comorbidities can help improve prognosis. Despite this, 1 study showed 20% of geriatric patients with an eating disorder die of complications from eating disorders.⁶

Eating disorders are thought to affect only the young. Although the mean age of presentation is 17 years for anorexia nervosa and 18 to 25 years for bulimia nervosa, many women >65 years suffer from these disorders.¹ Often, geriatric patients with a history of eating disorders during their youth that partially remitted have the same disorders re-emerge during their golden years. Because many practitioners think of eating disorders as a younger person’s illness, we could miss an opportunity to help these individuals when screening our geriatric patients.

DSM-5² categorizes feeding and eating disorders as:

• binge eating disorder
• anorexia nervosa
• bulimia nervosa
• other specified feeding and eating disorders
• pica
• avoidant/restrictive food intake disorder.

Binge eating disorder’s main feature is recurrent binge eating, which is the sense that one has lost control when consuming a larger amount of food within a discrete time period than what most people might eat in the same time period. Binge eating may include eating rapidly, feeling uncomfortably full, feeling embarrassment from the amount of food consumed, eating alone and/or feeling self-disgust. Because these patients lack compensatory behaviors, such as purging, they could be at risk of obesity.

Anorexia nervosa is defined as the restriction of energy intake relative to necessary energy requirements, leading to significantly low body weight in the context of age, sex, developmental trajectory, and physical health, as well as an intense fear of gaining weight or persistent behaviors interfering with weight gain.

Bulimia nervosa is repetitive loss of control when eating large amounts of food (more than most would eat in a period), with compensatory behaviors to prevent weight gain. It is possible that the value attached to youthful slenderness leads to dissatisfaction among older women as their bodies change; binging might provide a sense of control during a time of uncertainty.

Body mass index typically is highest at middle age and slowly declines. In part, this decline is caused by a reduction in energy intake because of modifications in eating habits and lowered appetite often seen during aging. Older women eat 30% fewer calories than younger women.^3,4 Social isolation, chronic disease, and depression also contribute to diminished food intake. It is important to remember that distorted body image can occur in older individuals as well. Anorexia nervosa has the highest fatality rate among psychiatric conditions,⁵ and geriatric patients could be at particularly high risk.

Assessment

Assess for eating disorders in a geriatric patient by exploring the patient’s perception of body image and ruling out underlying causes of weight loss and medical comorbidities. Take a detailed history, including:

• body image and disordered thinking about food
• abnormal behaviors or rituals surrounding food
• history of eating disorders, psychiatric illness, or hospitalization
• medical history
• current and past medications
• illicit drug use or addiction to prescription medications.

Collateral informants, such as partners and adult children of the patient, may yield important information. Because geriatric patients often take several medications, contacting the primary care physician is important in the integrated care of the patient.

A thorough physical and mental status examination will provide information about the patient’s physical appearance. For example, if the patient appears emaciated or weak, the content and process of thoughts related to food will help rule out other etiologies, such as psychosis, depressive disorders, or anxiety. Vital signs and a full physical examination are needed when caring for patients with an eating disorder, regardless of age, but particularly in medically fragile geriatric patients. Because osteoporosis and osteopenia are concerns for many older patients, it’s important to collaborate with the primary care physician early to help minimize bone loss.

Treatment

While ensuring medical stability of the patient, psychotherapy is the treatment of choice for eating disorders in geriatric patients. Moderate to severe binge eating disorder can be treated with lisdexamfetamine. For bulimia nervosa, consider a combination of SSRI and psychotherapy. There is no FDA-approved medication for treating anorexia nervosa; therefore identifying and treating underlying medical causes and/or psychiatric comorbidities can help improve prognosis. Despite this, 1 study showed 20% of geriatric patients with an eating disorder die of complications from eating disorders.⁶

Somatization is the experience of psychological distress in the form of bodily symptoms. Somatic symptom and related disorders frequently prompt psychiatric consultation. Patients with suspected somatization disorders might resist psychiatric intervention, therefore modified approaches to the initial interview are helpful. Here I present an approach to such resistance.

Collecting a detailed history of physical symptoms can help the patient feel that you are listening to him (her) and that the chief concern is important. A detailed review of psychiatric symptoms (eg, hallucinations, paranoia, suicidality, etc.) should be deferred until later in the examination. Asking questions relating to psychiatric symptoms early could lead to further resistance by reinforcing negative preconceptions that the patient might have regarding mental illness.

Explicitly express empathy regarding physical symptoms throughout the interview to acknowledge any real suffering the patient is experiencing and to contradict any notion that psychiatric evaluation implies that the suffering could be imaginary.

Ask, “How has this illness affected your life?” This question helps make the connection between the patient’s physical state and social milieu. If somatization is confirmed, then the provider should assist the patient in reversing the arrow of causation. Although the ultimate goal is for the patient to understand how his (her) life has affected the symptoms, simply understanding that there are connections between the two is a start toward this goal.¹

Explore the response to the previous question. Expand upon it to elicit a detailed social history, listening for any social stressors.

Obtain family and personal histories of allergies, substance abuse, and medical or psychiatric illness.

Review psychiatric symptoms. Make questions less jarring² by adapting them to the patient’s situation, such as “Has your illness become so painful that at times you don’t even want to live?”

Perform cognitive and physical examinations. Conducting a physical examination could further reassure the patient that you are not ignoring physical complaints.

Educate the patient that the mind and body are connected and emotions affect how one feels physically. Use examples, such as “When I feel anxious, my heart beats faster” or “A headache might hurt more at work than at the beach.”

Elicit feedback and questions from the patient.

Discuss your treatment plan with the patient. Resistant patients with confirmed somatization disorders might accept psychiatric care as a means of dealing with the stress or pain of their physical symptoms.

Consider asking:

• What would you be doing if you weren’t in the hospital right now?
• Aside from your health, what’s the biggest challenge in your life?
• Everything has a good side and a bad side. Is there anything positive about dealing with your illness? Providing the patient with an example of negative aspects of a good thing (such as the calories in ice cream, the high cost of gold, etc.) can help make this point.
• What would your life look like if you didn’t have these symptoms?

Somatization is the experience of psychological distress in the form of bodily symptoms. Somatic symptom and related disorders frequently prompt psychiatric consultation. Patients with suspected somatization disorders might resist psychiatric intervention, therefore modified approaches to the initial interview are helpful. Here I present an approach to such resistance.

Collecting a detailed history of physical symptoms can help the patient feel that you are listening to him (her) and that the chief concern is important. A detailed review of psychiatric symptoms (eg, hallucinations, paranoia, suicidality, etc.) should be deferred until later in the examination. Asking questions relating to psychiatric symptoms early could lead to further resistance by reinforcing negative preconceptions that the patient might have regarding mental illness.

Explicitly express empathy regarding physical symptoms throughout the interview to acknowledge any real suffering the patient is experiencing and to contradict any notion that psychiatric evaluation implies that the suffering could be imaginary.

Ask, “How has this illness affected your life?” This question helps make the connection between the patient’s physical state and social milieu. If somatization is confirmed, then the provider should assist the patient in reversing the arrow of causation. Although the ultimate goal is for the patient to understand how his (her) life has affected the symptoms, simply understanding that there are connections between the two is a start toward this goal.¹

Explore the response to the previous question. Expand upon it to elicit a detailed social history, listening for any social stressors.

Obtain family and personal histories of allergies, substance abuse, and medical or psychiatric illness.

Review psychiatric symptoms. Make questions less jarring² by adapting them to the patient’s situation, such as “Has your illness become so painful that at times you don’t even want to live?”

Perform cognitive and physical examinations. Conducting a physical examination could further reassure the patient that you are not ignoring physical complaints.

Educate the patient that the mind and body are connected and emotions affect how one feels physically. Use examples, such as “When I feel anxious, my heart beats faster” or “A headache might hurt more at work than at the beach.”

Elicit feedback and questions from the patient.

Discuss your treatment plan with the patient. Resistant patients with confirmed somatization disorders might accept psychiatric care as a means of dealing with the stress or pain of their physical symptoms.

Consider asking:

• What would you be doing if you weren’t in the hospital right now?
• Aside from your health, what’s the biggest challenge in your life?
• Everything has a good side and a bad side. Is there anything positive about dealing with your illness? Providing the patient with an example of negative aspects of a good thing (such as the calories in ice cream, the high cost of gold, etc.) can help make this point.
• What would your life look like if you didn’t have these symptoms?

Somatization is the experience of psychological distress in the form of bodily symptoms. Somatic symptom and related disorders frequently prompt psychiatric consultation. Patients with suspected somatization disorders might resist psychiatric intervention, therefore modified approaches to the initial interview are helpful. Here I present an approach to such resistance.

Collecting a detailed history of physical symptoms can help the patient feel that you are listening to him (her) and that the chief concern is important. A detailed review of psychiatric symptoms (eg, hallucinations, paranoia, suicidality, etc.) should be deferred until later in the examination. Asking questions relating to psychiatric symptoms early could lead to further resistance by reinforcing negative preconceptions that the patient might have regarding mental illness.

Explicitly express empathy regarding physical symptoms throughout the interview to acknowledge any real suffering the patient is experiencing and to contradict any notion that psychiatric evaluation implies that the suffering could be imaginary.

Ask, “How has this illness affected your life?” This question helps make the connection between the patient’s physical state and social milieu. If somatization is confirmed, then the provider should assist the patient in reversing the arrow of causation. Although the ultimate goal is for the patient to understand how his (her) life has affected the symptoms, simply understanding that there are connections between the two is a start toward this goal.¹

Explore the response to the previous question. Expand upon it to elicit a detailed social history, listening for any social stressors.

Obtain family and personal histories of allergies, substance abuse, and medical or psychiatric illness.

Review psychiatric symptoms. Make questions less jarring² by adapting them to the patient’s situation, such as “Has your illness become so painful that at times you don’t even want to live?”

Perform cognitive and physical examinations. Conducting a physical examination could further reassure the patient that you are not ignoring physical complaints.

Educate the patient that the mind and body are connected and emotions affect how one feels physically. Use examples, such as “When I feel anxious, my heart beats faster” or “A headache might hurt more at work than at the beach.”

Elicit feedback and questions from the patient.

Discuss your treatment plan with the patient. Resistant patients with confirmed somatization disorders might accept psychiatric care as a means of dealing with the stress or pain of their physical symptoms.

Consider asking:

• What would you be doing if you weren’t in the hospital right now?
• Aside from your health, what’s the biggest challenge in your life?
• Everything has a good side and a bad side. Is there anything positive about dealing with your illness? Providing the patient with an example of negative aspects of a good thing (such as the calories in ice cream, the high cost of gold, etc.) can help make this point.
• What would your life look like if you didn’t have these symptoms?

Acupuncture is an ancient therapeutic tool known to be the core of traditional Chinese medicine. Two theories suggest positive outcomes in patients treated with acupuncture:

• The oxidative stress reduction theory states that a “large body of evidences demonstrated that acupuncture has [an] antioxidative effect in various diseases, but the exact mechanism remains unclear.”¹
• The neurophysiological theory states that “acupuncture stimulation can facilitate the release of certain neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms.”²

For decades, acupuncture has been used for addiction management. Here we provide information on its utility for patients with substance use disorders.

Opioid use disorder. Multiple studies have looked at withdrawal, comorbid mood disorders, and its management with acupuncture alone or in combination with psychotherapy and/or opioid agonists. Studies from Asia reported good treatment outcomes but had low-method quality.³ Western studies had superior method quality but found that acupuncture was no better than placebo as monotherapy. When acupuncture is combined with psychotherapy and an opioid agonist, treatment results are promising, showing faster taper of medications (methadone and buprenorphine/naloxone) with fewer adverse effects.

Cocaine use disorder. Most studies had poor treatment outcomes of acupuncture over placebo and were of low quality. A number of small studies were promising and found that patients treated with acupuncture were most likely to have a negative urine drug screen.³ Although acupuncture is widely used in the United States to treat cocaine dependence, evidence does not confirm its efficacy.

Tobacco use disorder. A small group of studies favored acupuncture for smoking cessation.³ Other studies reported no benefit compared with placebo or neutral results. Some studies agreed that any intervention (acupuncture or sham acupuncture) with good results is better than no intervention at all.

Alcohol use disorder. Almost no advantage over placebo was found. Studies with significant findings were in small populations.³

Amphetamine, Cannabis, and other hallucinogen use disorders. Available data on stimulants were too limited to be relevant. No studies were found on Cannabis and hallucinogens.

Further studies are needed

There is a lack of conclusive, good quality studies supporting acupuncture’s benefits in treating substance abuse. Acupuncture has been known to lack adverse effects other than those related to needle manipulation, which is dependent on the methods (depth of needle insertion, accurate anatomical location, angle, etc.). Because this treatment option is virtually side-effect free, inexpensive, with positive synergistic results, more high-method quality studies are needed to consider it for our patients.

Acupuncture is an ancient therapeutic tool known to be the core of traditional Chinese medicine. Two theories suggest positive outcomes in patients treated with acupuncture:

• The oxidative stress reduction theory states that a “large body of evidences demonstrated that acupuncture has [an] antioxidative effect in various diseases, but the exact mechanism remains unclear.”¹
• The neurophysiological theory states that “acupuncture stimulation can facilitate the release of certain neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms.”²

For decades, acupuncture has been used for addiction management. Here we provide information on its utility for patients with substance use disorders.

Opioid use disorder. Multiple studies have looked at withdrawal, comorbid mood disorders, and its management with acupuncture alone or in combination with psychotherapy and/or opioid agonists. Studies from Asia reported good treatment outcomes but had low-method quality.³ Western studies had superior method quality but found that acupuncture was no better than placebo as monotherapy. When acupuncture is combined with psychotherapy and an opioid agonist, treatment results are promising, showing faster taper of medications (methadone and buprenorphine/naloxone) with fewer adverse effects.

Cocaine use disorder. Most studies had poor treatment outcomes of acupuncture over placebo and were of low quality. A number of small studies were promising and found that patients treated with acupuncture were most likely to have a negative urine drug screen.³ Although acupuncture is widely used in the United States to treat cocaine dependence, evidence does not confirm its efficacy.

Tobacco use disorder. A small group of studies favored acupuncture for smoking cessation.³ Other studies reported no benefit compared with placebo or neutral results. Some studies agreed that any intervention (acupuncture or sham acupuncture) with good results is better than no intervention at all.

Alcohol use disorder. Almost no advantage over placebo was found. Studies with significant findings were in small populations.³

Amphetamine, Cannabis, and other hallucinogen use disorders. Available data on stimulants were too limited to be relevant. No studies were found on Cannabis and hallucinogens.

Further studies are needed

There is a lack of conclusive, good quality studies supporting acupuncture’s benefits in treating substance abuse. Acupuncture has been known to lack adverse effects other than those related to needle manipulation, which is dependent on the methods (depth of needle insertion, accurate anatomical location, angle, etc.). Because this treatment option is virtually side-effect free, inexpensive, with positive synergistic results, more high-method quality studies are needed to consider it for our patients.

Acupuncture is an ancient therapeutic tool known to be the core of traditional Chinese medicine. Two theories suggest positive outcomes in patients treated with acupuncture:

• The oxidative stress reduction theory states that a “large body of evidences demonstrated that acupuncture has [an] antioxidative effect in various diseases, but the exact mechanism remains unclear.”¹
• The neurophysiological theory states that “acupuncture stimulation can facilitate the release of certain neuropeptides in the CNS, eliciting profound physiological effects and even activating self-healing mechanisms.”²

For decades, acupuncture has been used for addiction management. Here we provide information on its utility for patients with substance use disorders.

Opioid use disorder. Multiple studies have looked at withdrawal, comorbid mood disorders, and its management with acupuncture alone or in combination with psychotherapy and/or opioid agonists. Studies from Asia reported good treatment outcomes but had low-method quality.³ Western studies had superior method quality but found that acupuncture was no better than placebo as monotherapy. When acupuncture is combined with psychotherapy and an opioid agonist, treatment results are promising, showing faster taper of medications (methadone and buprenorphine/naloxone) with fewer adverse effects.

Cocaine use disorder. Most studies had poor treatment outcomes of acupuncture over placebo and were of low quality. A number of small studies were promising and found that patients treated with acupuncture were most likely to have a negative urine drug screen.³ Although acupuncture is widely used in the United States to treat cocaine dependence, evidence does not confirm its efficacy.

Tobacco use disorder. A small group of studies favored acupuncture for smoking cessation.³ Other studies reported no benefit compared with placebo or neutral results. Some studies agreed that any intervention (acupuncture or sham acupuncture) with good results is better than no intervention at all.

Alcohol use disorder. Almost no advantage over placebo was found. Studies with significant findings were in small populations.³

Amphetamine, Cannabis, and other hallucinogen use disorders. Available data on stimulants were too limited to be relevant. No studies were found on Cannabis and hallucinogens.

Further studies are needed

There is a lack of conclusive, good quality studies supporting acupuncture’s benefits in treating substance abuse. Acupuncture has been known to lack adverse effects other than those related to needle manipulation, which is dependent on the methods (depth of needle insertion, accurate anatomical location, angle, etc.). Because this treatment option is virtually side-effect free, inexpensive, with positive synergistic results, more high-method quality studies are needed to consider it for our patients.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has unveiled a plan to eliminate the agency’s existing backlog of orphan designation requests and ensure timely responses to all new requests with firm deadlines.

The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the US.

Orphan designation qualifies a product’s developer for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for 7 years of marketing exclusivity if the product is approved.

A request for orphan designation is one step that can be taken in the development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past 5 years.

In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012.

The FDA says this increased interest in the program is a positive development for patients with rare diseases, and, with the Orphan Drug Modernization Plan, the FDA is committing to advancing the program to ensure it can efficiently and adequately review these requests.

“People who suffer with rare diseases are too often faced with no or limited treatment options, and what treatment options they have may be quite expensive due, in part, to significant costs of developing therapies for smaller populations,” said FDA Commissioner Scott Gottlieb, MD.

“Congress gave us tools to incentivize the development of novel therapies for rare diseases, and we intend to use these resources to their fullest extent in order to ensure Americans get the safe and effective medicines they need, and that the process for developing these innovations is as modern and efficient as possible.”

Among the elements of the Orphan Drug Modernization Plan, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests.

The agency will also employ a streamlined Designation Review Template to increase consistency and efficiency of its reviews.

In addition, the Orphan Drug Designation Program will look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

To ensure all future requests receive a response within 90 days of receipt, the FDA will take a multifaceted approach.

These efforts include, among other new steps:

• Reorganizing the review staff to maximize expertise and improve workload efficiencies
• Better leveraging the expertise across the FDA’s medical product centers
• Establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

The FDA is planning for the backlog to be eliminated by mid-September.

The Orphan Drug Modernization Plan is the first element of several efforts the FDA plans to undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring the FDA’s regulatory tools and policies are modern, risk-based, and efficient.

The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective, and transformative medical innovations that have the potential to significantly impact disease and reduce overall healthcare costs.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has unveiled a plan to eliminate the agency’s existing backlog of orphan designation requests and ensure timely responses to all new requests with firm deadlines.

The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the US.

Orphan designation qualifies a product’s developer for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for 7 years of marketing exclusivity if the product is approved.

A request for orphan designation is one step that can be taken in the development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past 5 years.

In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012.

The FDA says this increased interest in the program is a positive development for patients with rare diseases, and, with the Orphan Drug Modernization Plan, the FDA is committing to advancing the program to ensure it can efficiently and adequately review these requests.

“People who suffer with rare diseases are too often faced with no or limited treatment options, and what treatment options they have may be quite expensive due, in part, to significant costs of developing therapies for smaller populations,” said FDA Commissioner Scott Gottlieb, MD.

“Congress gave us tools to incentivize the development of novel therapies for rare diseases, and we intend to use these resources to their fullest extent in order to ensure Americans get the safe and effective medicines they need, and that the process for developing these innovations is as modern and efficient as possible.”

Among the elements of the Orphan Drug Modernization Plan, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests.

The agency will also employ a streamlined Designation Review Template to increase consistency and efficiency of its reviews.

In addition, the Orphan Drug Designation Program will look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

To ensure all future requests receive a response within 90 days of receipt, the FDA will take a multifaceted approach.

These efforts include, among other new steps:

• Reorganizing the review staff to maximize expertise and improve workload efficiencies
• Better leveraging the expertise across the FDA’s medical product centers
• Establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

The FDA is planning for the backlog to be eliminated by mid-September.

The Orphan Drug Modernization Plan is the first element of several efforts the FDA plans to undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring the FDA’s regulatory tools and policies are modern, risk-based, and efficient.

The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective, and transformative medical innovations that have the potential to significantly impact disease and reduce overall healthcare costs.

Photo by Esther Dyson

The US Food and Drug Administration (FDA) has unveiled a plan to eliminate the agency’s existing backlog of orphan designation requests and ensure timely responses to all new requests with firm deadlines.

The agency’s Orphan Drug Modernization Plan comes a week after FDA Commissioner Scott Gottlieb committed to eliminating the backlog within 90 days and responding to all new requests for designation within 90 days of receipt during his testimony before a Senate subcommittee.

As authorized under the Orphan Drug Act, the Orphan Drug Designation Program provides orphan status to drugs and biologics intended for the treatment, diagnosis, or prevention of rare diseases, which are generally defined as diseases that affect fewer than 200,000 people in the US.

Orphan designation qualifies a product’s developer for various development incentives, including tax credits for clinical trial costs, relief from prescription drug user fee if the indication is for a rare disease or condition, and eligibility for 7 years of marketing exclusivity if the product is approved.

A request for orphan designation is one step that can be taken in the development process and is different than the filing of a marketing application with the FDA.

Currently, the FDA has about 200 orphan drug designation requests that are pending review. The number of orphan drug designation requests has steadily increased over the past 5 years.

In 2016, the FDA’s Office of Orphan Products Development received 568 new requests for designation – more than double the number of requests received in 2012.

The FDA says this increased interest in the program is a positive development for patients with rare diseases, and, with the Orphan Drug Modernization Plan, the FDA is committing to advancing the program to ensure it can efficiently and adequately review these requests.

“People who suffer with rare diseases are too often faced with no or limited treatment options, and what treatment options they have may be quite expensive due, in part, to significant costs of developing therapies for smaller populations,” said FDA Commissioner Scott Gottlieb, MD.

“Congress gave us tools to incentivize the development of novel therapies for rare diseases, and we intend to use these resources to their fullest extent in order to ensure Americans get the safe and effective medicines they need, and that the process for developing these innovations is as modern and efficient as possible.”

Among the elements of the Orphan Drug Modernization Plan, the FDA will deploy a Backlog SWAT team comprised of senior, experienced reviewers with significant expertise in orphan drug designation. The team will focus solely on the backlogged applications, starting with the oldest requests.

The agency will also employ a streamlined Designation Review Template to increase consistency and efficiency of its reviews.

In addition, the Orphan Drug Designation Program will look to collaborate within the agency’s medical product centers to create greater efficiency, including conducting joint reviews with the Office of Pediatric Therapeutics to review rare pediatric disease designation requests.

To ensure all future requests receive a response within 90 days of receipt, the FDA will take a multifaceted approach.

These efforts include, among other new steps:

• Reorganizing the review staff to maximize expertise and improve workload efficiencies
• Better leveraging the expertise across the FDA’s medical product centers
• Establishing a new FDA Orphan Products Council that will help address scientific and regulatory issues to ensure the agency is applying a consistent approach to regulating orphan drug products and reviewing designation requests.

The FDA is planning for the backlog to be eliminated by mid-September.

The Orphan Drug Modernization Plan is the first element of several efforts the FDA plans to undertake under its new “Medical Innovation Development Plan,” which is aimed at ensuring the FDA’s regulatory tools and policies are modern, risk-based, and efficient.

The goal of the plan is to seek ways the FDA can help facilitate the development of safe, effective, and transformative medical innovations that have the potential to significantly impact disease and reduce overall healthcare costs.

A 34-year-old woman presents to your office for unbearable sweating on her hands, face, and axillary regions. It occurs nearly daily, causing social embarrassment. She has tried multiple antiperspirants to no avail. What can she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem that affects 2% to 3% of the United States population.² Patients may complain of localized sweating of the hands, feet, face, or underarms, or more systemic, generalized sweating in multiple locations. Either way, patients note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research by both subjective report and objective measurements has shown that antiperspirants containing aluminum salt are effective at reducing sweating, particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis, with minimal adverse effects.⁵ The availability of low-cost prescription and OTC aluminum-based antiperspirant agents makes topicals the firstline choice.

More invasive treatments are available for hyperhidrosis refractory to topicals. In a double-blind RCT, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating four weeks after initial injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are thus not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist has historically been used to treat overactive bladder. But oxybutynin not only reduces urinary frequency, it also decreases secretions in various locations and can therefore reduce perspiration and cause dry mouth.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomly assigned to either oxybutynin (titrated from 2.5 mg orally once daily to 5 mg orally twice daily) or placebo for six weeks.⁷ Seventeen patients (73.9%) receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms, compared with six patients (27.3%) in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin versus 9.1% of those who received placebo; however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter RCT compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with both localized and generalized forms of the condition.

Patients were included if they were older than 18, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

Patients randomly assigned to oxybutynin took 2.5 mg/d by mouth initially and increased gradually over eight days until reaching an effective dose that was no more than 7.5 mg/d. They then continued at that dose for six weeks.

The primary outcome was improvement on the HDSS by one or more points, measured at the beginning of the trial and again at six weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where disease has no impact on quality of life) to 30 (maximum impact of disease on quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-30s. Sixty percent of patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS, compared to 27% in the placebo group. DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group.

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in three patients (11%) in the placebo group; it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (four patients; 13%).

WHAT’S NEW

This is the first RCT to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few, if any, challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[6]:392-394).

A 34-year-old woman presents to your office for unbearable sweating on her hands, face, and axillary regions. It occurs nearly daily, causing social embarrassment. She has tried multiple antiperspirants to no avail. What can she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem that affects 2% to 3% of the United States population.² Patients may complain of localized sweating of the hands, feet, face, or underarms, or more systemic, generalized sweating in multiple locations. Either way, patients note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research by both subjective report and objective measurements has shown that antiperspirants containing aluminum salt are effective at reducing sweating, particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis, with minimal adverse effects.⁵ The availability of low-cost prescription and OTC aluminum-based antiperspirant agents makes topicals the firstline choice.

More invasive treatments are available for hyperhidrosis refractory to topicals. In a double-blind RCT, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating four weeks after initial injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are thus not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist has historically been used to treat overactive bladder. But oxybutynin not only reduces urinary frequency, it also decreases secretions in various locations and can therefore reduce perspiration and cause dry mouth.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomly assigned to either oxybutynin (titrated from 2.5 mg orally once daily to 5 mg orally twice daily) or placebo for six weeks.⁷ Seventeen patients (73.9%) receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms, compared with six patients (27.3%) in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin versus 9.1% of those who received placebo; however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter RCT compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with both localized and generalized forms of the condition.

Patients were included if they were older than 18, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

Patients randomly assigned to oxybutynin took 2.5 mg/d by mouth initially and increased gradually over eight days until reaching an effective dose that was no more than 7.5 mg/d. They then continued at that dose for six weeks.

The primary outcome was improvement on the HDSS by one or more points, measured at the beginning of the trial and again at six weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where disease has no impact on quality of life) to 30 (maximum impact of disease on quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-30s. Sixty percent of patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS, compared to 27% in the placebo group. DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group.

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in three patients (11%) in the placebo group; it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (four patients; 13%).

WHAT’S NEW

This is the first RCT to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few, if any, challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[6]:392-394).

A 34-year-old woman presents to your office for unbearable sweating on her hands, face, and axillary regions. It occurs nearly daily, causing social embarrassment. She has tried multiple antiperspirants to no avail. What can she can take to reduce the sweating?

Hyperhidrosis is a common, self-limiting problem that affects 2% to 3% of the United States population.² Patients may complain of localized sweating of the hands, feet, face, or underarms, or more systemic, generalized sweating in multiple locations. Either way, patients note a significant impact on their quality of life.

Treatment of hyperhidrosis has traditionally focused on topical therapies to the affected areas. Research by both subjective report and objective measurements has shown that antiperspirants containing aluminum salt are effective at reducing sweating, particularly in the axilla, hands, and feet.^3,4 Additionally, a systematic review of observational and experimental studies found topical glycopyrrolate to be efficacious for craniofacial hyperhidrosis, with minimal adverse effects.⁵ The availability of low-cost prescription and OTC aluminum-based antiperspirant agents makes topicals the firstline choice.

More invasive treatments are available for hyperhidrosis refractory to topicals. In a double-blind RCT, researchers injected either botulinum toxin type A (BTX-A) 50 U or placebo in patients with bilateral primary axillary hyperhidrosis.⁶ Of the 207 patients who received treatment injections, 96.1% had at least a 50% reduction of axillary sweating four weeks after initial injection, as measured by gravimetric assessment. The BTX-A injections also produced a prolonged effect; mean duration between injections was 30.6 weeks.

Other invasive treatments include iontophoresis, surgery, and laser therapy; however, these methods are not suitable for body-wide application and are thus not appropriate for patients with generalized hyperhidrosis.

Oxybutynin is the first oral agent to emerge as a treatment option for hyperhidrosis. This cholinergic antagonist has historically been used to treat overactive bladder. But oxybutynin not only reduces urinary frequency, it also decreases secretions in various locations and can therefore reduce perspiration and cause dry mouth.

In one prospective placebo-controlled trial, 50 patients with generalized hyperhidrosis were randomly assigned to either oxybutynin (titrated from 2.5 mg orally once daily to 5 mg orally twice daily) or placebo for six weeks.⁷ Seventeen patients (73.9%) receiving oxybutynin for palmar or axillary hyperhidrosis reported moderate to “great” resolution of their symptoms, compared with six patients (27.3%) in the placebo group. Dry mouth was reported in 34.8% of patients receiving oxybutynin versus 9.1% of those who received placebo; however, no patients dropped out of the study due to this adverse effect.⁷

STUDY SUMMARY

This multicenter RCT compared oxybutynin to placebo in 62 adults with localized or generalized hyperhidrosis from 12 outpatient dermatology practices in France. It is the first study to include patients with both localized and generalized forms of the condition.

Patients were included if they were older than 18, enrolled in the National Health Insurance system in France, and reported a Hyperhidrosis Disease Severity Scale (HDSS) score ≥ 2. The HDSS is a validated, one-question tool (“How would you rate the severity of your sweating?”). Patients provide a score of 1 (no perceptible sweating and no interference with everyday life) to 4 (intolerable sweating with constant interference with everyday life).⁸ Patients were excluded if they had any contraindications to the use of an anticholinergic medication.

Patients randomly assigned to oxybutynin took 2.5 mg/d by mouth initially and increased gradually over eight days until reaching an effective dose that was no more than 7.5 mg/d. They then continued at that dose for six weeks.

The primary outcome was improvement on the HDSS by one or more points, measured at the beginning of the trial and again at six weeks. Secondary outcomes included change in quality of life, as measured by the Dermatology Life Quality Index (DLQI) and reported adverse effects. The DLQI is a dermatology-specific quality-of-life measure consisting of 10 questions. Scores range from 0 (where disease has no impact on quality of life) to 30 (maximum impact of disease on quality of life).⁹

Improved HDSS and DLQI scores. Most patients (83%) in the study had generalized hyperhidrosis. Patients were in their mid-30s. Sixty percent of patients in the oxybutynin group had an improvement of one point or more on the 4-point HDSS, compared to 27% in the placebo group. DLQI scores improved by 6.9 points in the oxybutynin group and 2.3 points in the placebo group.

The most common adverse effect was dry mouth, which occurred in 13 patients (43%) in the oxybutynin group and in three patients (11%) in the placebo group; it did not cause any patients to drop out of the study. The second most common adverse effect was blurred vision, which only occurred in the oxybutynin group (four patients; 13%).

WHAT’S NEW

This is the first RCT to demonstrate the efficacy of an oral agent for generalized primary hyperhidrosis. This trial used a relatively low dose of oxybutynin, which produced significant benefit while minimizing anticholinergic adverse effects.

CAVEATS

There are many situations for which anticholinergic medications are inappropriate, including use by geriatric patients and those with gastrointestinal disorders, urinary retention, or glaucoma.

CHALLENGES TO IMPLEMENTATION

Few, if any, challenges exist to the utilization of oxybutynin; inexpensive generic versions are widely available.

ACKNOWLEDGEMENT

The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center for Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center for Research Resources or the National Institutes of Health.

Copyright © 2017. The Family Physicians Inquiries Network. All rights reserved.

Reprinted with permission from the Family Physicians Inquires Network and The Journal of Family Practice (2017;66[6]:392-394).

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹

CASE 1 CONTINUED

Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.

• What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?

Safety Profile

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.⁵¹ Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.

Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.⁵²

Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.⁵³

Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.⁵⁴ Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.

CASE 1 CONTINUED

The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.

• How would you manage the patient at this point?

MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS

As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.⁴⁶ Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.^55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.⁵⁶ The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.³⁵ The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.^57,58

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.⁵⁹ Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).⁶⁰

For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.

ALK REARRANGEMENTS

CASE 2 PRESENTATION

A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.

• How would you respond to this patient’s inquiry?

FIRST-LINE TKIS FOR ALK REARRANGEMENTS

ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.⁶¹ The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.^7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.⁶²ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.⁶³ PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).⁶⁴ Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).⁶⁵ PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).⁶⁶ In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.

Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.⁶⁷ It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.⁶⁸ In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).⁶⁹ Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.⁷⁰

Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.⁷¹ Its indication will soon be broadened to the first-line setting based on the ALEX trial.⁷² Alectinib is a potent and highly selective TKI of ALK⁷³ with activity against known resistant mutations to crizotinib.^74,75 It also inhibits RET but not ROS1 or c-MET.⁷⁶ ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).⁷² Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.⁷⁷

Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).⁷⁸ Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.

Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.⁷⁹ Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.^69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.⁸¹

ROS1 REARRANGEMENTS

CASE PRESENTATION 3

A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.

• What treatment plan should be put in place for this patient?

FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.⁸² This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.⁸ It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.⁸³ As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.⁸⁴ Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.⁸⁵ The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).⁸⁶ During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.⁸⁵

Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.⁸⁶ FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.⁸⁷ NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.

For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,⁸⁶ plans should be made to repeat her scans in approximately 2 months.

BRAF V600E MUTATIONS

CASE PRESENTATION 4

A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.

• What would be your recommended systemic treatment?

TARGETED THERAPIES FOR BRAF V600E MUTATION

BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.^9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.^9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).⁹

For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.¹⁶

The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).¹⁴ Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).¹³ Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.

CONCLUSION

The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹

CASE 1 CONTINUED

Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.

• What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?

Safety Profile

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.⁵¹ Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.

Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.⁵²

Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.⁵³

Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.⁵⁴ Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.

CASE 1 CONTINUED

The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.

• How would you manage the patient at this point?

MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS

As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.⁴⁶ Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.^55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.⁵⁶ The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.³⁵ The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.^57,58

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.⁵⁹ Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).⁶⁰

For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.

ALK REARRANGEMENTS

CASE 2 PRESENTATION

A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.

• How would you respond to this patient’s inquiry?

FIRST-LINE TKIS FOR ALK REARRANGEMENTS

ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.⁶¹ The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.^7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.⁶²ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.⁶³ PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).⁶⁴ Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).⁶⁵ PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).⁶⁶ In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.

Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.⁶⁷ It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.⁶⁸ In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).⁶⁹ Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.⁷⁰

Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.⁷¹ Its indication will soon be broadened to the first-line setting based on the ALEX trial.⁷² Alectinib is a potent and highly selective TKI of ALK⁷³ with activity against known resistant mutations to crizotinib.^74,75 It also inhibits RET but not ROS1 or c-MET.⁷⁶ ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).⁷² Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.⁷⁷

Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).⁷⁸ Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.

Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.⁷⁹ Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.^69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.⁸¹

ROS1 REARRANGEMENTS

CASE PRESENTATION 3

A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.

• What treatment plan should be put in place for this patient?

FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.⁸² This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.⁸ It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.⁸³ As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.⁸⁴ Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.⁸⁵ The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).⁸⁶ During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.⁸⁵

Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.⁸⁶ FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.⁸⁷ NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.

For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,⁸⁶ plans should be made to repeat her scans in approximately 2 months.

BRAF V600E MUTATIONS

CASE PRESENTATION 4

A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.

• What would be your recommended systemic treatment?

TARGETED THERAPIES FOR BRAF V600E MUTATION

BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.^9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.^9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).⁹

For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.¹⁶

The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).¹⁴ Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).¹³ Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.

CONCLUSION

The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.

INTRODUCTION

Lung cancer is the second most common type of cancer in the United States, with 222,500 estimated new cases in 2017, according to the American Cancer Society.¹ However, it is by far the number one cause of death due to cancer, with an estimated 155,870 lung cancer–related deaths occurring in 2017, which is higher than the number of deaths due to breast cancer, prostate cancer, and colorectal cancer combined.^1,2 Despite slightly decreasing incidence and mortality over the past decade, largely due to smoking cessation, the 5-year survival rate of lung cancer remains dismal at approximately 18%.^2–4

Non-small cell lung cancer (NSCLC) accounts for 80% to 85% of all lung cancer cases.⁴ Traditionally, it is further divided based on histology: adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and not otherwise specified.⁵ Chemotherapy had been the cornerstone of treatment for stage IV NSCLC. It is not target-specific and is most effective against rapidly growing cells. Common adverse effects include alopecia, nausea/vomiting, myelosuppression, cardiotoxicity, neuropathy, and nephrotoxicity. However, this paradigm has shifted following the discovery of mutations of the epidermal growth factor receptor (EGFR) gene as an oncogenic driver that confers sensitivity to small molecule tyrosine kinase inhibitors (TKIs) targeting EGFR.⁶ The EGFR inhibitors are given orally and have a spectrum of toxicities (eg, such as rash, diarrhea, and elevated transaminases) different from that of systemic chemotherapy, which is often administered intravenously. Following the discovery of EGFR mutations, rearrangements of the anaplastic lymphoma kinase (ALK) gene⁷ and ROS1 gene⁸ were identified as targetable driver mutations in NSCLC. The frequency of both rearrangements is lower than that of EGFR mutations. Additionally, BRAF V600E mutation has been identified in NSCLC.^9–12 This activation mutation is commonly seen in melanoma. Agents that have already been approved for the treatment of melanoma with the BRAF V600E mutation are being tested in NSCLC patients with this mutation.^13–16

Given the effectiveness and tolerability of targeted therapy, identifying this distinct molecular subset of NSCLC patients is critical in treatment. Currently, molecular testing is mandatory in all stage IV patients with non-squamous cell carcinoma, as a preponderance of patients with driver mutations have this histology subtype.^5,17–19 For patients with squamous cell carcinoma, molecular testing should be considered if the biopsy specimen is small, there is mixed histology, or the patient is a nonsmoker.^5,20 Several techniques are commonly utilized in detecting these genetic alterations. EGFR mutation can be detected by polymerase chain reaction (PCR), ALK or ROS1 rearrangement can be detected by fluorescence in-situ hybridization (FISH), and immunohistochemistry (IHC) can also be used to detect ALK rearrangement. The current guideline is to use comprehensive genomic profiling to capture all the potential molecular targets simultaneously instead of running stepwise tests just for EGFR, ALK, and ROS1.⁵BRAF V600E mutation,^13–16 MET exon 14 skipping mutation,^21–24 RET rearrangements,^25–27 and HER2 mutations^28–30 are among the emergent genetic alterations with various responses to targeted therapy.³¹ Some of these targeted agents have been approved for other types of malignancy, and others are still in the development phase.

Several initiatives worldwide have reported better outcomes of patients with driver mutations treated with targeted therapy. For instance, the Lung Cancer Mutation Consortium in the United States demonstrated that the median survival of patients without driver mutations, with drivers mutations but not treated with targeted therapy, and with driver mutations and treated with targeted therapy was 2.08 years, 2.38 years, and 3.49 years, respectively.³² The French Cooperative Thoracic Intergroup-French National Cancer Institute demonstrated that the median survival for patients with driver mutations versus those without driver mutations was 16.5 months versus 11.8 months.³³ The Spanish Lung Cancer Group demonstrated that the overall survival (OS) for patients with EGFR mutations treated with erlotinib was 27 months.³⁴ The mutations in lung cancer, their frequencies, and the downstream signaling pathways are depicted in the Figure.³⁵

In this article, we discuss targeted therapy for patients with EGFR mutations, ALK rearrangements, ROS1 rearrangements, and BRAF V600E mutation. We also discuss the management of patients with EGFR mutations who develop a secondary mutation after TKI therapy. Almost all of the targeted agents discussed herein have been approved by the US Food and Drug Administration (FDA), so they are considered standard of care. All available phase 3 trials pertinent to these targeted therapies are included in the discussion.

EGFR MUTATIONS

CASE PRESENTATION 1

A 54-year-old Caucasian man who is a former smoker with a 10 pack-year history and past medical history of hypertension and dyslipidemia presents with progressive dyspnea for several weeks. A chest x-ray shows moderate pleural effusion on the left side with possible mass-like opacity on the left upper lung field. An ultrasound-guided thoracentesis is performed and cytology is positive for adenocarcinoma of likely pulmonary origin. Staging workup including positron emission tomography (PET)/computed tomography (CT) and magnetic resonance imaging of the brain with and without contrast is done. PET/CT shows a 5.5-cm mass in the left upper lobe of the lung with high fluorodeoxyglucose (FDG) uptake, several 1- to 2-cm mediastinal lymph nodes with moderate FDG uptake, and small pleural effusion on both sides with moderate FDG uptake. MRI-brain is negative for malignancy. The patient subsequently undergoes a CT-guided biopsy of the lung mass, which shows moderately differentiated adenocarcinoma. Comprehensive molecular profiling reveals EGFR L858R mutation only. The patient now presents for the initial consultation. Of note, his Eastern Cooperative Oncology Group performance status is 1.

• What is the next step in the management of this patient?

FIRST-LINE TKI FOR SENSITIZING EGFR MUTATIONS

The 2 most common EGFR mutations are deletions in exon 19 and substitution of arginine for leucine in exon 21 (L858R), found in approximately 45% and 40% of patients with EGFR mutations, respectively.³⁶ Both mutations are sensitive to EGFR TKIs. The benefit may be greater in patients with exon 19 deletions as compared to exon 21 L858R substitution,^37,38 but this has not been demonstrated consistently in clinical trials.^39-43 In the United States, EGFR mutations are found in approximately 10% of patients with NSCLC, while the incidence can be as high as 50% in Asia.⁴⁴ Even though the cobas EGFR mutation test is the companion diagnostic approved by the US FDA, a positive test result from any laboratory with the Clinical Laboratory Improvement Amendments (CLIA) certificate should prompt the use of an EGFR TKI as the initial treatment.

Three EGFR TKIs that have been approved as first-line therapy in the United States are available: erlotinib, afatinib, and gefitinib.⁵ Both erlotinib and gefitinib are considered first-generation TKIs. They have higher binding affinity for the 2 common EGFR mutations than wild-type EGFR. In addition, they reversibly bind to the intracellular tyrosine kinase domain, resulting in inhibition of autophosphorylation of the tyrosine residues. Afatinib, a second-generation and irreversible TKI, targets EGFR (HER1) as well as HER2 and HER4.⁴⁵

The superior efficacy of the EGFR TKIs over platinum doublet chemotherapy in treatment-naïve patients with EGFR mutations has been demonstrated in 7 randomized trials to date (Table).⁴⁶ Erlotinib was the TKI arm for the OPTIMAL,⁴¹ EURTAC,⁴² and ENSURE trials;³⁸ afatinib was the TKI arm for LUX-LUNG 3³⁷ and 6;⁴³ gefitinib was the TKI arm for NEJ002^39,47 and WJTOG3405.⁴⁰ A meta-analysis of these 7 trials by Lee et al showed that progression-free survival (PFS) was significantly prolonged by EGFR TKIs (hazard ratio [HR] 0.37 [95% confidence interval {CI} 0.32 to 0.42]).⁴⁶ For instance, in the EURTAC trial, median PFS was 9.7 months for patients treated with erlotinib as compared to 5.2 months for patients treated with platinum/gemcitabine or platinum/docetaxel.⁴² In this meta-analysis, prespecified subgroups included age, sex, ethnicity, smoking status, performance status, tumor histology, and EGFR mutation subtype. The superior outcome with TKIs was observed in all subgroups. Furthermore, patients with exon 19 deletions, nonsmokers, and women had even better outcomes.⁴⁶

Erlotinib is the most commonly used TKI in the United States largely because gefitinib was off the market for some time until it was re-approved by the FDA in 2015. Interestingly, this “re-approval” was not based on either 1 of the 2 prospective trials (NEJ002^39,47 and WJTOG3405⁴⁰), but rather was based on an exploratory analysis of the IPASS trial^48,49 as well as a prospective phase 4, single-arm trial in Europe (IFUM).⁵⁰ The superior efficacy of gefitinib over carboplatin/paclitaxel among patients with EGFR mutations in the IPASS trial was confirmed by blind independent central review, with longer PFS (HR 0.54 [95% CI 0.38 to 0.79] P = 0.0012) and higher objective response rate (ORR; odds ratio 3 [95% CI 1.63 to 5.54], P = 0.0004).⁴⁹

CASE 1 CONTINUED

Based on the EGFR L858R mutation status, the patient is started on erlotinib. He is quite happy that he does not need intravenous chemotherapy but wants to know what toxicities he might potentially have with erlotinib.

• What are the common adverse effects (AEs) of EGFR TKIs? How are AEs of TKIs managed?

Safety Profile

The important toxicities associated with EGFR TKIs are rash, gastrointestinal toxicity, hepatic toxicity, and pulmonary toxicity. Rash is an AE specific to all agents blocking the EGFR pathway, including small molecules and monoclonal antibodies such as cetuximab. The epidermis has a high level of expression of EGFR, which contributes to this toxicity.⁵¹ Rash usually presents as dry skin or acneiform eruption. Prophylactic treatment with oral tetracyclines and topical corticosteroids is generally recommended upon initiation of TKI therapy. Diarrhea is the most prevalent gastrointestinal toxicity. All patients starting treatment should be given prescriptions to manage diarrhea such as loperamide and be advised to call when it occurs. Hepatic toxicity is often manifested as elevated transaminases or bilirubin. Interstitial lung disease (ILD) is a rare but potentially fatal pulmonary toxicity.

Rash of any grade was reported in 49.2% of patients treated with erlotinib in clinical trials, while grade 3 rash occurred in 6% of patients and no grade 4 was reported. Diarrhea of any grade was reported in 20.3% of patients, grade 3 diarrhea occurred in 1.8%, and no grade 4 was reported. Grade 2 and 3 alanine aminotransferase (ALT) elevations were seen in 2% and 1% of patients, respectively. Grade 2 and 3 bilirubin elevations were seen in 4% and less than 1% of patients, respectively. The incidence of serious ILD-like events was less than 1%.⁵²

Afatinib is associated with higher incidences of rash and diarrhea. Specifically, diarrhea and rash of all grades were reported in 96% and 90% of patients treated with afatinib, respectively. Paronychia of all grades occurred in 58% of patients. Elevated ALT of all grades was seen in 11% of patients. Approximately 1.5% of patients treated with afatinib across clinical trials had ILD or ILD-like AEs.⁵³

Gefitinib, the most commonly used TKI outside United States, has a toxicity profile similar to erlotinib, except for hepatic toxicity. For instance, rash of all grades occurred in 47% of patients, diarrhea of all grades occurred in 29% of patients, and ILD or ILD-like AEs occurred in 1.3% of patients across clinical trials. In comparison, elevated ALT and aspartate aminotransferase (AST) of all grades was seen in 38% and 40% of patients, respectively.⁵⁴ Therefore, close monitoring of liver function is clinically warranted. In particular, patients need to be advised to avoid concomitant use of herbal supplements, a common practice in Asian countries.

CASE 1 CONTINUED

The patient does well while on erlotinib at 150 mg orally once daily for about 8 months, until he develops increasing abdominal pain. A CT scan of the abdomen and pelvis with contrast shows a new 8-cm right adrenal mass. Additionally, a repeat CT scan of the chest with contrast shows a stable lung mass but enlarging mediastinal lymphadenopathy.

• How would you manage the patient at this point?

MANAGEMENT OF T790M MUTATION AFTER PROGRESSION ON FIRST-LINE EGFR TKIS

As mentioned above, the median PFS of patients with EGFR mutations treated with 1 of the 3 TKIs is around 9 to 13 months.⁴⁶ Of the various resistance mechanisms that have been described, the T790M mutation is found in approximately 60% of patients who progress after treatment with first-line TKIs.^55,56 Other mechanisms, such as HER2 amplification, MET amplification, or rarely small cell transformation, have been reported.⁵⁶ The first- and second-generation EGFR TKIs function by binding to the ATP-binding domain of mutated EGFR, leading to inhibition of the downstream signaling pathways (Figure, part B) and ultimately cell death.³⁵ The T790M mutation hinders the interaction between the ATP-binding domain of EGFR kinase and TKIs, resulting in treatment resistance and disease progression.^57,58

Osimertinib is a third-generation irreversible EGFR TKI with activity against both sensitizing EGFR and resistant T790M mutations. It has low affinity for wide-type EGFR as well as insulin receptor and insulin-like growth factor receptor.⁵⁹ Osimertinib has been fully approved for NSCLC patients with EGFR mutations who have progressed on first-line EGFR TKIs with the development of T790M mutation. An international phase 3 trial (AURA3) randomly assigned 419 patients in a 2:1 ratio to either osimertinib or platinum/pemetrexed. Eligible patients all had the documented EGFR mutations and disease progression after first-line EGFR TKIs. Central confirmation of the T790M mutation was required. Median PFS by investigator assessment, the trial’s primary end point, was 10.1 months for osimertinib versus 4.4 months for chemotherapy (HR 0.3 [95% CI 0.23 to 0.41]; P < 0.001). ORR was 71% for osimertinib versus 31% for chemotherapy (HR 5.39 [95% CI 3.47 to 8.48], P < 0.001). A total of 144 patients with stable and asymptomatic brain metastases were also eligible. Median PFS for this subset of patients treated with osimertinib and chemotherapy was 8.5 months and 4.2 months, respectively (HR 0.32 [95% CI 0.21 to 0.49]). In the AURA3 trial, osimertinib was better tolerated than chemotherapy, with 23% of patients treated with osimertinib experiencing grade 3 or 4 AEs as compared to 47% of chemotherapy-treated patients. The most common AEs of any grade were diarrhea (41%), rash (34%), dry skin (23%), and paronychia (22%).⁶⁰

For the case patient, a reasonable approach would be to obtain a tissue biopsy of the adrenal mass and more importantly to check for the T790M mutation. Similar to the companion diagnostic for EGFR mutations, the cobas EGFR mutation test v2 is the FDA-approved test for T790M. However, if this resistance mutation is detected by any CLIA-certified laboratories, osimertinib should be the recommended treatment option. If tissue biopsy is not feasible, plasma-based testing should be considered. A blood-based companion diagnostic also is FDA approved.

ALK REARRANGEMENTS

CASE 2 PRESENTATION

A 42-year-old Korean woman who is a non-smoker with no significant past medical history presents with fatigue, unintentional weight loss of 20 lb in the past 4 months, and vague abdominal pain. A CT can of the abdomen and pelvis without contrast shows multiple foci in the liver and an indeterminate nodule in the right lung base. She subsequently undergoes PET/CT, which confirms multiple liver nodules/masses ranging from 1 to 3 cm with moderate FDG uptake. In addition, there is a 3.5-cm pleura-based lung mass on the right side with moderate FDG uptake. MRI-brain with and without contrast is negative for malignancy. A CT-guided biopsy of 1 of the liver masses is ordered and pathology returns positive for poorly differentiated adenocarcinoma consistent with lung primary. Molecular analysis reveals an echinoderm microtubule-associated protein-like 4 (EML4)-ALK rearrangement. She is placed on crizotinib by an outside oncologist and after about 3 weeks of therapy is doing well. She is now in your clinic for a second opinion. She says that some of her friends told her about another medication called ceritinib and was wondering if she would need to switch her cancer treatment.

• How would you respond to this patient’s inquiry?

FIRST-LINE TKIS FOR ALK REARRANGEMENTS

ALK rearrangements are found in 2% to 7% of NSCLC, with EML4-ALK being the most prevalent fusion variant.⁶¹ The inversion of chromosome 2p leads to the fusion of the EML4 gene and the ALK gene, which causes the constitutive activation of the fusion protein and ultimately increased transformation and tumorigenicity.^7,61 Patients harboring ALK rearrangements tend to be non-smokers. Adenocarcinoma, especially signet ring cell subtype, is the predominant histology. Compared to EGFR mutations, patients with ALK mutations are significantly younger and more likely to be men.⁶²ALK rearrangements can be detected by either FISH or IHC, and most next-generation sequencing (NGS) panels have the ability to identify this driver mutation.

Crizotinib is the first approved ALK inhibitor for the treatment of NSCLC in this molecular subset of patients.⁶³ PROFILE 1014 is a phase 3 randomized trial that compared crizotinib with chemotherapy containing platinum/pemetrexed for up to 6 cycles. Crossover to crizotinib was allowed for patients with disease progression on chemotherapy. The primary end point was PFS by independent radiologic review. The crizotinib arm demonstrated superior PFS (10.9 months versus 7 months; HR 0.45 [95% CI 0.35 to 0.6], P < 0.001) and ORR (74% versus 45%, P < 0.001). Median survival was not reached in either arm (HR 0.82 [95% CI 0.54 to 1.26], P = 0.36).⁶⁴ Based on this international trial, crizotinib is considered standard of care in the United States for treatment-naïve patients with advanced NSCLC harboring ALK rearrangements. The current recommended dose is 250 mg orally twice daily. Common treatment-related AEs of all grades include vision disorder (62%), nausea (53%), diarrhea (43%), vomiting (40%), edema (28%), and constipation (27%).⁶⁵ PROFILE 1007 compared crizotinib with pemetrexed or docetaxel in ALK-rearranged NSCLC patients with prior exposure to 1 platinum-based chemotherapy. The median PFS was 7.7 months for crizotinib as compared to 3 months for chemotherapy (HR 0.49 [95% CI 0.37 to 0.64], P < 0.001). The response rates were 65% and 20% for crizotinib and chemotherapy, respectively (P < 0.001).⁶⁶ In other countries, crizotinib following 1 prior platinum-based regimen may be considered standard of care based on this trial.

Ceritinib is an oral second-generation ALK inhibitor that is 20 times more potent than crizotinib based on enzymatic assays.⁶⁷ It also targets ROS1 and insulin-like growth factor 1 receptor but not c-MET. It was first approved by the FDA in April 2014 for metastatic ALK-rearranged NSCLC following crizotinib.⁶⁸ In May 2017, the FDA granted approval of ceritinib for treatment-naïve patients. This decision was based on the results of the ASCEND-4 trial, a randomized phase 3 trial assessing the efficacy and safety of ceritinib over chemotherapy in the first-line setting. The trial assigned 376 patients to either ceritinib at 750 mg once daily or platinum/pemetrexed for 4 cycles followed by maintenance pemetrexed. Median PFS was 16.6 months for ceritinib versus 8.1 months for chemotherapy (HR 0.55 [95% CI 0.42 to 0.73]; P < 0.00001).⁶⁹ Toxicities of ceritinib are not negligible, with gastrointestinal toxicity being the most prevalent. For instance, diarrhea, nausea, vomiting, abdominal pain, and constipation of all grades were seen in 86%, 80%, 60%, 54%, and 29% of patients, respectively. Furthermore, fatigue and decreased appetite occurred in 52% and 34% of patients, respectively. In terms of laboratory abnormalities, 84% of patients experienced decreased hemoglobin of all grades; 80% increased ALT; 75% increased AST; 58% increased creatinine; 49% increased glucose; 36% decreased phosphate; and 28% increased lipase. Due to these AEs, the incidence of dose reduction was about 58% and the median onset was around 7 weeks.⁷⁰

Alectinib is another oral second-generation ALK inhibitor that was approved by the FDA in December 2015 for the treatment of NSCLC patients with ALK rearrangements who have progressed on or are intolerant to crizotinib.⁷¹ Its indication will soon be broadened to the first-line setting based on the ALEX trial.⁷² Alectinib is a potent and highly selective TKI of ALK⁷³ with activity against known resistant mutations to crizotinib.^74,75 It also inhibits RET but not ROS1 or c-MET.⁷⁶ ALEX, a randomized phase 3 study, compared alectinib with crizotinib in treatment-naïve patients with NSCLC harboring ALK rearrangements. The trial enrolled 303 patients and the median follow-up was approximately 18 months. The alectinib arm (600 mg twice daily) demonstrated significantly higher PFS by investigator-assessment, the trial’s primary end point. The 12-month event-free survival was 68.4% (95% CI 61% to 75.9%) versus 48.7% (95% CI 40.4% to 56.9%) for alectinib and crizotinib, respectively (HR 0.47 [95% CI 0.34 to 0.65], P < 0.001). The median PFS was not reached in the alectinib arm (95% CI 17.7 months to not estimable) as compared to 11.1 months in the crizotinib arm (95% CI 9.1 to 13.1 months).⁷² Alectinib is generally well tolerated. Common AEs of all grades include fatigue (41%), constipation (34%), edema (30%), and myalgia (29%). As alectinib can cause anemia, lymphopenia, hepatic toxicity, increased creatine phosphokinase, hyperglycemia, electrolyte abnormalities, and increased creatinine, periodic monitoring of these laboratory values is important, although most of these abnormalities are grade 1 or 2.⁷⁷

Brigatinib, another oral second-generation ALK inhibitor, was granted accelerated approval by the FDA in April 2017 for ALK-rearranged and crizotinib-resistant NSCLC based on the ALTA trial. This randomized phase 2 study of brigatinib showed an ORR by investigator assessment of 54% (97.5% CI 43% to 65%) in the 180 mg once daily arm with lead-in of 90 mg once daily for 7 days. Median PFS was 12.9 months (95% CI 11.1 months to not reached [NR]).⁷⁸ Currently, a phase 3 study of brigatinib versus crizotinib in ALK inhibitor–naïve patients is recruiting participants (ALTA-1L). It will be interesting to see if brigatinib can achieve a front-line indication.

Starting the case patient on crizotinib is well within the treatment guidelines. One may consider ceritinib or alectinib in the first-line setting, but both TKIs can be reserved upon disease progression. We would recommend a repeat biopsy at that point to look for resistant mechanisms, as certain secondary ALK mutations may be rescued by certain next-generation ALK inhibitors. For instance, the F1174V mutation has been reported to confer resistance to ceritinib but sensitivity to alectinib, while the opposite is true for I1171T. The G1202R mutation is resistant to ceritinib, alectinib, and brigatinib, but lorlatinib, a third-generation ALK inhibitor, has shown activity against this mutation.⁷⁹ Furthermore, brain metastasis represents a treatment challenge for patients with ALK rearrangements. It is also an efficacy measure of next-generation ALK inhibitors, all of which have demonstrated better central nervous system activity than crizotinib.^69,78,80 If the case patient were found to have brain metastasis at the initial diagnosis, either ceritinib or alectinib would be a reasonable choice since crizotinib has limited penetration of blood-brain barrier.⁸¹

ROS1 REARRANGEMENTS

CASE PRESENTATION 3

A 66-year-old Chinese woman who is a non-smoker with a past medical history of hypertension and hypothyroidism presents to the emergency department for worsening lower back pain. Initial workup includes x-ray of the lumbar spine followed by MRI with contrast, which shows a soft tissue mass at L3-4 without cord compression. CT of the chest, abdomen, and pelvis with contrast shows a 7-cm right hilar mass, bilateral small lung nodules, mediastinal lymphadenopathy, and multiple lytic lesions in ribs, lumbar spine, and pelvis. MRI-brain with and without contrast is negative for malignancy. She undergoes endo-bronchial ultrasound and biopsy of the right hilar mass, which shows poorly differentiated adenocarcinoma. While waiting for the result of the molecular analysis, the patient undergoes palliative radiation therapy to L2-5 with good pain relief. She is discharged from the hospital and presents to your clinic for follow up. Molecular analysis now reveals ROS1 rearrangement with CD74-ROS1 fusion.

• What treatment plan should be put in place for this patient?

FIRST-LINE THERAPY FOR ROS1 REARRANGEMENTS

Approximately 2.4% of lung adenocarcinomas harbor ROS1 rearrangements.⁸² This distinct genetic alteration occurs more frequently in NSCLC patients who are younger, female, and never-smokers, and who have adenocarcinomas.⁸ It has been shown that ROS1 rearrangements rarely overlap with other genetic alterations including KRAS mutations, EGFR mutations, and ALK rearrangements.⁸³ As a receptor tyrosine kinase, ROS1 is similar to ALK and insulin receptor family members.⁸⁴ Crizotinib, which targets ALK, ROS1, and c-MET, was approved by the FDA on March 11, 2016, for the treatment of metastatic ROS1-rearranged NSCLC.⁸⁵ The approval was based on a phase 2 expansion cohort of the original phase 1 study. Among 50 US patients enrolled in this expansion cohort, 3 had complete responses and 33 had partial responses with ORR of 72% (95% CI 58% to 84%). Median PFS was 19.2 months (95% CI 14.4 months to NR) and median duration of response (DOR) was 17.6 months (95% CI 14.5 months to NR).⁸⁶ During longer follow-up, independent radiology review confirmed high ORR of 66% and median DOR of 18.3 months.⁸⁵

Interestingly, no companion diagnostic assay has been approved for the detection of ROS1 rearrangements with the approval of crizotinib. In the United States, break apart FISH is the most common detection method. In fact, in the above mentioned phase 2 study, ROS1 rearrangements were detected in 49 out of 50 patients by this method.⁸⁶ FISH can be technically challenging when dealing with high volume and multiple targets. Reverse transcriptase-PCR is another detection method, but it requires knowledge of the fusion partners. To date, at least 14 ROS1 fusion partners have been reported, with CD74 being the most common.⁸⁷ NGS with appropriate design and validation can also be used to detect ROS1 rearrangements.

For the case patient, the recommendation would be to start her on crizotinib at 250 mg twice daily. Monitoring for vision disturbance, gastrointestinal complaints, and edema is warranted. Because the estimated onset of response is around 7.9 weeks,⁸⁶ plans should be made to repeat her scans in approximately 2 months.

BRAF V600E MUTATIONS

CASE PRESENTATION 4

A 71-year-old Caucasian man with a past medical history of hypertension, dyslipidemia, and ischemic cerebrovascular accident without residual deficits was diagnosed with stage IV adenocarcinoma of the lung about 8 months ago. He has a 40 pack-year smoking history and quit smoking when he was diagnosed with lung cancer. His disease burden involved a large mediastinal mass, scattered pleural nodules, multiple lymphadenopathy, and several soft tissue masses. His outside oncologist started him on chemotherapy containing carboplatin and pemetrexed for 6 cycles followed by maintenance pemetrexed. The most recent restaging scans show disease progression with enlarging soft tissue masses and several new lytic bone lesions. MRI-brain with and without contrast shows 2 subcentimeter enhancing lesions. He transferred care to you approximately 4 weeks ago. You ordered a repeat biopsy of 1 of the enlarging soft tissue masses. Molecular analysis revealed BRAF V600E mutation. In the interim, he underwent stereotactic radiosurgery for the 2 brain lesions without any complications. The patient is now in your clinic for follow up.

• What would be your recommended systemic treatment?

TARGETED THERAPIES FOR BRAF V600E MUTATION

BRAF mutations were first recognized as activating mutations in advanced melanomas, with BRAF V600E, resulting from the substitution of glutamic acid for valine at amino acid 600, being the most common. BRAF plays an important role in the mitogen-activated protein kinase (MAPK) signaling pathway. Briefly, the activation of MAPK pathway occurs upon ligand binding of receptor tyrosine kinases, which then involves RAS/BRAF/MEK/ERK in a stepwise manner, ultimately leading to cell survival. BRAF mutations have been increasingly recognized also as driver mutations in NSCLC.^9–12 They can be detected by PCR or NGS method. The characteristics of NSCLC patients harboring BRAF mutations have been described by various groups.^9–12 For instance, 1 case series showed that the incidence was 2.2% among patients with advanced lung adenocarcinoma; 50% of mutations were V600E, while G469A and D594G accounted for the remaining 39% and 11% of patients, respectively. All patients were either current or former smokers. The median OS of patients with BRAF mutations in this case series was NR, while it was 37 months for patients with EGFR mutations (P = 0.73) and NR for patients with ALK rearrangements (P = 0.64).⁹

For patients with BRAF V600E–mutant NSCLC who have progressed on platinum-based chemotherapy, the combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) may represent a new treatment paradigm. This was illustrated in a phase 2, nonrandomized, open-label study. A total of 57 patients were enrolled and 36 patients (63.2% [95% CI 49.3% to 75.6%]) achieved an overall response by investigator assessment, the trial’s primary end point. Disease control rate was 78.9% (95% CI 66.1% to 88.6%), with 4% complete response, 60% partial response, and 16% stable disease. PFS was 9.7 months (95% CI [6.9 to 19.6 months]). The safety profile was comparable to what had been observed in patients with melanoma treated with this regimen. More specifically, 56% of patients on this trial reported serious AEs, including pyrexia (16%), anemia (5%), confusional state (4%), decreased appetite (4%), hemoptysis (4%), hypercalcemia (4%), nausea (4%), and cutaneous squamous cell carcinoma (4%). In addition, neutropenia (9%) and hyponatremia (7%) were the most common grade 3-4 AEs.¹⁶

The case patient has experienced disease progression after 1 line of platinum-based chemotherapy, so the combination of dabrafenib and trametinib would be a robust systemic treatment option. dabrafenib as a single agent has also been studied in BRAF V600E–mutant NSCLC in a phase 2 trial. The overall response by investigator assessment among 84 patients was 33% (95% CI 23% to 45%).¹⁴ Vemurafenib, another oral BRAF TKI, has demonstrated efficacy for NSCLC patients harboring BRAF V600E mutation. In the cohort of 20 patients with NSCLC, the response rate was 42% (95% CI 20% to 67%) and median PFS was 7.3 months (95% CI 3.5 to 10.8 months).¹³ Patients with non-V600E mutations have shown variable responses to targeted therapies. MEK TKIs may be considered in this setting; however, the details of this discussion are beyond the scope of this review.

CONCLUSION

The management of advanced NSCLC with driver mutations has seen revolutionary changes over the past decade. Tremendous research has been done in order to first understand the molecular pathogenesis of NSCLC and then discover driver mutations that would lead to development of targeted therapies with clinically significant efficacy as well as tolerability. More recently, increasing efforts have focused on how to conquer acquired resistance in patients with disease progression after first-line TKIs. The field of EGFR-mutant NSCLC has set a successful example, but the work is nowhere near finished. The goals are to search for more driver mutations and to design agents that could potentially block cell survival signals once and for all.

INTRODUCTION

The incidence of cutaneous melanoma has increased over the past 2 decades, with SEER estimates indicating that the number of new cases of melanoma diagnosed annually rose from 38,300 in 1996 to 76,000 in 2016.¹ Among persons younger than 50 years, the incidence is higher in females, and younger women (aged 15–39 years) are especially vulnerable.² Among persons older than 50, melanoma incidence in men is nearly twice that of women, in whom melanomas are often thicker and often associated with worse outcomes.^1,2 Approximately 85% of melanomas are diagnosed at early stages when surgery is curative, but the lifetime probability of developing invasive disease is 3% in men and 2% in women.

Prior to the advent of effective immunotherapies and targeted therapies, melanoma was often managed with chemotherapy, which had dismal response rates and commensurately poor outcomes. Advances in the understanding of the molecular etiopathogenesis and immune escape responses of cutaneous metastatic melanoma have transformed therapeutic approaches. Specifically, improved understanding of the genetic mutations driving melanoma tumorigenesis coupled with insights into mechanisms of tumor-mediated immune evasion resulted in development of inhibitors of mitogen-activated protein kinases (MAPK; BRAF and MEK) along with inhibitors of negative regulatory immune checkpoints (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4] and programmed cell death-1 [PD-1]). In this review, we discuss the role of immune therapy, targeted therapy, and combinations of these in the treatment of metastatic cutaneous melanoma. We limit the immuno-therapy discussion to approved CTLA-4/PD-1 inhibitors and the targeted therapy discussion to approved BRAF/NRAS/MEK inhibitors and do not discuss non-checkpoint immunotherapies including cytokines (HD IL-2), vaccines, or adoptive T-cell approaches. Interested readers are directed to other excellent works covering these important topics.^26–29

DEVELOPMENT OF TARGETED AND NOVEL IMMUNE THERAPIES

For many years the degree of ultraviolet (UV) light exposure was considered the sole major risk factor for melanoma oncogenesis, even though its mechanism was largely unknown.³ However, clinical observations regarding the occurrence of melanoma on less exposed areas (trunk and limbs) in individuals with intermittent sun exposure led to the proposition that melanomas that arose in younger patients with intermittent sun exposure were distinct from melanomas that arose in older patients in association with markers of chronic sun exposure—the “divergent pathway” hypothesis.³ Critical to this understanding were whole-exome sequencing data from multiple groups, including The Cancer Genome Atlas, that identified patterns of mutations in oncogenic drivers that were distinct in patients with and without chronically sun-damaged (CSD) skin.^4–7 It is now clear that based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma have distinct clinico-pathological characteristics and are associated with different driver mutations. CSD melanomas typically arise in older patients on sun-exposed areas (head/neck, dorsal surfaces of distal extremities) and are associated with particular driver mutations (BRAF non-V600E, NRAS, NF1, or KIT) and genetic signatures of UV-induced DNA damage (G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in younger (< 55 years) patients on intermittently sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K driver mutations and often lack genetic signatures of UV mutagenesis.

Identification of driver mutations in components of the MAPK pathway, including BRAF and NRAS, facilitated the development of targeted inhibitors. The BRAF inhibitors vemurafenib and dabrafenib have been shown in pivotal phase 3 studies to significantly improve overall and progression-free survival in patients with metastatic melanoma compared with chemotherapy and garnered regulatory approval (vemurafenib, BRIM-3;^8,9 dabrafenib, BREAK-3¹⁰). Concomitant MEK and BRAF inhibition extends the duration of benefit by preventing downstream kinase activation in the MAPK pathway. Notably, concomitant MEK inhibition alters the side-effect profile of BRAF inhibitors, with reduced incidence of keratoacanthomas and cutaneous squamous cell carcinomas that are attributable to on-target, off-tumor effects of BRAF inhibitors. Combined BRAF and MEK inhibition (vemurafenib/cobimetinib and dabrafenib/trametinib) further improved overall and progression-free survival compared to single-agent BRAF inhibition in phase 3 studies (COMBI-d,¹¹ COMBI-v,¹² and coBRIM¹³). Although often deep, the responses seen with the use of targeted kinase inhibitors are not often durable, with the vast majority of patients progressing after 12 to 15 months of therapy.In parallel, work primarily done in murine models of chronic viral infection uncovered the role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune responses. These efforts clarified that tumor-mediated immune suppression primarily occurs through enhancement of inhibitory signals via the negative T-cell immune checkpoints CTLA-4 or PD-1.^14,15 Blockade of negative T-cell immune checkpoints resulted in activation of the adaptive immune system, resulting in durable anti-tumor responses as demonstrated in studies of the CTLA-4 inhibitor ipilimumab (CA184-020¹⁶ and CA184-024¹⁷) and the PD-1 inhibitors nivolumab (CA209-003,¹⁸ CheckMate 037,¹⁹ and CheckMate 066²⁰) and pembrolizumab (KEYNOTE-001²¹ and KEYNOTE-006²²). Compared to the deep but short-lived responses seen with targeted kinase inhibitors, patients treated with CTLA-4 or PD-1 immune checkpoint blockade often developed durable responses that persisted even after completion of therapy. Combined CTLA-4 and PD-1 blockade results in greater magnitude of response with proportionately increased toxicity.^23–25

IMMUNOTHERAPY

CTLA-4 AND PD-1 IMMUNE CHECKPOINT INHIBITORS

The novel success of immunotherapy in recent decades is largely attributable to improved understanding of adaptive immune physiology, specifically T-cell activation and regulation. T-cell activation requires 2 independent signaling events: it is initiated upon recognition of the antigen-MHC class II-receptor complex on antigen-presenting cells (APC), and requires a secondary co-stimulatory interaction of CD80/CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event, T-cells enter an anergic state.^30–32 Upon successful signaling and co-stimulation, newly activated T-cells upregulate CTLA-4, which can bind to B7 molecules with a nearly 100-fold greater affinity than CD28.^33,34 Unlike CD28, CTLA-4 engagement negatively regulates T-cell activation. The opposing signals produced by CD28 and CTLA-4 are integrated by the T-cell to determine eventual response to activation, and provide a means by which T-cell activation is homeostatically regulated to prevent exaggerated physiologic immune responses.³⁵ It was hypothesized that CTLA-4 blockade would permit T-cell activation, which is thwarted in the tumor microenvironment by tumor-mediated CTLA-4 engagement, thereby unleashing an anti-tumor immune response.³⁶

PD-1 is a member of the CD28 and CTLA-4 immunoglobulin super family and, similar to CTLA-4, binds activated T-cells. PD-1 has 2 ligands on activated T-cells: PD-L1 and PD-L2.³⁷ PD-L1 is constitutively expressed by a variety of immune and non-immune cells, particularly in inflammatory environments including tumor microenvironments, in response to the release of inflammatory cytokines such as interferon (IFN)-γ.^37,38 Conversely, PD-L2 is only minimally expressed constitutively, although its expression on immune and non-immune cells can be induced by similar cues from inflammatory microenvironments. PD-L1 and PD-L2 cross-compete for binding to PD-1, with PD-L2 exhibiting 2- to 6-fold greater relative affinity than PD-L1.³⁹ PD-L1/PD-1 binding results in phosphorylation of 2 tyrosinases in the intracellular portion of PD-1, which contains immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). PD-1 ITSM subsequently recruits either of 2 SH2-domain–containing protein tyrosine phosphatases: SHP-1 and SHP-2. SHP-2 signaling suppresses PI3K/Akt activation, down-regulates Bcl-xL, and suppresses expression of multiple transcription factors that mediate T-cell effector function including GATA-3, Eomes, and T-bet.^40–42 The net effect of PD-L1/PD-1 engagement is to suppress T-cell proliferation, cytokine production, cytolytic function, and survival. Unlike CTLA-4, which primarily affects the priming phase of naive T-cell activation, PD-1 chiefly regulates the effector phase of T-cell function. Furthermore, because PD-L1/PD-L2 expression is limited to inflammatory microenvironments, the effects of PD-1 are less generalized than those of CTLA-4.

SINGLE AGENT ACTIVITY OF CTLA-4 AND PD-1 INHIBITORS

Ipilimumab (MDX-010) is a human IgG1 monoclonal antibody shown to inhibit CTLA-4.⁴³ Early studies tested different formulations (transfectoma-derived and hybridoma-derived), doses, and schedules of ipilimumab primarily in patients with advanced refractory melanoma.^44–46 Although responses were infrequent, responding patients experienced durable remissions at 1- and 2-year time points. Notably, in a foreshadowing of changes to response criteria used to evaluate these agents, several treated patients who initially had radiographically stable disease upon completion of therapy subsequently experienced a gradual decline in tumor burden.

Ipilimumab was subsequently evaluated in 2 phase 3 trials. The first study (MDX010-020/CA184-020), which involved 676 HLA-A*0201–positive patients with advanced melanoma, compared ipilimumab 3 mg/kg every 3 weeks for 4 doses either singly or in combination with gp100 vaccine with a gp100-only control arm.¹⁶ Ipilimumab administration resulted in objective responses in 11% of patients and improved progression-free and overall survival compared to gp100 alone. Of note, ipilimumab monotherapy was superior to ipilimumab/gp100 combination, possibly related to timing of vaccine in relation to ipilimumab. A confirmatory study (CA184-024) compared a higher dose of ipilimumab (10 mg/kg) in combination with dacarbazine to dacarbazine monotherapy in previously untreated melanoma and was positive.¹⁷ Given the lack of augmented efficacy with the higher (10 mg/kg) dose, ipilimumab received regulatory approval in 2011 for the treatment of melanoma at the lower dose: 3 mg/kg administered every 3 weeks for 4 doses (Table 1). Survival data was strikingly similar to patterns observed in prior phase 2 studies, with survival curves plateauing after 2 years at 23.5% to 28.5% of treated patients. Pooled survival data from prospective and retrospective studies of ipilimumab corroborate the plateau of 22% (26% treated; 20% untreated) reached at year 3 regardless of prior therapy or ipilimumab dose, underscoring the durability of long-term survival in ipilimumab-treated patients.⁴⁷ Ipilimumab administration resulted in an unusual spectrum of toxicities including diarrhea, rash, hepatitis, and hypophysitis (termed immune-related adverse events, or irAEs) in up to a third of patients.

Pembrolizumab and nivolumab are humanized IgG4 monoclonal antibodies that target the PD-1 receptor found on activated T cells, B cells, and myeloid cells. Pembrolizumab and nivolumab are engineered similarly: by immunizing transgenic mice with recombinant human PD-1-Fc protein and subsequently screening murine splenic cells fused with myeloma cells for hybridomas producing antibodies reactive to PD-1-Fc.^48,49 Unlike IgG1, the IgG4 moiety neither engages Fc receptors nor activates complement, avoiding cytotoxic effects of the antibody upon binding to the T cells that it is intended to activate. Both pembrolizumab and nivolumab bind PD-1 with high affinity and specificity, effectively inhibiting the interaction between PD-1 and ligands PD-L1 and PD-L2.

Nivolumab was first studied in a phase 1 study (CA209-003) of 296 patients with advanced cancers who received 1, 3, or 10 mg/kg administered every 2 weeks.¹⁸ Histologies tested included melanoma, non–small-cell lung cancer (NSCLC), renal-cell cancer (RCC), castration-resistant prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma and RCC and unusually in NSCLC, including in both squamous and non-squamous tumors. Objective responses were noted in 41% of the 107 melanoma patients treated at 3 mg/kg. Survival was improved, with 1- and 2-year survival rates of 62% and 43% at extended follow up.⁵⁰

Subsequently, nivolumab was compared to chemotherapy in a pair of phase 3 studies involving both previously untreated (Checkmate 066) and ipilimumab/BRAF inhibitor–refractory (CheckMate 037) patients.^19,20 In both studies, nivolumab produced durable responses in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower with nivolumab. The depth and magnitude of responses observed led to regulatory approval for nivolumab in both indications (untreated and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.

Pembrolizumab was first evaluated in a phase 1 study of 30 patients with a variety of solid organ malignancies in which no dose-limiting toxicities were observed and no defined maximal tolerated dose was reached.⁵¹ Per protocol, maximal administered dose was 10 mg/kg every 2 weeks. Following startling responses including 2 complete responses of long duration, pembrolizumab was evaluated in a large phase 1 study (KEYNOTE-001) of 1260 patients that evaluated 3 doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in separate melanoma and NSCLC substudies.²¹ Both ipilimumab-naïve and ipilimumab-treated patients were enrolled in the melanoma substudy. Objective responses were seen in 38% ofpatients across all 3 dosing schedules and were similar in both ipilimumab-naïve and ipilimumab-treated patients. Similar to nivolumab, most responders experienced durable remissions.

Pembrolizumab was subsequently compared to ipilimumab in untreated patients (KEYNOTE-006) in which patients were randomly assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2 weeks and pembrolizumab 10 mg/kg every 3 weeks.²² Response rates were greater with pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates of treatment-related adverse events requiring discontinuation of study drug were much lower with pembrolizumab than ipilimumab. This trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for second-line treatment of melanoma in 2014, and updated this to include a first-line indication in 2015 (Table 1).

EFFICACY OF COMBINED CTLA-4 AND PD-1 INHIBITION

Preclinical studies demonstrated that PD-1 blockade was more effective than CTLA-4 blockade and combination PD-1/CTLA-4 blockade was synergistic, with complete rejection of tumors in approximately half of the treated animals.¹⁴ This hypothesis was evaluated in a phase 1 study that explored both concurrent and sequential combinations of ipilimumab and nivolumab along with increasing doses of both agents in PD-1/CTLA-4–naïve advanced melanoma.²³ Responses were greater in the concurrent arm (40%) than in the sequential arm (20%) across dose-levels with a small fraction of patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor burden.

The superiority of ipilimumab/nivolumab combination to ipilimumab monotherapy was demonstrated in a randomized blinded phase 2 study (CheckMate 069).²⁴ Of the 4 different ipilimumab/nivolumab doses explored in the phase 1 study (3 mg/kg and 0.3 mg/kg, 3 mg/kg and 1 mg/kg, 1 mg/kg and 3 mg/kg, 3 mg/kg and 3 mg/kg), ipilimumab 3 mg/kg and nivolumab 1 mg/kg (followed by nivolumab 3 mg/kg) was compared to ipilimumab and nivolumab-matched placebo. Responses were significantly greater with dual PD-1/CTLA-4 blockade compared to CTLA-4 blockade alone (59% versus 11%). Concurrently, a 3-arm randomized phase 3 study compared the same dose of ipilimumab/nivolumab to ipilimumab and nivolumab in previously untreated advanced melanoma (CheckMate 067).²⁵ Similar to CheckMate 069, CheckMate 067 demonstrated that ipilimumab/nivolumab combination resulted in more profound responses (58%) than either ipilimumab (19%) or nivolumab (44%) alone. Toxicity, primarily diarrhea, fatigue, pruritus, and rash, was considerable in the combination arm (55% grade 3/4 adverse events) and resulted in treatment discontinuation in 30% of patients. The profound and durable responses observed led to accelerated approval of ipilimumab/nivolumab combination in 2015 (Table 1).

Efforts to improve the toxicity/benefit ratio of ipilimumab/nivolumab combination have centered around studying lower doses and/or extended dosing schedules of ipilimumab, including ipilimumab 1 mg/kg every 6 or 12 weeks with nivolumab dosed at 3 mg/kg every 2 weeks or 480 mg every 4 weeks. Promising data from a first-line study in NSCLC (CheckMate 012) support the evaluation of nivolumab in combination with lower-dosed ipilimumab (1 mg/kg every 6 or 12 weeks).⁵² This approach is being tested against platinum doublet chemotherapy in a confirmatory phase 3 study in NSCLC (CheckMate 227).

TARGETED THERAPY

MAPK KINASE PATHWAY IN MELANOMA TUMORIGENESIS

The MAPK pathway mediates cellular responses to growth signals. RAF kinases are central mediators in the MAPK pathway and exert their effect primarily through MEK phosphorylation and activation following dimerization (hetero- or homo-) of RAF molecules. As a result, RAF is integral to multiple cellular processes, including transcriptional regulation, cellular differentiation, and cell proliferation. MAPK pathway activation is a common event in many cancers, primarily due to activating mutations in BRAF or RAS. Alternatively, MAPK pathway activation can occur in the absence of activating mutations in BRAF or NRAS through down-regulation of MAPK pathway inhibitory proteins (RAF-1 inhibitory protein or SPRY-2), C-MET overexpression, or activating mutations in non-BRAF/NRAS kinases including CRAF, HRAS, and NRAS.^53,54

Somatic point mutations in BRAF are frequently observed (37%–50%) in malignant melanomas and at lower frequency in a range of human cancers including NSCLC, colorectal cancer, papillary thyroid cancer, ovarian cancer, glioma, and gastrointestinal stromal tumor.^6,55,56BRAF mutations in melanoma typically occur within the activation segment of the kinase domain (exon 15). Between 80% and 90% of activating mutations result in an amino acid substitution of glutamate (E) for valine (V) at position 600: V600E.^57,58 V600E mutations are true oncogenic drivers, resulting in increased kinase activity with demonstrable transformational capacity in vitro. BRAF mutations are usually mutually exclusive, with tumors typically containing no other driver mutations in NRAS, KIT, NF1, or other genes.

NRAS mutations are less common than BRAF mutations, having a reported frequency of 13% to 25% in melanoma.⁴NRAS mutations generally occur within the P-loop region of the G domain (exon 2), or less commonly in the switch II region of the G domain (exon 3). Most NRAS exon 2 mutations comprise amino acid substitutions at position 61 from glutamine (Q) to arginine (R; 35%), lysine (K; 34%) and less often to glutamate (E), leucine (L), or proline (P). Preclinical data suggest that NRAS mutations paradoxically stimulate the MAPK pathway and thus enhance tumor growth in vitro.^59,60 Several important phenotypic differences distinguish NRAS- from BRAF-mutated melanoma. NRAS-mutated tumors are typically associated with increasing age and CSD skin, while BRAF-mutated tumors arise in younger patients in non-CSD skin. A large population-based study suggested that NRAS-mutated melanomas were associated with mitoses and lower tumor infiltrating lymphocytes (TIL) grade, and arose in anatomic sites other than the head/neck, while BRAF-mutated tumors were associated with mitoses and superficial spreading histology.⁶¹ Although the lower TIL grade seen with NRAS-mutated melanomas suggests a more immunosuppressed microenvironment and argues for poorer responses to immune therapies, clinical studies comparing responses to immunotherapies in various categories of driver mutations provide conflicting results for the prognostic role of NRAS mutations in relation to immune checkpoint blockade and other immune therapies.^62–64

NF1 represents the third known driver in cutaneous melanoma, with mutations reported in 12% of cases.^6,7NF1 encodes neurofibromin, which has GTPase activity and regulates RAS proteins; NF1 loss results in increased RAS.⁶⁵ Unlike BRAF or NRAS, which are usually mutually exclusive, NF1 mutations in melanoma can occur singly or in combination with either BRAF or NRAS mutations. In these settings, NF1 mutations are associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.⁶⁶

MAPK PATHWAY INHIBITION SINGLY AND IN COMBINATION

Although multiple MEK 1/2 inhibitors (AS703026, AZD8330/ARRY-704, AZD6244, CH5126766, CI-1040, GSK1120212, PD0325901, RDEA119, and XL518) and RAF inhibitors (ARQ 680, GDC-0879, GSK2118436, PLX4032, RAF265, sorafenib, XL281/BMS-908662) were developed, the initial evaluation of MAPK pathway inhibitors in advanced human cancers began with CI-1040. Preclinical data suggested that CI-1040 potently and selectively inhibited both MEK1 and MEK2, but phase 1 and 2 human trial results were disappointing, likely because these trials were not selectively enriched for NRAS/BRAF–mutated tumors or cancers in which these oncogenic mutations were most commonly detected, such as melanoma.^67,68 The subsequent evaluation of selumetinib (AZD6244/ARRY-142886) in a phase 2 study was also negative. Although investigators enrolled a presumably enriched population (cutaneous melanoma), the incidence of NRAS/BRAF–mutated tumors was not ascertained to determine this, but rather assumed, which led to a discrepancy between the assumed (prestudy) and observed (on-study) proportions of BRAF/NRAS mutations that was not accounted for in power calculations.^69,70 Lessons learned from these earlier misadventures informed the current paradigm of targeted therapy development: (1) identification of a highly specific and potent inhibitor through high-throughput screening; (2) establishment of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in unselected patients; (3) confirmation of RP2D in selected tumor types enriched for target of interest; and (4) confirmatory study against standard comparator to seek regulatory approval.

Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

CONCLUSION AND FUTURE DIRECTIONS

Prior to 2011, the only approved agents for the treatment of advanced melanoma were dacarbazine and high-dose interleukin-2. Since 2011, drug approvals in melanoma have proceeded at a frenetic pace unmatched in any other disease. The primary events underlying this are advances in our understanding of the gene mutation landscape driving melanoma tumorigenesis, accompanied by insights into the means by which tumors circumvent the induction of effective anti-tumor T-cell responses. These insights have resulted in the development of inhibitors targeting MAPK pathway kinases BRAF, MEK, and NRAS), KIT, and regulatory immune checkpoints (CTLA-4 and PD-1). Although BRAF/MEK inhibition results in profound reductions and even occasional complete responses in patients, these responses are typically short lived, rarely lasting more than 9 to 11 months; the encorafenib/binimetinib combination may improve that duration marginally. However, the signature therapeutic advance in melanoma of the past decade is immunotherapy, particularly the development of inhibitors of CTLA-4 and PD-1 immune checkpoints. With these agents, significant proportions of treated patients remain free of progression off-therapy (ipilimumab 23%; nivolumab 34%; pembrolizumab 35%; ipilimumab/nivolumab 64%), and some patients can be successfully re-induced after delayed progression. Separately, the high response rates observed with the use of KIT inhibitors in CML and GIST have not been observed in KIT mutated/amplified melanoma and development of agents in this space has been limited. The challenges ahead center around identifying predictive biomarkers and circumventing primary or acquired resistance, with the eventual goal of producing durable remissions in the majority of treated patients.

Our improved understanding of the mechanisms of acquired resistance to BRAF/MEK inhibitors suggests that anti-tumor activity may be achieved by targeting multiple pathways, possibly with combination regimens comprising other inhibitors and/or immunotherapy. Preclinical data supports the use of combination strategies targeting both ERK and PI3K/mTOR to circumvent acquired resistance.⁹⁰ Ongoing studies are evaluating combinations with biguanides (metformin: NCT02143050 and NCT01638676; phenformin: NCT03026517), HSP90 inhibitors (XL888: NCT02721459; AT13387: NCT02097225), and decitabine (NCT01876641).

One complexity affecting management of resistance in the targeted therapy landscape remains tumor heterogeneity, particularly intra- and intertumoral heterogeneity, which may explain the apparent contradiction between continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting slower progression of resistant tumors on cessation of BRAF inhibitors.^91–94 These data provide a rationale to investigate intermittent dosing regimens with BRAF/MEK inhibitors; several studies exploring this approach are ongoing (NCT01894672 and NCT02583516).

Given the specificity, adaptability, and memory response associated with immunotherapy, it is likely that these agents will be used to treat the majority of patients regardless of mutational status. Hence, identifying predictive biomarkers of response to immune checkpoint inhibitors is vital. The presence of CD8+ T-cell infiltrate and IFN-γ gene signature, which indicate an “inflamed” tumor microenvironment, are highly predictive of clinical benefit from PD-1 inhibitors.^95,96 However, not all PD-1 responders have “inflamed” tumor microenvironments, and not all patients with an “inflamed” tumor microenvironment respond to immune checkpoint inhibitors. The complexity of the immune system is reflected in the multiple non-redundant immunologic pathways, both positive and negative, with checkpoints and ligands that emerge dynamically in response to treatment. Given the dynamic nature of the immune response, it is unlikely that any single immunologic biomarker identified pre-treatment will be completely predictive. Rather, the complexity of the biomarker approach must match the complexity of the immune response elicited, and will likely incorporate multifarious elements including CD8+ T-cell infiltrate, IFN-γ gene signature, and additional elements including microbiome, genetic polymorphisms, and tumor mutation load. The goal is to use multiple markers to guide development of combinations and then, depending on initial response, to examine tumors for alterations to guide decisions about additional treatment(s) to improve responses, with the eventual goal being durable clinical responses for all patients.

INTRODUCTION

The incidence of cutaneous melanoma has increased over the past 2 decades, with SEER estimates indicating that the number of new cases of melanoma diagnosed annually rose from 38,300 in 1996 to 76,000 in 2016.¹ Among persons younger than 50 years, the incidence is higher in females, and younger women (aged 15–39 years) are especially vulnerable.² Among persons older than 50, melanoma incidence in men is nearly twice that of women, in whom melanomas are often thicker and often associated with worse outcomes.^1,2 Approximately 85% of melanomas are diagnosed at early stages when surgery is curative, but the lifetime probability of developing invasive disease is 3% in men and 2% in women.

Prior to the advent of effective immunotherapies and targeted therapies, melanoma was often managed with chemotherapy, which had dismal response rates and commensurately poor outcomes. Advances in the understanding of the molecular etiopathogenesis and immune escape responses of cutaneous metastatic melanoma have transformed therapeutic approaches. Specifically, improved understanding of the genetic mutations driving melanoma tumorigenesis coupled with insights into mechanisms of tumor-mediated immune evasion resulted in development of inhibitors of mitogen-activated protein kinases (MAPK; BRAF and MEK) along with inhibitors of negative regulatory immune checkpoints (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4] and programmed cell death-1 [PD-1]). In this review, we discuss the role of immune therapy, targeted therapy, and combinations of these in the treatment of metastatic cutaneous melanoma. We limit the immuno-therapy discussion to approved CTLA-4/PD-1 inhibitors and the targeted therapy discussion to approved BRAF/NRAS/MEK inhibitors and do not discuss non-checkpoint immunotherapies including cytokines (HD IL-2), vaccines, or adoptive T-cell approaches. Interested readers are directed to other excellent works covering these important topics.^26–29

DEVELOPMENT OF TARGETED AND NOVEL IMMUNE THERAPIES

For many years the degree of ultraviolet (UV) light exposure was considered the sole major risk factor for melanoma oncogenesis, even though its mechanism was largely unknown.³ However, clinical observations regarding the occurrence of melanoma on less exposed areas (trunk and limbs) in individuals with intermittent sun exposure led to the proposition that melanomas that arose in younger patients with intermittent sun exposure were distinct from melanomas that arose in older patients in association with markers of chronic sun exposure—the “divergent pathway” hypothesis.³ Critical to this understanding were whole-exome sequencing data from multiple groups, including The Cancer Genome Atlas, that identified patterns of mutations in oncogenic drivers that were distinct in patients with and without chronically sun-damaged (CSD) skin.^4–7 It is now clear that based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma have distinct clinico-pathological characteristics and are associated with different driver mutations. CSD melanomas typically arise in older patients on sun-exposed areas (head/neck, dorsal surfaces of distal extremities) and are associated with particular driver mutations (BRAF non-V600E, NRAS, NF1, or KIT) and genetic signatures of UV-induced DNA damage (G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in younger (< 55 years) patients on intermittently sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K driver mutations and often lack genetic signatures of UV mutagenesis.

Identification of driver mutations in components of the MAPK pathway, including BRAF and NRAS, facilitated the development of targeted inhibitors. The BRAF inhibitors vemurafenib and dabrafenib have been shown in pivotal phase 3 studies to significantly improve overall and progression-free survival in patients with metastatic melanoma compared with chemotherapy and garnered regulatory approval (vemurafenib, BRIM-3;^8,9 dabrafenib, BREAK-3¹⁰). Concomitant MEK and BRAF inhibition extends the duration of benefit by preventing downstream kinase activation in the MAPK pathway. Notably, concomitant MEK inhibition alters the side-effect profile of BRAF inhibitors, with reduced incidence of keratoacanthomas and cutaneous squamous cell carcinomas that are attributable to on-target, off-tumor effects of BRAF inhibitors. Combined BRAF and MEK inhibition (vemurafenib/cobimetinib and dabrafenib/trametinib) further improved overall and progression-free survival compared to single-agent BRAF inhibition in phase 3 studies (COMBI-d,¹¹ COMBI-v,¹² and coBRIM¹³). Although often deep, the responses seen with the use of targeted kinase inhibitors are not often durable, with the vast majority of patients progressing after 12 to 15 months of therapy.In parallel, work primarily done in murine models of chronic viral infection uncovered the role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune responses. These efforts clarified that tumor-mediated immune suppression primarily occurs through enhancement of inhibitory signals via the negative T-cell immune checkpoints CTLA-4 or PD-1.^14,15 Blockade of negative T-cell immune checkpoints resulted in activation of the adaptive immune system, resulting in durable anti-tumor responses as demonstrated in studies of the CTLA-4 inhibitor ipilimumab (CA184-020¹⁶ and CA184-024¹⁷) and the PD-1 inhibitors nivolumab (CA209-003,¹⁸ CheckMate 037,¹⁹ and CheckMate 066²⁰) and pembrolizumab (KEYNOTE-001²¹ and KEYNOTE-006²²). Compared to the deep but short-lived responses seen with targeted kinase inhibitors, patients treated with CTLA-4 or PD-1 immune checkpoint blockade often developed durable responses that persisted even after completion of therapy. Combined CTLA-4 and PD-1 blockade results in greater magnitude of response with proportionately increased toxicity.^23–25

IMMUNOTHERAPY

CTLA-4 AND PD-1 IMMUNE CHECKPOINT INHIBITORS

The novel success of immunotherapy in recent decades is largely attributable to improved understanding of adaptive immune physiology, specifically T-cell activation and regulation. T-cell activation requires 2 independent signaling events: it is initiated upon recognition of the antigen-MHC class II-receptor complex on antigen-presenting cells (APC), and requires a secondary co-stimulatory interaction of CD80/CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event, T-cells enter an anergic state.^30–32 Upon successful signaling and co-stimulation, newly activated T-cells upregulate CTLA-4, which can bind to B7 molecules with a nearly 100-fold greater affinity than CD28.^33,34 Unlike CD28, CTLA-4 engagement negatively regulates T-cell activation. The opposing signals produced by CD28 and CTLA-4 are integrated by the T-cell to determine eventual response to activation, and provide a means by which T-cell activation is homeostatically regulated to prevent exaggerated physiologic immune responses.³⁵ It was hypothesized that CTLA-4 blockade would permit T-cell activation, which is thwarted in the tumor microenvironment by tumor-mediated CTLA-4 engagement, thereby unleashing an anti-tumor immune response.³⁶

PD-1 is a member of the CD28 and CTLA-4 immunoglobulin super family and, similar to CTLA-4, binds activated T-cells. PD-1 has 2 ligands on activated T-cells: PD-L1 and PD-L2.³⁷ PD-L1 is constitutively expressed by a variety of immune and non-immune cells, particularly in inflammatory environments including tumor microenvironments, in response to the release of inflammatory cytokines such as interferon (IFN)-γ.^37,38 Conversely, PD-L2 is only minimally expressed constitutively, although its expression on immune and non-immune cells can be induced by similar cues from inflammatory microenvironments. PD-L1 and PD-L2 cross-compete for binding to PD-1, with PD-L2 exhibiting 2- to 6-fold greater relative affinity than PD-L1.³⁹ PD-L1/PD-1 binding results in phosphorylation of 2 tyrosinases in the intracellular portion of PD-1, which contains immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). PD-1 ITSM subsequently recruits either of 2 SH2-domain–containing protein tyrosine phosphatases: SHP-1 and SHP-2. SHP-2 signaling suppresses PI3K/Akt activation, down-regulates Bcl-xL, and suppresses expression of multiple transcription factors that mediate T-cell effector function including GATA-3, Eomes, and T-bet.^40–42 The net effect of PD-L1/PD-1 engagement is to suppress T-cell proliferation, cytokine production, cytolytic function, and survival. Unlike CTLA-4, which primarily affects the priming phase of naive T-cell activation, PD-1 chiefly regulates the effector phase of T-cell function. Furthermore, because PD-L1/PD-L2 expression is limited to inflammatory microenvironments, the effects of PD-1 are less generalized than those of CTLA-4.

SINGLE AGENT ACTIVITY OF CTLA-4 AND PD-1 INHIBITORS

Ipilimumab (MDX-010) is a human IgG1 monoclonal antibody shown to inhibit CTLA-4.⁴³ Early studies tested different formulations (transfectoma-derived and hybridoma-derived), doses, and schedules of ipilimumab primarily in patients with advanced refractory melanoma.^44–46 Although responses were infrequent, responding patients experienced durable remissions at 1- and 2-year time points. Notably, in a foreshadowing of changes to response criteria used to evaluate these agents, several treated patients who initially had radiographically stable disease upon completion of therapy subsequently experienced a gradual decline in tumor burden.

Ipilimumab was subsequently evaluated in 2 phase 3 trials. The first study (MDX010-020/CA184-020), which involved 676 HLA-A*0201–positive patients with advanced melanoma, compared ipilimumab 3 mg/kg every 3 weeks for 4 doses either singly or in combination with gp100 vaccine with a gp100-only control arm.¹⁶ Ipilimumab administration resulted in objective responses in 11% of patients and improved progression-free and overall survival compared to gp100 alone. Of note, ipilimumab monotherapy was superior to ipilimumab/gp100 combination, possibly related to timing of vaccine in relation to ipilimumab. A confirmatory study (CA184-024) compared a higher dose of ipilimumab (10 mg/kg) in combination with dacarbazine to dacarbazine monotherapy in previously untreated melanoma and was positive.¹⁷ Given the lack of augmented efficacy with the higher (10 mg/kg) dose, ipilimumab received regulatory approval in 2011 for the treatment of melanoma at the lower dose: 3 mg/kg administered every 3 weeks for 4 doses (Table 1). Survival data was strikingly similar to patterns observed in prior phase 2 studies, with survival curves plateauing after 2 years at 23.5% to 28.5% of treated patients. Pooled survival data from prospective and retrospective studies of ipilimumab corroborate the plateau of 22% (26% treated; 20% untreated) reached at year 3 regardless of prior therapy or ipilimumab dose, underscoring the durability of long-term survival in ipilimumab-treated patients.⁴⁷ Ipilimumab administration resulted in an unusual spectrum of toxicities including diarrhea, rash, hepatitis, and hypophysitis (termed immune-related adverse events, or irAEs) in up to a third of patients.

Pembrolizumab and nivolumab are humanized IgG4 monoclonal antibodies that target the PD-1 receptor found on activated T cells, B cells, and myeloid cells. Pembrolizumab and nivolumab are engineered similarly: by immunizing transgenic mice with recombinant human PD-1-Fc protein and subsequently screening murine splenic cells fused with myeloma cells for hybridomas producing antibodies reactive to PD-1-Fc.^48,49 Unlike IgG1, the IgG4 moiety neither engages Fc receptors nor activates complement, avoiding cytotoxic effects of the antibody upon binding to the T cells that it is intended to activate. Both pembrolizumab and nivolumab bind PD-1 with high affinity and specificity, effectively inhibiting the interaction between PD-1 and ligands PD-L1 and PD-L2.

Nivolumab was first studied in a phase 1 study (CA209-003) of 296 patients with advanced cancers who received 1, 3, or 10 mg/kg administered every 2 weeks.¹⁸ Histologies tested included melanoma, non–small-cell lung cancer (NSCLC), renal-cell cancer (RCC), castration-resistant prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma and RCC and unusually in NSCLC, including in both squamous and non-squamous tumors. Objective responses were noted in 41% of the 107 melanoma patients treated at 3 mg/kg. Survival was improved, with 1- and 2-year survival rates of 62% and 43% at extended follow up.⁵⁰

Subsequently, nivolumab was compared to chemotherapy in a pair of phase 3 studies involving both previously untreated (Checkmate 066) and ipilimumab/BRAF inhibitor–refractory (CheckMate 037) patients.^19,20 In both studies, nivolumab produced durable responses in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower with nivolumab. The depth and magnitude of responses observed led to regulatory approval for nivolumab in both indications (untreated and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.

Pembrolizumab was first evaluated in a phase 1 study of 30 patients with a variety of solid organ malignancies in which no dose-limiting toxicities were observed and no defined maximal tolerated dose was reached.⁵¹ Per protocol, maximal administered dose was 10 mg/kg every 2 weeks. Following startling responses including 2 complete responses of long duration, pembrolizumab was evaluated in a large phase 1 study (KEYNOTE-001) of 1260 patients that evaluated 3 doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in separate melanoma and NSCLC substudies.²¹ Both ipilimumab-naïve and ipilimumab-treated patients were enrolled in the melanoma substudy. Objective responses were seen in 38% ofpatients across all 3 dosing schedules and were similar in both ipilimumab-naïve and ipilimumab-treated patients. Similar to nivolumab, most responders experienced durable remissions.

Pembrolizumab was subsequently compared to ipilimumab in untreated patients (KEYNOTE-006) in which patients were randomly assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2 weeks and pembrolizumab 10 mg/kg every 3 weeks.²² Response rates were greater with pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates of treatment-related adverse events requiring discontinuation of study drug were much lower with pembrolizumab than ipilimumab. This trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for second-line treatment of melanoma in 2014, and updated this to include a first-line indication in 2015 (Table 1).

EFFICACY OF COMBINED CTLA-4 AND PD-1 INHIBITION

Preclinical studies demonstrated that PD-1 blockade was more effective than CTLA-4 blockade and combination PD-1/CTLA-4 blockade was synergistic, with complete rejection of tumors in approximately half of the treated animals.¹⁴ This hypothesis was evaluated in a phase 1 study that explored both concurrent and sequential combinations of ipilimumab and nivolumab along with increasing doses of both agents in PD-1/CTLA-4–naïve advanced melanoma.²³ Responses were greater in the concurrent arm (40%) than in the sequential arm (20%) across dose-levels with a small fraction of patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor burden.

The superiority of ipilimumab/nivolumab combination to ipilimumab monotherapy was demonstrated in a randomized blinded phase 2 study (CheckMate 069).²⁴ Of the 4 different ipilimumab/nivolumab doses explored in the phase 1 study (3 mg/kg and 0.3 mg/kg, 3 mg/kg and 1 mg/kg, 1 mg/kg and 3 mg/kg, 3 mg/kg and 3 mg/kg), ipilimumab 3 mg/kg and nivolumab 1 mg/kg (followed by nivolumab 3 mg/kg) was compared to ipilimumab and nivolumab-matched placebo. Responses were significantly greater with dual PD-1/CTLA-4 blockade compared to CTLA-4 blockade alone (59% versus 11%). Concurrently, a 3-arm randomized phase 3 study compared the same dose of ipilimumab/nivolumab to ipilimumab and nivolumab in previously untreated advanced melanoma (CheckMate 067).²⁵ Similar to CheckMate 069, CheckMate 067 demonstrated that ipilimumab/nivolumab combination resulted in more profound responses (58%) than either ipilimumab (19%) or nivolumab (44%) alone. Toxicity, primarily diarrhea, fatigue, pruritus, and rash, was considerable in the combination arm (55% grade 3/4 adverse events) and resulted in treatment discontinuation in 30% of patients. The profound and durable responses observed led to accelerated approval of ipilimumab/nivolumab combination in 2015 (Table 1).

Efforts to improve the toxicity/benefit ratio of ipilimumab/nivolumab combination have centered around studying lower doses and/or extended dosing schedules of ipilimumab, including ipilimumab 1 mg/kg every 6 or 12 weeks with nivolumab dosed at 3 mg/kg every 2 weeks or 480 mg every 4 weeks. Promising data from a first-line study in NSCLC (CheckMate 012) support the evaluation of nivolumab in combination with lower-dosed ipilimumab (1 mg/kg every 6 or 12 weeks).⁵² This approach is being tested against platinum doublet chemotherapy in a confirmatory phase 3 study in NSCLC (CheckMate 227).

TARGETED THERAPY

MAPK KINASE PATHWAY IN MELANOMA TUMORIGENESIS

The MAPK pathway mediates cellular responses to growth signals. RAF kinases are central mediators in the MAPK pathway and exert their effect primarily through MEK phosphorylation and activation following dimerization (hetero- or homo-) of RAF molecules. As a result, RAF is integral to multiple cellular processes, including transcriptional regulation, cellular differentiation, and cell proliferation. MAPK pathway activation is a common event in many cancers, primarily due to activating mutations in BRAF or RAS. Alternatively, MAPK pathway activation can occur in the absence of activating mutations in BRAF or NRAS through down-regulation of MAPK pathway inhibitory proteins (RAF-1 inhibitory protein or SPRY-2), C-MET overexpression, or activating mutations in non-BRAF/NRAS kinases including CRAF, HRAS, and NRAS.^53,54

Somatic point mutations in BRAF are frequently observed (37%–50%) in malignant melanomas and at lower frequency in a range of human cancers including NSCLC, colorectal cancer, papillary thyroid cancer, ovarian cancer, glioma, and gastrointestinal stromal tumor.^6,55,56BRAF mutations in melanoma typically occur within the activation segment of the kinase domain (exon 15). Between 80% and 90% of activating mutations result in an amino acid substitution of glutamate (E) for valine (V) at position 600: V600E.^57,58 V600E mutations are true oncogenic drivers, resulting in increased kinase activity with demonstrable transformational capacity in vitro. BRAF mutations are usually mutually exclusive, with tumors typically containing no other driver mutations in NRAS, KIT, NF1, or other genes.

NRAS mutations are less common than BRAF mutations, having a reported frequency of 13% to 25% in melanoma.⁴NRAS mutations generally occur within the P-loop region of the G domain (exon 2), or less commonly in the switch II region of the G domain (exon 3). Most NRAS exon 2 mutations comprise amino acid substitutions at position 61 from glutamine (Q) to arginine (R; 35%), lysine (K; 34%) and less often to glutamate (E), leucine (L), or proline (P). Preclinical data suggest that NRAS mutations paradoxically stimulate the MAPK pathway and thus enhance tumor growth in vitro.^59,60 Several important phenotypic differences distinguish NRAS- from BRAF-mutated melanoma. NRAS-mutated tumors are typically associated with increasing age and CSD skin, while BRAF-mutated tumors arise in younger patients in non-CSD skin. A large population-based study suggested that NRAS-mutated melanomas were associated with mitoses and lower tumor infiltrating lymphocytes (TIL) grade, and arose in anatomic sites other than the head/neck, while BRAF-mutated tumors were associated with mitoses and superficial spreading histology.⁶¹ Although the lower TIL grade seen with NRAS-mutated melanomas suggests a more immunosuppressed microenvironment and argues for poorer responses to immune therapies, clinical studies comparing responses to immunotherapies in various categories of driver mutations provide conflicting results for the prognostic role of NRAS mutations in relation to immune checkpoint blockade and other immune therapies.^62–64

NF1 represents the third known driver in cutaneous melanoma, with mutations reported in 12% of cases.^6,7NF1 encodes neurofibromin, which has GTPase activity and regulates RAS proteins; NF1 loss results in increased RAS.⁶⁵ Unlike BRAF or NRAS, which are usually mutually exclusive, NF1 mutations in melanoma can occur singly or in combination with either BRAF or NRAS mutations. In these settings, NF1 mutations are associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.⁶⁶

MAPK PATHWAY INHIBITION SINGLY AND IN COMBINATION

Although multiple MEK 1/2 inhibitors (AS703026, AZD8330/ARRY-704, AZD6244, CH5126766, CI-1040, GSK1120212, PD0325901, RDEA119, and XL518) and RAF inhibitors (ARQ 680, GDC-0879, GSK2118436, PLX4032, RAF265, sorafenib, XL281/BMS-908662) were developed, the initial evaluation of MAPK pathway inhibitors in advanced human cancers began with CI-1040. Preclinical data suggested that CI-1040 potently and selectively inhibited both MEK1 and MEK2, but phase 1 and 2 human trial results were disappointing, likely because these trials were not selectively enriched for NRAS/BRAF–mutated tumors or cancers in which these oncogenic mutations were most commonly detected, such as melanoma.^67,68 The subsequent evaluation of selumetinib (AZD6244/ARRY-142886) in a phase 2 study was also negative. Although investigators enrolled a presumably enriched population (cutaneous melanoma), the incidence of NRAS/BRAF–mutated tumors was not ascertained to determine this, but rather assumed, which led to a discrepancy between the assumed (prestudy) and observed (on-study) proportions of BRAF/NRAS mutations that was not accounted for in power calculations.^69,70 Lessons learned from these earlier misadventures informed the current paradigm of targeted therapy development: (1) identification of a highly specific and potent inhibitor through high-throughput screening; (2) establishment of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in unselected patients; (3) confirmation of RP2D in selected tumor types enriched for target of interest; and (4) confirmatory study against standard comparator to seek regulatory approval.

Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

CONCLUSION AND FUTURE DIRECTIONS

Prior to 2011, the only approved agents for the treatment of advanced melanoma were dacarbazine and high-dose interleukin-2. Since 2011, drug approvals in melanoma have proceeded at a frenetic pace unmatched in any other disease. The primary events underlying this are advances in our understanding of the gene mutation landscape driving melanoma tumorigenesis, accompanied by insights into the means by which tumors circumvent the induction of effective anti-tumor T-cell responses. These insights have resulted in the development of inhibitors targeting MAPK pathway kinases BRAF, MEK, and NRAS), KIT, and regulatory immune checkpoints (CTLA-4 and PD-1). Although BRAF/MEK inhibition results in profound reductions and even occasional complete responses in patients, these responses are typically short lived, rarely lasting more than 9 to 11 months; the encorafenib/binimetinib combination may improve that duration marginally. However, the signature therapeutic advance in melanoma of the past decade is immunotherapy, particularly the development of inhibitors of CTLA-4 and PD-1 immune checkpoints. With these agents, significant proportions of treated patients remain free of progression off-therapy (ipilimumab 23%; nivolumab 34%; pembrolizumab 35%; ipilimumab/nivolumab 64%), and some patients can be successfully re-induced after delayed progression. Separately, the high response rates observed with the use of KIT inhibitors in CML and GIST have not been observed in KIT mutated/amplified melanoma and development of agents in this space has been limited. The challenges ahead center around identifying predictive biomarkers and circumventing primary or acquired resistance, with the eventual goal of producing durable remissions in the majority of treated patients.

Our improved understanding of the mechanisms of acquired resistance to BRAF/MEK inhibitors suggests that anti-tumor activity may be achieved by targeting multiple pathways, possibly with combination regimens comprising other inhibitors and/or immunotherapy. Preclinical data supports the use of combination strategies targeting both ERK and PI3K/mTOR to circumvent acquired resistance.⁹⁰ Ongoing studies are evaluating combinations with biguanides (metformin: NCT02143050 and NCT01638676; phenformin: NCT03026517), HSP90 inhibitors (XL888: NCT02721459; AT13387: NCT02097225), and decitabine (NCT01876641).

One complexity affecting management of resistance in the targeted therapy landscape remains tumor heterogeneity, particularly intra- and intertumoral heterogeneity, which may explain the apparent contradiction between continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting slower progression of resistant tumors on cessation of BRAF inhibitors.^91–94 These data provide a rationale to investigate intermittent dosing regimens with BRAF/MEK inhibitors; several studies exploring this approach are ongoing (NCT01894672 and NCT02583516).

Given the specificity, adaptability, and memory response associated with immunotherapy, it is likely that these agents will be used to treat the majority of patients regardless of mutational status. Hence, identifying predictive biomarkers of response to immune checkpoint inhibitors is vital. The presence of CD8+ T-cell infiltrate and IFN-γ gene signature, which indicate an “inflamed” tumor microenvironment, are highly predictive of clinical benefit from PD-1 inhibitors.^95,96 However, not all PD-1 responders have “inflamed” tumor microenvironments, and not all patients with an “inflamed” tumor microenvironment respond to immune checkpoint inhibitors. The complexity of the immune system is reflected in the multiple non-redundant immunologic pathways, both positive and negative, with checkpoints and ligands that emerge dynamically in response to treatment. Given the dynamic nature of the immune response, it is unlikely that any single immunologic biomarker identified pre-treatment will be completely predictive. Rather, the complexity of the biomarker approach must match the complexity of the immune response elicited, and will likely incorporate multifarious elements including CD8+ T-cell infiltrate, IFN-γ gene signature, and additional elements including microbiome, genetic polymorphisms, and tumor mutation load. The goal is to use multiple markers to guide development of combinations and then, depending on initial response, to examine tumors for alterations to guide decisions about additional treatment(s) to improve responses, with the eventual goal being durable clinical responses for all patients.

INTRODUCTION

The incidence of cutaneous melanoma has increased over the past 2 decades, with SEER estimates indicating that the number of new cases of melanoma diagnosed annually rose from 38,300 in 1996 to 76,000 in 2016.¹ Among persons younger than 50 years, the incidence is higher in females, and younger women (aged 15–39 years) are especially vulnerable.² Among persons older than 50, melanoma incidence in men is nearly twice that of women, in whom melanomas are often thicker and often associated with worse outcomes.^1,2 Approximately 85% of melanomas are diagnosed at early stages when surgery is curative, but the lifetime probability of developing invasive disease is 3% in men and 2% in women.

Prior to the advent of effective immunotherapies and targeted therapies, melanoma was often managed with chemotherapy, which had dismal response rates and commensurately poor outcomes. Advances in the understanding of the molecular etiopathogenesis and immune escape responses of cutaneous metastatic melanoma have transformed therapeutic approaches. Specifically, improved understanding of the genetic mutations driving melanoma tumorigenesis coupled with insights into mechanisms of tumor-mediated immune evasion resulted in development of inhibitors of mitogen-activated protein kinases (MAPK; BRAF and MEK) along with inhibitors of negative regulatory immune checkpoints (cytotoxic T lymphocyte–associated antigen 4 [CTLA-4] and programmed cell death-1 [PD-1]). In this review, we discuss the role of immune therapy, targeted therapy, and combinations of these in the treatment of metastatic cutaneous melanoma. We limit the immuno-therapy discussion to approved CTLA-4/PD-1 inhibitors and the targeted therapy discussion to approved BRAF/NRAS/MEK inhibitors and do not discuss non-checkpoint immunotherapies including cytokines (HD IL-2), vaccines, or adoptive T-cell approaches. Interested readers are directed to other excellent works covering these important topics.^26–29

DEVELOPMENT OF TARGETED AND NOVEL IMMUNE THERAPIES

For many years the degree of ultraviolet (UV) light exposure was considered the sole major risk factor for melanoma oncogenesis, even though its mechanism was largely unknown.³ However, clinical observations regarding the occurrence of melanoma on less exposed areas (trunk and limbs) in individuals with intermittent sun exposure led to the proposition that melanomas that arose in younger patients with intermittent sun exposure were distinct from melanomas that arose in older patients in association with markers of chronic sun exposure—the “divergent pathway” hypothesis.³ Critical to this understanding were whole-exome sequencing data from multiple groups, including The Cancer Genome Atlas, that identified patterns of mutations in oncogenic drivers that were distinct in patients with and without chronically sun-damaged (CSD) skin.^4–7 It is now clear that based on its association with CSD skin, melanoma can be subclassified into CSD or non-CSD melanoma. CSD and non-CSD melanoma have distinct clinico-pathological characteristics and are associated with different driver mutations. CSD melanomas typically arise in older patients on sun-exposed areas (head/neck, dorsal surfaces of distal extremities) and are associated with particular driver mutations (BRAF non-V600E, NRAS, NF1, or KIT) and genetic signatures of UV-induced DNA damage (G > T [UVA] or C > T [UVB]) transitions. Conversely, non-CSD melanomas typically arise in younger (< 55 years) patients on intermittently sun-exposed areas (trunk, proximal extremities) and are associated with BRAF V600E/K driver mutations and often lack genetic signatures of UV mutagenesis.

Identification of driver mutations in components of the MAPK pathway, including BRAF and NRAS, facilitated the development of targeted inhibitors. The BRAF inhibitors vemurafenib and dabrafenib have been shown in pivotal phase 3 studies to significantly improve overall and progression-free survival in patients with metastatic melanoma compared with chemotherapy and garnered regulatory approval (vemurafenib, BRIM-3;^8,9 dabrafenib, BREAK-3¹⁰). Concomitant MEK and BRAF inhibition extends the duration of benefit by preventing downstream kinase activation in the MAPK pathway. Notably, concomitant MEK inhibition alters the side-effect profile of BRAF inhibitors, with reduced incidence of keratoacanthomas and cutaneous squamous cell carcinomas that are attributable to on-target, off-tumor effects of BRAF inhibitors. Combined BRAF and MEK inhibition (vemurafenib/cobimetinib and dabrafenib/trametinib) further improved overall and progression-free survival compared to single-agent BRAF inhibition in phase 3 studies (COMBI-d,¹¹ COMBI-v,¹² and coBRIM¹³). Although often deep, the responses seen with the use of targeted kinase inhibitors are not often durable, with the vast majority of patients progressing after 12 to 15 months of therapy.In parallel, work primarily done in murine models of chronic viral infection uncovered the role played by co-inhibitory or co-excitatory immune checkpoints in mediating T-cell immune responses. These efforts clarified that tumor-mediated immune suppression primarily occurs through enhancement of inhibitory signals via the negative T-cell immune checkpoints CTLA-4 or PD-1.^14,15 Blockade of negative T-cell immune checkpoints resulted in activation of the adaptive immune system, resulting in durable anti-tumor responses as demonstrated in studies of the CTLA-4 inhibitor ipilimumab (CA184-020¹⁶ and CA184-024¹⁷) and the PD-1 inhibitors nivolumab (CA209-003,¹⁸ CheckMate 037,¹⁹ and CheckMate 066²⁰) and pembrolizumab (KEYNOTE-001²¹ and KEYNOTE-006²²). Compared to the deep but short-lived responses seen with targeted kinase inhibitors, patients treated with CTLA-4 or PD-1 immune checkpoint blockade often developed durable responses that persisted even after completion of therapy. Combined CTLA-4 and PD-1 blockade results in greater magnitude of response with proportionately increased toxicity.^23–25

IMMUNOTHERAPY

CTLA-4 AND PD-1 IMMUNE CHECKPOINT INHIBITORS

The novel success of immunotherapy in recent decades is largely attributable to improved understanding of adaptive immune physiology, specifically T-cell activation and regulation. T-cell activation requires 2 independent signaling events: it is initiated upon recognition of the antigen-MHC class II-receptor complex on antigen-presenting cells (APC), and requires a secondary co-stimulatory interaction of CD80/CD86 (B7.1/B7.2) on APCs and CD28 molecule on T-cells; without this second event, T-cells enter an anergic state.^30–32 Upon successful signaling and co-stimulation, newly activated T-cells upregulate CTLA-4, which can bind to B7 molecules with a nearly 100-fold greater affinity than CD28.^33,34 Unlike CD28, CTLA-4 engagement negatively regulates T-cell activation. The opposing signals produced by CD28 and CTLA-4 are integrated by the T-cell to determine eventual response to activation, and provide a means by which T-cell activation is homeostatically regulated to prevent exaggerated physiologic immune responses.³⁵ It was hypothesized that CTLA-4 blockade would permit T-cell activation, which is thwarted in the tumor microenvironment by tumor-mediated CTLA-4 engagement, thereby unleashing an anti-tumor immune response.³⁶

PD-1 is a member of the CD28 and CTLA-4 immunoglobulin super family and, similar to CTLA-4, binds activated T-cells. PD-1 has 2 ligands on activated T-cells: PD-L1 and PD-L2.³⁷ PD-L1 is constitutively expressed by a variety of immune and non-immune cells, particularly in inflammatory environments including tumor microenvironments, in response to the release of inflammatory cytokines such as interferon (IFN)-γ.^37,38 Conversely, PD-L2 is only minimally expressed constitutively, although its expression on immune and non-immune cells can be induced by similar cues from inflammatory microenvironments. PD-L1 and PD-L2 cross-compete for binding to PD-1, with PD-L2 exhibiting 2- to 6-fold greater relative affinity than PD-L1.³⁹ PD-L1/PD-1 binding results in phosphorylation of 2 tyrosinases in the intracellular portion of PD-1, which contains immunoreceptor tyrosine-based inhibitory motif (ITIM) and immunoreceptor tyrosine-based switch motif (ITSM). PD-1 ITSM subsequently recruits either of 2 SH2-domain–containing protein tyrosine phosphatases: SHP-1 and SHP-2. SHP-2 signaling suppresses PI3K/Akt activation, down-regulates Bcl-xL, and suppresses expression of multiple transcription factors that mediate T-cell effector function including GATA-3, Eomes, and T-bet.^40–42 The net effect of PD-L1/PD-1 engagement is to suppress T-cell proliferation, cytokine production, cytolytic function, and survival. Unlike CTLA-4, which primarily affects the priming phase of naive T-cell activation, PD-1 chiefly regulates the effector phase of T-cell function. Furthermore, because PD-L1/PD-L2 expression is limited to inflammatory microenvironments, the effects of PD-1 are less generalized than those of CTLA-4.

SINGLE AGENT ACTIVITY OF CTLA-4 AND PD-1 INHIBITORS

Ipilimumab (MDX-010) is a human IgG1 monoclonal antibody shown to inhibit CTLA-4.⁴³ Early studies tested different formulations (transfectoma-derived and hybridoma-derived), doses, and schedules of ipilimumab primarily in patients with advanced refractory melanoma.^44–46 Although responses were infrequent, responding patients experienced durable remissions at 1- and 2-year time points. Notably, in a foreshadowing of changes to response criteria used to evaluate these agents, several treated patients who initially had radiographically stable disease upon completion of therapy subsequently experienced a gradual decline in tumor burden.

Ipilimumab was subsequently evaluated in 2 phase 3 trials. The first study (MDX010-020/CA184-020), which involved 676 HLA-A*0201–positive patients with advanced melanoma, compared ipilimumab 3 mg/kg every 3 weeks for 4 doses either singly or in combination with gp100 vaccine with a gp100-only control arm.¹⁶ Ipilimumab administration resulted in objective responses in 11% of patients and improved progression-free and overall survival compared to gp100 alone. Of note, ipilimumab monotherapy was superior to ipilimumab/gp100 combination, possibly related to timing of vaccine in relation to ipilimumab. A confirmatory study (CA184-024) compared a higher dose of ipilimumab (10 mg/kg) in combination with dacarbazine to dacarbazine monotherapy in previously untreated melanoma and was positive.¹⁷ Given the lack of augmented efficacy with the higher (10 mg/kg) dose, ipilimumab received regulatory approval in 2011 for the treatment of melanoma at the lower dose: 3 mg/kg administered every 3 weeks for 4 doses (Table 1). Survival data was strikingly similar to patterns observed in prior phase 2 studies, with survival curves plateauing after 2 years at 23.5% to 28.5% of treated patients. Pooled survival data from prospective and retrospective studies of ipilimumab corroborate the plateau of 22% (26% treated; 20% untreated) reached at year 3 regardless of prior therapy or ipilimumab dose, underscoring the durability of long-term survival in ipilimumab-treated patients.⁴⁷ Ipilimumab administration resulted in an unusual spectrum of toxicities including diarrhea, rash, hepatitis, and hypophysitis (termed immune-related adverse events, or irAEs) in up to a third of patients.

Pembrolizumab and nivolumab are humanized IgG4 monoclonal antibodies that target the PD-1 receptor found on activated T cells, B cells, and myeloid cells. Pembrolizumab and nivolumab are engineered similarly: by immunizing transgenic mice with recombinant human PD-1-Fc protein and subsequently screening murine splenic cells fused with myeloma cells for hybridomas producing antibodies reactive to PD-1-Fc.^48,49 Unlike IgG1, the IgG4 moiety neither engages Fc receptors nor activates complement, avoiding cytotoxic effects of the antibody upon binding to the T cells that it is intended to activate. Both pembrolizumab and nivolumab bind PD-1 with high affinity and specificity, effectively inhibiting the interaction between PD-1 and ligands PD-L1 and PD-L2.

Nivolumab was first studied in a phase 1 study (CA209-003) of 296 patients with advanced cancers who received 1, 3, or 10 mg/kg administered every 2 weeks.¹⁸ Histologies tested included melanoma, non–small-cell lung cancer (NSCLC), renal-cell cancer (RCC), castration-resistant prostate cancer (CRPC), and colorectal cancer (CRC). Responses were seen in melanoma and RCC and unusually in NSCLC, including in both squamous and non-squamous tumors. Objective responses were noted in 41% of the 107 melanoma patients treated at 3 mg/kg. Survival was improved, with 1- and 2-year survival rates of 62% and 43% at extended follow up.⁵⁰

Subsequently, nivolumab was compared to chemotherapy in a pair of phase 3 studies involving both previously untreated (Checkmate 066) and ipilimumab/BRAF inhibitor–refractory (CheckMate 037) patients.^19,20 In both studies, nivolumab produced durable responses in 32% to 34% of patients and improved survival over chemotherapy. Compared to ipilimumab, the incidence of irAEs was much lower with nivolumab. The depth and magnitude of responses observed led to regulatory approval for nivolumab in both indications (untreated and ipilimumab/BRAF inhibitor–treated melanoma) in 2014. Data from both studies are summarized in Table 1.

Pembrolizumab was first evaluated in a phase 1 study of 30 patients with a variety of solid organ malignancies in which no dose-limiting toxicities were observed and no defined maximal tolerated dose was reached.⁵¹ Per protocol, maximal administered dose was 10 mg/kg every 2 weeks. Following startling responses including 2 complete responses of long duration, pembrolizumab was evaluated in a large phase 1 study (KEYNOTE-001) of 1260 patients that evaluated 3 doses (10 mg/kg every 2 weeks, 10 mg/kg every 3 weeks, and 2 mg/kg every 3 weeks) in separate melanoma and NSCLC substudies.²¹ Both ipilimumab-naïve and ipilimumab-treated patients were enrolled in the melanoma substudy. Objective responses were seen in 38% ofpatients across all 3 dosing schedules and were similar in both ipilimumab-naïve and ipilimumab-treated patients. Similar to nivolumab, most responders experienced durable remissions.

Pembrolizumab was subsequently compared to ipilimumab in untreated patients (KEYNOTE-006) in which patients were randomly assigned to receive either ipilimumab or pembrolizumab at 1 of 2 doses: 10 mg/kg every 2 weeks and pembrolizumab 10 mg/kg every 3 weeks.²² Response rates were greater with pembrolizumab than ipilimumab, with commensurately greater 1-year survival rates. Rates of treatment-related adverse events requiring discontinuation of study drug were much lower with pembrolizumab than ipilimumab. This trial was instrumental in proving the superior profile of pembrolizumab over ipilimumab. The US Food and Drug Administration (FDA) granted pembrolizumab accelerated approval for second-line treatment of melanoma in 2014, and updated this to include a first-line indication in 2015 (Table 1).

EFFICACY OF COMBINED CTLA-4 AND PD-1 INHIBITION

Preclinical studies demonstrated that PD-1 blockade was more effective than CTLA-4 blockade and combination PD-1/CTLA-4 blockade was synergistic, with complete rejection of tumors in approximately half of the treated animals.¹⁴ This hypothesis was evaluated in a phase 1 study that explored both concurrent and sequential combinations of ipilimumab and nivolumab along with increasing doses of both agents in PD-1/CTLA-4–naïve advanced melanoma.²³ Responses were greater in the concurrent arm (40%) than in the sequential arm (20%) across dose-levels with a small fraction of patients treated in the concurrent arm experiencing a profound reduction (80%) in tumor burden.

The superiority of ipilimumab/nivolumab combination to ipilimumab monotherapy was demonstrated in a randomized blinded phase 2 study (CheckMate 069).²⁴ Of the 4 different ipilimumab/nivolumab doses explored in the phase 1 study (3 mg/kg and 0.3 mg/kg, 3 mg/kg and 1 mg/kg, 1 mg/kg and 3 mg/kg, 3 mg/kg and 3 mg/kg), ipilimumab 3 mg/kg and nivolumab 1 mg/kg (followed by nivolumab 3 mg/kg) was compared to ipilimumab and nivolumab-matched placebo. Responses were significantly greater with dual PD-1/CTLA-4 blockade compared to CTLA-4 blockade alone (59% versus 11%). Concurrently, a 3-arm randomized phase 3 study compared the same dose of ipilimumab/nivolumab to ipilimumab and nivolumab in previously untreated advanced melanoma (CheckMate 067).²⁵ Similar to CheckMate 069, CheckMate 067 demonstrated that ipilimumab/nivolumab combination resulted in more profound responses (58%) than either ipilimumab (19%) or nivolumab (44%) alone. Toxicity, primarily diarrhea, fatigue, pruritus, and rash, was considerable in the combination arm (55% grade 3/4 adverse events) and resulted in treatment discontinuation in 30% of patients. The profound and durable responses observed led to accelerated approval of ipilimumab/nivolumab combination in 2015 (Table 1).

Efforts to improve the toxicity/benefit ratio of ipilimumab/nivolumab combination have centered around studying lower doses and/or extended dosing schedules of ipilimumab, including ipilimumab 1 mg/kg every 6 or 12 weeks with nivolumab dosed at 3 mg/kg every 2 weeks or 480 mg every 4 weeks. Promising data from a first-line study in NSCLC (CheckMate 012) support the evaluation of nivolumab in combination with lower-dosed ipilimumab (1 mg/kg every 6 or 12 weeks).⁵² This approach is being tested against platinum doublet chemotherapy in a confirmatory phase 3 study in NSCLC (CheckMate 227).

TARGETED THERAPY

MAPK KINASE PATHWAY IN MELANOMA TUMORIGENESIS

The MAPK pathway mediates cellular responses to growth signals. RAF kinases are central mediators in the MAPK pathway and exert their effect primarily through MEK phosphorylation and activation following dimerization (hetero- or homo-) of RAF molecules. As a result, RAF is integral to multiple cellular processes, including transcriptional regulation, cellular differentiation, and cell proliferation. MAPK pathway activation is a common event in many cancers, primarily due to activating mutations in BRAF or RAS. Alternatively, MAPK pathway activation can occur in the absence of activating mutations in BRAF or NRAS through down-regulation of MAPK pathway inhibitory proteins (RAF-1 inhibitory protein or SPRY-2), C-MET overexpression, or activating mutations in non-BRAF/NRAS kinases including CRAF, HRAS, and NRAS.^53,54

Somatic point mutations in BRAF are frequently observed (37%–50%) in malignant melanomas and at lower frequency in a range of human cancers including NSCLC, colorectal cancer, papillary thyroid cancer, ovarian cancer, glioma, and gastrointestinal stromal tumor.^6,55,56BRAF mutations in melanoma typically occur within the activation segment of the kinase domain (exon 15). Between 80% and 90% of activating mutations result in an amino acid substitution of glutamate (E) for valine (V) at position 600: V600E.^57,58 V600E mutations are true oncogenic drivers, resulting in increased kinase activity with demonstrable transformational capacity in vitro. BRAF mutations are usually mutually exclusive, with tumors typically containing no other driver mutations in NRAS, KIT, NF1, or other genes.

NRAS mutations are less common than BRAF mutations, having a reported frequency of 13% to 25% in melanoma.⁴NRAS mutations generally occur within the P-loop region of the G domain (exon 2), or less commonly in the switch II region of the G domain (exon 3). Most NRAS exon 2 mutations comprise amino acid substitutions at position 61 from glutamine (Q) to arginine (R; 35%), lysine (K; 34%) and less often to glutamate (E), leucine (L), or proline (P). Preclinical data suggest that NRAS mutations paradoxically stimulate the MAPK pathway and thus enhance tumor growth in vitro.^59,60 Several important phenotypic differences distinguish NRAS- from BRAF-mutated melanoma. NRAS-mutated tumors are typically associated with increasing age and CSD skin, while BRAF-mutated tumors arise in younger patients in non-CSD skin. A large population-based study suggested that NRAS-mutated melanomas were associated with mitoses and lower tumor infiltrating lymphocytes (TIL) grade, and arose in anatomic sites other than the head/neck, while BRAF-mutated tumors were associated with mitoses and superficial spreading histology.⁶¹ Although the lower TIL grade seen with NRAS-mutated melanomas suggests a more immunosuppressed microenvironment and argues for poorer responses to immune therapies, clinical studies comparing responses to immunotherapies in various categories of driver mutations provide conflicting results for the prognostic role of NRAS mutations in relation to immune checkpoint blockade and other immune therapies.^62–64

NF1 represents the third known driver in cutaneous melanoma, with mutations reported in 12% of cases.^6,7NF1 encodes neurofibromin, which has GTPase activity and regulates RAS proteins; NF1 loss results in increased RAS.⁶⁵ Unlike BRAF or NRAS, which are usually mutually exclusive, NF1 mutations in melanoma can occur singly or in combination with either BRAF or NRAS mutations. In these settings, NF1 mutations are associated with RAS activation, MEK-dependence, and resistance to RAF inhibition.⁶⁶

MAPK PATHWAY INHIBITION SINGLY AND IN COMBINATION

Although multiple MEK 1/2 inhibitors (AS703026, AZD8330/ARRY-704, AZD6244, CH5126766, CI-1040, GSK1120212, PD0325901, RDEA119, and XL518) and RAF inhibitors (ARQ 680, GDC-0879, GSK2118436, PLX4032, RAF265, sorafenib, XL281/BMS-908662) were developed, the initial evaluation of MAPK pathway inhibitors in advanced human cancers began with CI-1040. Preclinical data suggested that CI-1040 potently and selectively inhibited both MEK1 and MEK2, but phase 1 and 2 human trial results were disappointing, likely because these trials were not selectively enriched for NRAS/BRAF–mutated tumors or cancers in which these oncogenic mutations were most commonly detected, such as melanoma.^67,68 The subsequent evaluation of selumetinib (AZD6244/ARRY-142886) in a phase 2 study was also negative. Although investigators enrolled a presumably enriched population (cutaneous melanoma), the incidence of NRAS/BRAF–mutated tumors was not ascertained to determine this, but rather assumed, which led to a discrepancy between the assumed (prestudy) and observed (on-study) proportions of BRAF/NRAS mutations that was not accounted for in power calculations.^69,70 Lessons learned from these earlier misadventures informed the current paradigm of targeted therapy development: (1) identification of a highly specific and potent inhibitor through high-throughput screening; (2) establishment of maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) in unselected patients; (3) confirmation of RP2D in selected tumor types enriched for target of interest; and (4) confirmatory study against standard comparator to seek regulatory approval.

Vemurafenib and dabrafenib were evaluated in this tiered fashion in phase 1 dose-finding studies comprising unselected patients, followed by phase 2 studies in advanced BRAF V600E–mutated melanoma. Both were subsequently evaluated in randomized phase 3 trials (vemurafenib, BRIM-38; dabrafenib, BREAK-310) that compared them with dacarbazine (1000 mg/m² intravenously every 3 weeks) in the treatment of advanced BRAF V600E–mutated melanoma. Response kinetics for both agents were remarkably similar: single-agent BRAF inhibitors resulted in rapid (time to response 2–3 months), profound (approximately 50% objective responses) reductions in tumor burden that lasted 6 to 7 months. Adverse events common to both agents included rash, fatigue, and arthralgia, although clinically significant photosensitivity was more common with vemurafenib and clinically significant pyrexia was more common with dabrafenib. Class-specific adverse events included the development of cutaneous squamous-cell carcinomas and keratoacanthomas secondary to paradoxical activation of MAPK pathway signaling either through activating mutations in HRAS or mutations or amplifications in receptor tyrosine kinases upstream of BRAF, resulting in elevated levels of RAS–guanosine triphosphate complexes.⁷¹ Results of these studies resulted in regulatory approval of single-agent BRAF inhibitors for the treatment of BRAF V600E (and later V600K)–mutated melanoma (vemurafenib in 2011; dabrafenib in 2013). Details regarding trial populations, study interventions, efficacy, and adverse events are summarized in Table 2.

Responses to BRAF inhibitors are typically profound but temporary. Mechanisms of acquired resistance are diverse and include reactivation of MAPK pathway–dependent signaling (RAS activation or increased RAF expression), and development of MAPK pathway–independent signaling (COT overexpression; increased PI3K or AKT signaling) that permits bypass of inhibited BRAF signaling within the MAPK pathway.^72–76 These findings suggested that upfront inhibition of both MEK and mutant BRAF may produce more durable responses than BRAF inhibition alone. Three pivotal phase 3 studies established the superiority of combination BRAF and MEK inhibition over BRAF inhibition alone: COMBI-d11 (dabrafenib/trametinib versus dabrafenib/placebo), COMBI-v12 (dabrafenib/trametinib versus vemurafenib), and coBRIM13 (vemurafenib/cobimetinib versus vemurafenib/placebo). As expected, compared to BRAF inhibitor monotherapy, combination BRAF and MEK inhibition produced greater responses and improved progression-free and overall survival (Table 2). Interestingly, the rate of cutaneous squamous-cell carcinomas was much lower with combination therapy, reflecting the more profound degree of MAPK pathway inhibition achieved with combination BRAF and MEK inhibition. Based on these results, FDA approval was granted for both dabrafenib/trametinib and vemurafenib/cobimetinib combinations in 2015. Although the dabrafenib/trametinib combination was only approved in 2015, trametinib had independently gained FDA approval in 2013 for the treatment of BRAF V600E/K–mutated melanoma on the basis of the phase 3 METRIC study.⁷⁷

Encorafenib (LGX818) and binimetinib (MEK162, ARRY-162, ARRY-438162) are new BRAF and MEK inhibitors currently being evaluated in clinical trials. Encorafenib/binimetinib combination was first evaluated in a phase 3 study (COLUMBUS) that compared it with vemurafenib monotherapy in BRAF-mutant melanoma.⁷⁸ Unsurprisingly, encorafenib/binimetinib combination produced greater and more durable responses compared to vemurafenib monotherapy. The median progression-free survival of the encorafenib/binimetinib combination (14.9 months) was greater than vemurafenib monotherapy (7.3 months) in this study, and intriguingly greater than that seen with vemurafenib/cobimetinib (coBRIM 9.9 months) and dabrafenib/trametinib (COMBI-d 9.3 months; COMBI-v 11.4 months). Of note, although encorafenib has an IC50 midway between dabrafenib and vemurafenib in cell-free assays (0.8 nM dabrafenib, 4 nM encorafenib, and 31 nM vemurafenib), it has an extremely slower off-rate from BRAF V600E, which results in significantly greater target inhibition in cells following drug wash-out.⁷⁹ This may account for the significantly greater clinical benefit seen with encorafenib/binimetinib in clinical trials. Final study data are eagerly awaited. Regulatory approval has been sought, and is pending at this time.

Binimetinib has been compared to dacarbazine in a phase 3 study (NEMO) of patients with NRAS-mutant melanoma, most of whom had been previously treated with immunotherapy.⁸⁰ Response rates were low in both arms, although slightly greater with binimetinib than dacarbazine (15% versus 9%), commensurate with a modest improvement in progression-free survival. FDA approval has been sought and remains pending at this time.

KIT INHIBITION SINGLY AND IN COMBINATION

The KIT receptor protein tyrosine kinase is a transmembrane protein consisting of extracellular and intracellular domains. Activating KIT mutations occur in 2% to 8% of all melanoma patients and may be found in all melanoma subtypes but are commonest in acral melanomas (10%–20%) and mucosal melanomas (15%–20%). Activating KIT mutations primarily occur in exons 11 and 13, which code for the juxtamembrane and kinase domains, respectively.^5,81–83

Imatinib mesylate is a tyrosine kinase inhibitor of the 2-phenyl amino pyrimidine class that occupies the tyrosine kinase active site with resultant blocking of tyrosine kinase activity. Imatinib mesylate is known to block KIT and has been extensively studied in patients with gastrointestinal stromal tumors (GIST), 80% of whom harbor KIT mutations, in both the adjuvant and the metastatic settings. In melanoma, imatinib mesylate was studied in a Chinese open-label, phase 2 study of imatinib mesylate monotherapy in metastatic melanoma harboring KIT mutation or amplification; 25% of the study patients had mucosal disease and the rest had cutaneous disease, with acral involvement in 50% of all patients.⁸⁴ Overall response rate was 23%, while 51% of patients remained alive at 1 year with no differences in response rate and/or survival being noted between patients with either KIT mutations or amplifications. In a separate study of imatinib mesylate at 400 mg daily or 400 mg twice daily in Caucasian patients with KIT-mutated/amplified melanoma, similar response and survival rates were reported, although patients with KIT mutations did nonsignificantly better than those with KIT amplifications.⁸⁵

Other novel studies evaluating KIT inhibitors include KIT inhibition in combination with the VEGF inhibitor bevacizumab and a study of selective BCR-ABL kinase inhibitor nilotinib in imatinib-resistant melanoma. In the former phase 1/2 study, Flaherty and colleagues studied imatinib 800 mg daily and bevacizumab at 10 mg/kg every 2 weeks in 63 patients with advanced tumors, including 23 with metastatic melanoma. Although the combination was relatively nontoxic, no significant efficacy signal was seen and further accrual to the phase 2 portion was halted after the first stage was completed.⁸⁶ Nilotinib is a BCR-ABL1 tyrosine kinase inhibitor intelligently designed based on the structure of the ABL-imatinib complex that is 10 to 30 times more potent than imatinib in inhibiting BCR-ABL1 tyrosine kinase activity. Nilotinib is approved for the treatment of imatinib-resistant chronic myelogenous leukemia (CML), with reported efficacy in patients with central nervous system (CNS) involvement.^87,88 Nilotinib has been studied in a single study of KIT-mutated/amplified melanoma that included patients with imatinib-resistance and those with treated CNS disease. Nilotinib appeared to be active in imatinib-resistant melanoma, although no responses were seen in the CNS disease cohort.⁸⁹ Overall, the response rates observed with KIT inhibition in melanoma are much lower than those observed in CML and GIST.

CONCLUSION AND FUTURE DIRECTIONS

Prior to 2011, the only approved agents for the treatment of advanced melanoma were dacarbazine and high-dose interleukin-2. Since 2011, drug approvals in melanoma have proceeded at a frenetic pace unmatched in any other disease. The primary events underlying this are advances in our understanding of the gene mutation landscape driving melanoma tumorigenesis, accompanied by insights into the means by which tumors circumvent the induction of effective anti-tumor T-cell responses. These insights have resulted in the development of inhibitors targeting MAPK pathway kinases BRAF, MEK, and NRAS), KIT, and regulatory immune checkpoints (CTLA-4 and PD-1). Although BRAF/MEK inhibition results in profound reductions and even occasional complete responses in patients, these responses are typically short lived, rarely lasting more than 9 to 11 months; the encorafenib/binimetinib combination may improve that duration marginally. However, the signature therapeutic advance in melanoma of the past decade is immunotherapy, particularly the development of inhibitors of CTLA-4 and PD-1 immune checkpoints. With these agents, significant proportions of treated patients remain free of progression off-therapy (ipilimumab 23%; nivolumab 34%; pembrolizumab 35%; ipilimumab/nivolumab 64%), and some patients can be successfully re-induced after delayed progression. Separately, the high response rates observed with the use of KIT inhibitors in CML and GIST have not been observed in KIT mutated/amplified melanoma and development of agents in this space has been limited. The challenges ahead center around identifying predictive biomarkers and circumventing primary or acquired resistance, with the eventual goal of producing durable remissions in the majority of treated patients.

Our improved understanding of the mechanisms of acquired resistance to BRAF/MEK inhibitors suggests that anti-tumor activity may be achieved by targeting multiple pathways, possibly with combination regimens comprising other inhibitors and/or immunotherapy. Preclinical data supports the use of combination strategies targeting both ERK and PI3K/mTOR to circumvent acquired resistance.⁹⁰ Ongoing studies are evaluating combinations with biguanides (metformin: NCT02143050 and NCT01638676; phenformin: NCT03026517), HSP90 inhibitors (XL888: NCT02721459; AT13387: NCT02097225), and decitabine (NCT01876641).

One complexity affecting management of resistance in the targeted therapy landscape remains tumor heterogeneity, particularly intra- and intertumoral heterogeneity, which may explain the apparent contradiction between continued efficacy of BRAF inhibitors in BRAF-resistant tumors and preclinical data predicting slower progression of resistant tumors on cessation of BRAF inhibitors.^91–94 These data provide a rationale to investigate intermittent dosing regimens with BRAF/MEK inhibitors; several studies exploring this approach are ongoing (NCT01894672 and NCT02583516).

Given the specificity, adaptability, and memory response associated with immunotherapy, it is likely that these agents will be used to treat the majority of patients regardless of mutational status. Hence, identifying predictive biomarkers of response to immune checkpoint inhibitors is vital. The presence of CD8+ T-cell infiltrate and IFN-γ gene signature, which indicate an “inflamed” tumor microenvironment, are highly predictive of clinical benefit from PD-1 inhibitors.^95,96 However, not all PD-1 responders have “inflamed” tumor microenvironments, and not all patients with an “inflamed” tumor microenvironment respond to immune checkpoint inhibitors. The complexity of the immune system is reflected in the multiple non-redundant immunologic pathways, both positive and negative, with checkpoints and ligands that emerge dynamically in response to treatment. Given the dynamic nature of the immune response, it is unlikely that any single immunologic biomarker identified pre-treatment will be completely predictive. Rather, the complexity of the biomarker approach must match the complexity of the immune response elicited, and will likely incorporate multifarious elements including CD8+ T-cell infiltrate, IFN-γ gene signature, and additional elements including microbiome, genetic polymorphisms, and tumor mutation load. The goal is to use multiple markers to guide development of combinations and then, depending on initial response, to examine tumors for alterations to guide decisions about additional treatment(s) to improve responses, with the eventual goal being durable clinical responses for all patients.