Clinical Edge Journal Scan Commentary

The Janus kinase (JAK) family has become a popular target for novel drug development. There are four JAK subunits, JAK1, JAK2, JAK3, and TYK2, each playing different roles in vital immunologic, hematologic, and homeostatic functions. A wide array of topical JAK-inhibitors has been or are currently being investigated for the treatment of AD, each with different profiles of selectivity across the JAK family.

Ruxolitinib is a preferential JAK1 and JAK2 inhibitor. Oral ruxolitinib is currently approved for the treatment of myelofibrosis. Topical ruxolitinib cream is also approved in the United States for the treatment of mild-to-moderate AD and, more recently, vitiligo.

Blauvelt and colleagues published the findings from a post hoc analysis of data related to itch responses from two randomized, double-blind, vehicle-controlled, phase 3 studies of patients with mild-to-moderate AD. Topical ruxolitinib applied twice daily led to a significant increase in the proportion of patients achieving at least a 2-point or 4-point reduction in Peak Pruritus Numeric Rating Scale (PP-NRS) within 12 hours of initial application and continued improvements out to week 8. Patients treated with ruxolitinib cream were also significantly more likely to achieve an itch-free state and faster reductions in itch compared with vehicle. Rapid improvement of itch is an important feature for any topical therapy that may be used as needed for AD flares.

Brepocitinib is a preferential JAK1 and tyrosine kinase 2 inhibitor. Oral brepocitinib is currently under investigation for several immune-mediated disorders, including dermatomyositis and lupus. Topical brepocitinib cream was also studied in a randomized, double-blind, vehicle-controlled, phase 2 study of patients with mild-to-moderate AD. Brepocitinib cream applied daily or twice daily led to significant decreases in the Eczema Area and Severity Index (EASI), increases in the proportion of patients who achieved Investigator Global Assessment (IGA) scores of clear or almost clear, EASI-75 responses, and 2-point or 4-point reductions in PP-NRS. Overall, topical brepocitinib was well tolerated. Though more studies are needed, topical brepocitinib may become an important addition to our toolbox for managing AD and perhaps other chronic inflammatory skin diseases.

Let's move along to yet another novel mechanism studied in AD: ectoine. Ectoine is a naturally derived chemical from some bacteria that can act as an osmolyte and protect organisms from osmotic stress. It is used in some skin care products because it can protect against xerosis and ultraviolet exposure. Alexopoulos and colleagues published the results of a randomized, single-blind, vehicle-controlled study of a novel cream containing 1% ectoine and 0.1% hyaluronic acid (EHA) in children with mild-to-moderate AD. At week 4, application of EHA cream led to significant decreases in SCORing AD (SCORAD) and IGA scores compared with vehicle cream as well all secondary outcome measures. EHA cream was well-tolerated overall, with most adverse events being cutaneous and mild.

All of these topical agents were studied as "reactive" therapies, ie, to be applied to active AD lesions. It would be nice to have approaches that can also prevent AD. Ní Chaoimh and colleagues published findings from the STOP AD trial that examined whether routine application of emollients in the first 8 weeks of life can prevent AD at age 12 months. They found that early emollient use resulted in significantly lower incidence of AD and similar rates of skin infections at age 12 months. Previous studies found mixed results regarding the efficacy of routine application of emollients in newborns. Though more studies are needed, these results are promising and suggest that early life use of emollients could be a cheap, feasible, and effective option to prevent AD.

The Janus kinase (JAK) family has become a popular target for novel drug development. There are four JAK subunits, JAK1, JAK2, JAK3, and TYK2, each playing different roles in vital immunologic, hematologic, and homeostatic functions. A wide array of topical JAK-inhibitors has been or are currently being investigated for the treatment of AD, each with different profiles of selectivity across the JAK family.

Ruxolitinib is a preferential JAK1 and JAK2 inhibitor. Oral ruxolitinib is currently approved for the treatment of myelofibrosis. Topical ruxolitinib cream is also approved in the United States for the treatment of mild-to-moderate AD and, more recently, vitiligo.

Blauvelt and colleagues published the findings from a post hoc analysis of data related to itch responses from two randomized, double-blind, vehicle-controlled, phase 3 studies of patients with mild-to-moderate AD. Topical ruxolitinib applied twice daily led to a significant increase in the proportion of patients achieving at least a 2-point or 4-point reduction in Peak Pruritus Numeric Rating Scale (PP-NRS) within 12 hours of initial application and continued improvements out to week 8. Patients treated with ruxolitinib cream were also significantly more likely to achieve an itch-free state and faster reductions in itch compared with vehicle. Rapid improvement of itch is an important feature for any topical therapy that may be used as needed for AD flares.

Brepocitinib is a preferential JAK1 and tyrosine kinase 2 inhibitor. Oral brepocitinib is currently under investigation for several immune-mediated disorders, including dermatomyositis and lupus. Topical brepocitinib cream was also studied in a randomized, double-blind, vehicle-controlled, phase 2 study of patients with mild-to-moderate AD. Brepocitinib cream applied daily or twice daily led to significant decreases in the Eczema Area and Severity Index (EASI), increases in the proportion of patients who achieved Investigator Global Assessment (IGA) scores of clear or almost clear, EASI-75 responses, and 2-point or 4-point reductions in PP-NRS. Overall, topical brepocitinib was well tolerated. Though more studies are needed, topical brepocitinib may become an important addition to our toolbox for managing AD and perhaps other chronic inflammatory skin diseases.

Let's move along to yet another novel mechanism studied in AD: ectoine. Ectoine is a naturally derived chemical from some bacteria that can act as an osmolyte and protect organisms from osmotic stress. It is used in some skin care products because it can protect against xerosis and ultraviolet exposure. Alexopoulos and colleagues published the results of a randomized, single-blind, vehicle-controlled study of a novel cream containing 1% ectoine and 0.1% hyaluronic acid (EHA) in children with mild-to-moderate AD. At week 4, application of EHA cream led to significant decreases in SCORing AD (SCORAD) and IGA scores compared with vehicle cream as well all secondary outcome measures. EHA cream was well-tolerated overall, with most adverse events being cutaneous and mild.

All of these topical agents were studied as "reactive" therapies, ie, to be applied to active AD lesions. It would be nice to have approaches that can also prevent AD. Ní Chaoimh and colleagues published findings from the STOP AD trial that examined whether routine application of emollients in the first 8 weeks of life can prevent AD at age 12 months. They found that early emollient use resulted in significantly lower incidence of AD and similar rates of skin infections at age 12 months. Previous studies found mixed results regarding the efficacy of routine application of emollients in newborns. Though more studies are needed, these results are promising and suggest that early life use of emollients could be a cheap, feasible, and effective option to prevent AD.

The Janus kinase (JAK) family has become a popular target for novel drug development. There are four JAK subunits, JAK1, JAK2, JAK3, and TYK2, each playing different roles in vital immunologic, hematologic, and homeostatic functions. A wide array of topical JAK-inhibitors has been or are currently being investigated for the treatment of AD, each with different profiles of selectivity across the JAK family.

Ruxolitinib is a preferential JAK1 and JAK2 inhibitor. Oral ruxolitinib is currently approved for the treatment of myelofibrosis. Topical ruxolitinib cream is also approved in the United States for the treatment of mild-to-moderate AD and, more recently, vitiligo.

Blauvelt and colleagues published the findings from a post hoc analysis of data related to itch responses from two randomized, double-blind, vehicle-controlled, phase 3 studies of patients with mild-to-moderate AD. Topical ruxolitinib applied twice daily led to a significant increase in the proportion of patients achieving at least a 2-point or 4-point reduction in Peak Pruritus Numeric Rating Scale (PP-NRS) within 12 hours of initial application and continued improvements out to week 8. Patients treated with ruxolitinib cream were also significantly more likely to achieve an itch-free state and faster reductions in itch compared with vehicle. Rapid improvement of itch is an important feature for any topical therapy that may be used as needed for AD flares.

Brepocitinib is a preferential JAK1 and tyrosine kinase 2 inhibitor. Oral brepocitinib is currently under investigation for several immune-mediated disorders, including dermatomyositis and lupus. Topical brepocitinib cream was also studied in a randomized, double-blind, vehicle-controlled, phase 2 study of patients with mild-to-moderate AD. Brepocitinib cream applied daily or twice daily led to significant decreases in the Eczema Area and Severity Index (EASI), increases in the proportion of patients who achieved Investigator Global Assessment (IGA) scores of clear or almost clear, EASI-75 responses, and 2-point or 4-point reductions in PP-NRS. Overall, topical brepocitinib was well tolerated. Though more studies are needed, topical brepocitinib may become an important addition to our toolbox for managing AD and perhaps other chronic inflammatory skin diseases.

Let's move along to yet another novel mechanism studied in AD: ectoine. Ectoine is a naturally derived chemical from some bacteria that can act as an osmolyte and protect organisms from osmotic stress. It is used in some skin care products because it can protect against xerosis and ultraviolet exposure. Alexopoulos and colleagues published the results of a randomized, single-blind, vehicle-controlled study of a novel cream containing 1% ectoine and 0.1% hyaluronic acid (EHA) in children with mild-to-moderate AD. At week 4, application of EHA cream led to significant decreases in SCORing AD (SCORAD) and IGA scores compared with vehicle cream as well all secondary outcome measures. EHA cream was well-tolerated overall, with most adverse events being cutaneous and mild.

All of these topical agents were studied as "reactive" therapies, ie, to be applied to active AD lesions. It would be nice to have approaches that can also prevent AD. Ní Chaoimh and colleagues published findings from the STOP AD trial that examined whether routine application of emollients in the first 8 weeks of life can prevent AD at age 12 months. They found that early emollient use resulted in significantly lower incidence of AD and similar rates of skin infections at age 12 months. Previous studies found mixed results regarding the efficacy of routine application of emollients in newborns. Though more studies are needed, these results are promising and suggest that early life use of emollients could be a cheap, feasible, and effective option to prevent AD.

Diabetes guidelines recommend sodium-glucose transport protein 2 (SGLT2) inhibitors to reduce kidney disease progression in patients with type 2 diabetes (T2D) and moderate-to-severe albuminuric kidney disease on the basis of renal outcomes trials, such as CREDENCE and DAPA-CKD. However, these trials did not include patients who are at low risk for kidney disease progression.

Mozenson and colleagues published a post hoc analysis of the DECLARE-TIMI 58 trial and focused on patients with low kidney risk. They demonstated that dapagliflozin slowed the progression of kidney disease in patients with T2D at high cardiovascular risk, including those who are at low risk for kidney progression. The absolute benefit for slowing kidney progression was much lower in patients with low kidney risk compared with those who are at high or very high risk (number needed to treat 177 vs 13-23). Though dapagliflozin does provide kidney protection across a spectrum of patients with kidney risk, clinicians should consider the level of risk when starting an SGLT2 inhibitor for slowing kidney disease.

SGLT2 inhibitor outcome trials and meta-analyses have mainly shown neutral results for ischemic stroke, except for sotagliflozin vs placebo in the SCORED trial. In this trial, sotagliflozin was shown to reduce total stroke. Recently, in a retrospective longitudinal cohort study of patients with T2D in Taiwan, Lin and colleagues have shown a significant reduction in new onset stroke among those who use SGLT2 inhibitor compared with those who don't. A 15% relative risk reduction in stroke was shown in an analysis that adjusted for age, sex, and duration of T2D, with a similar reduction in a propensity score-matched analysis. Although limited by its observational design, this study suggests that further research should be continued regarding the impact of SGLT2 inhibitors on stroke outcomes.

Severe hypoglycemia is a serious complication of insulin and insulin secretagogue therapy. There have been few studies regarding the association between long-term glycemic variability of A1c and fasting plasma glucose (FPG) and the risk for severe hypoglycemia. Long and colleagues performed a post hoc analysis of the ACCORD study and found that both A1c and FPG variability were associated with a greater risk for severe hypoglycemia in T2D, with FPG being a more sensitive indicator than is A1c variability. Clinicians need to be aware that A1c and FPG variability in insulin- or insulin secretagogue–treated patients with T2D places them at greater risk for severe hypoglycemia and such variability should be considered a potential target of treatment.

Although a higher mean A1c has been linked to diabetes microvascular and macrovascular complications, there is a paucity of data comparing mean A1c and A1c variability and diabetes complications. In a prospective study from Taiwan, Wu and colleagues demonstrated that both mean A1c and A1c variability predicted most diabetes-related complications, with mean A1c being more effective at predicting retinopathy and A1c variability being more effective at predicting a decline in kidney function and cardiovascular and total mortality. Perhaps physicians need to pay more attention to A1c variability and not just the mean A1c over time when assessing an individual and their overall risk for diabetes complications.

Diabetes guidelines recommend sodium-glucose transport protein 2 (SGLT2) inhibitors to reduce kidney disease progression in patients with type 2 diabetes (T2D) and moderate-to-severe albuminuric kidney disease on the basis of renal outcomes trials, such as CREDENCE and DAPA-CKD. However, these trials did not include patients who are at low risk for kidney disease progression.

Mozenson and colleagues published a post hoc analysis of the DECLARE-TIMI 58 trial and focused on patients with low kidney risk. They demonstated that dapagliflozin slowed the progression of kidney disease in patients with T2D at high cardiovascular risk, including those who are at low risk for kidney progression. The absolute benefit for slowing kidney progression was much lower in patients with low kidney risk compared with those who are at high or very high risk (number needed to treat 177 vs 13-23). Though dapagliflozin does provide kidney protection across a spectrum of patients with kidney risk, clinicians should consider the level of risk when starting an SGLT2 inhibitor for slowing kidney disease.

SGLT2 inhibitor outcome trials and meta-analyses have mainly shown neutral results for ischemic stroke, except for sotagliflozin vs placebo in the SCORED trial. In this trial, sotagliflozin was shown to reduce total stroke. Recently, in a retrospective longitudinal cohort study of patients with T2D in Taiwan, Lin and colleagues have shown a significant reduction in new onset stroke among those who use SGLT2 inhibitor compared with those who don't. A 15% relative risk reduction in stroke was shown in an analysis that adjusted for age, sex, and duration of T2D, with a similar reduction in a propensity score-matched analysis. Although limited by its observational design, this study suggests that further research should be continued regarding the impact of SGLT2 inhibitors on stroke outcomes.

Severe hypoglycemia is a serious complication of insulin and insulin secretagogue therapy. There have been few studies regarding the association between long-term glycemic variability of A1c and fasting plasma glucose (FPG) and the risk for severe hypoglycemia. Long and colleagues performed a post hoc analysis of the ACCORD study and found that both A1c and FPG variability were associated with a greater risk for severe hypoglycemia in T2D, with FPG being a more sensitive indicator than is A1c variability. Clinicians need to be aware that A1c and FPG variability in insulin- or insulin secretagogue–treated patients with T2D places them at greater risk for severe hypoglycemia and such variability should be considered a potential target of treatment.

Although a higher mean A1c has been linked to diabetes microvascular and macrovascular complications, there is a paucity of data comparing mean A1c and A1c variability and diabetes complications. In a prospective study from Taiwan, Wu and colleagues demonstrated that both mean A1c and A1c variability predicted most diabetes-related complications, with mean A1c being more effective at predicting retinopathy and A1c variability being more effective at predicting a decline in kidney function and cardiovascular and total mortality. Perhaps physicians need to pay more attention to A1c variability and not just the mean A1c over time when assessing an individual and their overall risk for diabetes complications.

Diabetes guidelines recommend sodium-glucose transport protein 2 (SGLT2) inhibitors to reduce kidney disease progression in patients with type 2 diabetes (T2D) and moderate-to-severe albuminuric kidney disease on the basis of renal outcomes trials, such as CREDENCE and DAPA-CKD. However, these trials did not include patients who are at low risk for kidney disease progression.

Mozenson and colleagues published a post hoc analysis of the DECLARE-TIMI 58 trial and focused on patients with low kidney risk. They demonstated that dapagliflozin slowed the progression of kidney disease in patients with T2D at high cardiovascular risk, including those who are at low risk for kidney progression. The absolute benefit for slowing kidney progression was much lower in patients with low kidney risk compared with those who are at high or very high risk (number needed to treat 177 vs 13-23). Though dapagliflozin does provide kidney protection across a spectrum of patients with kidney risk, clinicians should consider the level of risk when starting an SGLT2 inhibitor for slowing kidney disease.

SGLT2 inhibitor outcome trials and meta-analyses have mainly shown neutral results for ischemic stroke, except for sotagliflozin vs placebo in the SCORED trial. In this trial, sotagliflozin was shown to reduce total stroke. Recently, in a retrospective longitudinal cohort study of patients with T2D in Taiwan, Lin and colleagues have shown a significant reduction in new onset stroke among those who use SGLT2 inhibitor compared with those who don't. A 15% relative risk reduction in stroke was shown in an analysis that adjusted for age, sex, and duration of T2D, with a similar reduction in a propensity score-matched analysis. Although limited by its observational design, this study suggests that further research should be continued regarding the impact of SGLT2 inhibitors on stroke outcomes.

Severe hypoglycemia is a serious complication of insulin and insulin secretagogue therapy. There have been few studies regarding the association between long-term glycemic variability of A1c and fasting plasma glucose (FPG) and the risk for severe hypoglycemia. Long and colleagues performed a post hoc analysis of the ACCORD study and found that both A1c and FPG variability were associated with a greater risk for severe hypoglycemia in T2D, with FPG being a more sensitive indicator than is A1c variability. Clinicians need to be aware that A1c and FPG variability in insulin- or insulin secretagogue–treated patients with T2D places them at greater risk for severe hypoglycemia and such variability should be considered a potential target of treatment.

Although a higher mean A1c has been linked to diabetes microvascular and macrovascular complications, there is a paucity of data comparing mean A1c and A1c variability and diabetes complications. In a prospective study from Taiwan, Wu and colleagues demonstrated that both mean A1c and A1c variability predicted most diabetes-related complications, with mean A1c being more effective at predicting retinopathy and A1c variability being more effective at predicting a decline in kidney function and cardiovascular and total mortality. Perhaps physicians need to pay more attention to A1c variability and not just the mean A1c over time when assessing an individual and their overall risk for diabetes complications.

Let's start with tralokinumab. I previously had the privilege of being lead author on a study of the efficacy of tralokinumab beyond week 16 — the ECZTRA3 study.¹ ECZTRA3 studied tralokinumab at the approved dose (600 mg loading dose followed by 300 mg every other week) vs placebo with concomitant topical corticosteroids (TCS) for an initial 16-week treatment period. Patients who achieved an Investigator's Global Assessment (IGA) score of 0 or 1 or 75% improvement in the Eczema Area and Severity Index (EASI-75) response were then randomly assigned again to receive 300 mg tralokinumab either continuously at every-other-week intervals or a prolonged interval of every 4 weeks (again with concomitant TCS).

With ECZTRA3, we found that patients continued to improve on tralokinumab + TCS well beyond week 16, with increased EASI-75 responses (week 16: 56%; week 32: 70.2%) and sustained or increased improvement across multiple patient-reported outcomes. Together, these results indicate that clinical responses may take more than 16 weeks to achieve with tralokinumab. In addition, some patients may be able to maintain clinical responses using fewer injections at 4-week intervals. This may allow tailoring dosing to individual patient needs. In fact, tralokinumab is approved in the United States and other regions with the option of every-2-week or every-4-week maintenance dosing in patients who have a good clinical response at week 16.

Since AD can be a lifelong disease, we expect that some patients will need to remain on various therapies for extended periods of time, perhaps many years, in order to maintain long-term control. It is imperative that any long-term treatment demonstrate a good long-term safety and efficacy profile. Blauvelt and colleagues published 2-year interim results from the ongoing ECZTEND long-term, open-label extension study of tralokinumab. They showed no new safety signals and stable rates of adverse events compared with earlier time points. Additionally, they showed that 82.5% of patients treated with open-label tralokinumab + TCS for 2 years maintained EASI-75 responses. These data are reassuring and support the potential use of tralokinumab as a long-term treatment option in AD.

While dupilumab is not approved for every-4-week maintenance dosing, a recent study by Spekhorst and colleagues confirmed that dupilumab can also be safely and effectively administered at intervals of every 4 weeks or every 6-8 weeks. Analyzing data from the BioDay real-world observational registry, they found that among patients who achieved good clinical responses (EASI scores ≤ 7) after 52 weeks of treatment with dupilumab administered every 2 weeks, many patients were able to maintain those responses at 3 months after the interval of administration was increased to every 4 weeks (> 80%) or 6-8 weeks (93.3%). These real-world data confirm the results previously observed in the phase 3 SOLO-CONTINUE study² and support the use of maintenance dosing of dupilumab at prolonged intervals, though such use would technically be considered off-label.

Let’s also review some new data for abrocitinib, a once-daily oral preferential Janus kinase (JAK) 1 inhibitor. Reich and colleagues reported results from a phase 3 trial of adults with moderate-to-severe AD that compared the safety and efficacy of oral abrocitinib at the higher 200 mg dose vs subcutaneous dupilumab over 26 weeks. They found that more patients achieved ≥ 4-point improvement in the Peak Pruritus Numerical Rating Scale score at week 2 with 200 mg abrocitinib compared with 300 mg dupilumab every other week (48% vs 26%). There were also improved EASI-90 responses at week 4 (29% vs 15%). A dose of 200 mg abrocitinib was also significantly more effective than dupilumab for a number of additional investigator- and patient-reported outcomes. In general, abrocitinib had a faster onset of treatment benefit than dupilumab. However, treatment-emergent adverse events were more common with abrocitinib compared with dupilumab (74% vs 65%). Dupilumab was associated with more ocular adverse events (eg, conjunctivitis), whereas abrocitinib was associated with more headaches, nausea, and herpes zoster infections. These results provide important insights into the comparative effectiveness of treatments in moderate-to-severe AD. Of note, this study compared the higher dose of abrocitinib (200 mg) vs dupilumab. However, in the United States, the FDA-approved label recommends initiating abrocitinib therapy with the lower 100 mg dose and increasing to 200 mg only in those who had an inadequate response to 100 mg.

Additional References

1. Silverberg JI, Toth D, Bieber T, et al, for the ECZTRA 3 study investigators. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: Results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-463. Doi: 10.1111/bjd.19573

2. Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2020;156(2):131-143. Doi: 10.1001/jamadermatol.2019.3617

Let's start with tralokinumab. I previously had the privilege of being lead author on a study of the efficacy of tralokinumab beyond week 16 — the ECZTRA3 study.¹ ECZTRA3 studied tralokinumab at the approved dose (600 mg loading dose followed by 300 mg every other week) vs placebo with concomitant topical corticosteroids (TCS) for an initial 16-week treatment period. Patients who achieved an Investigator's Global Assessment (IGA) score of 0 or 1 or 75% improvement in the Eczema Area and Severity Index (EASI-75) response were then randomly assigned again to receive 300 mg tralokinumab either continuously at every-other-week intervals or a prolonged interval of every 4 weeks (again with concomitant TCS).

With ECZTRA3, we found that patients continued to improve on tralokinumab + TCS well beyond week 16, with increased EASI-75 responses (week 16: 56%; week 32: 70.2%) and sustained or increased improvement across multiple patient-reported outcomes. Together, these results indicate that clinical responses may take more than 16 weeks to achieve with tralokinumab. In addition, some patients may be able to maintain clinical responses using fewer injections at 4-week intervals. This may allow tailoring dosing to individual patient needs. In fact, tralokinumab is approved in the United States and other regions with the option of every-2-week or every-4-week maintenance dosing in patients who have a good clinical response at week 16.

Since AD can be a lifelong disease, we expect that some patients will need to remain on various therapies for extended periods of time, perhaps many years, in order to maintain long-term control. It is imperative that any long-term treatment demonstrate a good long-term safety and efficacy profile. Blauvelt and colleagues published 2-year interim results from the ongoing ECZTEND long-term, open-label extension study of tralokinumab. They showed no new safety signals and stable rates of adverse events compared with earlier time points. Additionally, they showed that 82.5% of patients treated with open-label tralokinumab + TCS for 2 years maintained EASI-75 responses. These data are reassuring and support the potential use of tralokinumab as a long-term treatment option in AD.

While dupilumab is not approved for every-4-week maintenance dosing, a recent study by Spekhorst and colleagues confirmed that dupilumab can also be safely and effectively administered at intervals of every 4 weeks or every 6-8 weeks. Analyzing data from the BioDay real-world observational registry, they found that among patients who achieved good clinical responses (EASI scores ≤ 7) after 52 weeks of treatment with dupilumab administered every 2 weeks, many patients were able to maintain those responses at 3 months after the interval of administration was increased to every 4 weeks (> 80%) or 6-8 weeks (93.3%). These real-world data confirm the results previously observed in the phase 3 SOLO-CONTINUE study² and support the use of maintenance dosing of dupilumab at prolonged intervals, though such use would technically be considered off-label.

Let’s also review some new data for abrocitinib, a once-daily oral preferential Janus kinase (JAK) 1 inhibitor. Reich and colleagues reported results from a phase 3 trial of adults with moderate-to-severe AD that compared the safety and efficacy of oral abrocitinib at the higher 200 mg dose vs subcutaneous dupilumab over 26 weeks. They found that more patients achieved ≥ 4-point improvement in the Peak Pruritus Numerical Rating Scale score at week 2 with 200 mg abrocitinib compared with 300 mg dupilumab every other week (48% vs 26%). There were also improved EASI-90 responses at week 4 (29% vs 15%). A dose of 200 mg abrocitinib was also significantly more effective than dupilumab for a number of additional investigator- and patient-reported outcomes. In general, abrocitinib had a faster onset of treatment benefit than dupilumab. However, treatment-emergent adverse events were more common with abrocitinib compared with dupilumab (74% vs 65%). Dupilumab was associated with more ocular adverse events (eg, conjunctivitis), whereas abrocitinib was associated with more headaches, nausea, and herpes zoster infections. These results provide important insights into the comparative effectiveness of treatments in moderate-to-severe AD. Of note, this study compared the higher dose of abrocitinib (200 mg) vs dupilumab. However, in the United States, the FDA-approved label recommends initiating abrocitinib therapy with the lower 100 mg dose and increasing to 200 mg only in those who had an inadequate response to 100 mg.

Additional References

1. Silverberg JI, Toth D, Bieber T, et al, for the ECZTRA 3 study investigators. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: Results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-463. Doi: 10.1111/bjd.19573

2. Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2020;156(2):131-143. Doi: 10.1001/jamadermatol.2019.3617

Let's start with tralokinumab. I previously had the privilege of being lead author on a study of the efficacy of tralokinumab beyond week 16 — the ECZTRA3 study.¹ ECZTRA3 studied tralokinumab at the approved dose (600 mg loading dose followed by 300 mg every other week) vs placebo with concomitant topical corticosteroids (TCS) for an initial 16-week treatment period. Patients who achieved an Investigator's Global Assessment (IGA) score of 0 or 1 or 75% improvement in the Eczema Area and Severity Index (EASI-75) response were then randomly assigned again to receive 300 mg tralokinumab either continuously at every-other-week intervals or a prolonged interval of every 4 weeks (again with concomitant TCS).

With ECZTRA3, we found that patients continued to improve on tralokinumab + TCS well beyond week 16, with increased EASI-75 responses (week 16: 56%; week 32: 70.2%) and sustained or increased improvement across multiple patient-reported outcomes. Together, these results indicate that clinical responses may take more than 16 weeks to achieve with tralokinumab. In addition, some patients may be able to maintain clinical responses using fewer injections at 4-week intervals. This may allow tailoring dosing to individual patient needs. In fact, tralokinumab is approved in the United States and other regions with the option of every-2-week or every-4-week maintenance dosing in patients who have a good clinical response at week 16.

Since AD can be a lifelong disease, we expect that some patients will need to remain on various therapies for extended periods of time, perhaps many years, in order to maintain long-term control. It is imperative that any long-term treatment demonstrate a good long-term safety and efficacy profile. Blauvelt and colleagues published 2-year interim results from the ongoing ECZTEND long-term, open-label extension study of tralokinumab. They showed no new safety signals and stable rates of adverse events compared with earlier time points. Additionally, they showed that 82.5% of patients treated with open-label tralokinumab + TCS for 2 years maintained EASI-75 responses. These data are reassuring and support the potential use of tralokinumab as a long-term treatment option in AD.

While dupilumab is not approved for every-4-week maintenance dosing, a recent study by Spekhorst and colleagues confirmed that dupilumab can also be safely and effectively administered at intervals of every 4 weeks or every 6-8 weeks. Analyzing data from the BioDay real-world observational registry, they found that among patients who achieved good clinical responses (EASI scores ≤ 7) after 52 weeks of treatment with dupilumab administered every 2 weeks, many patients were able to maintain those responses at 3 months after the interval of administration was increased to every 4 weeks (> 80%) or 6-8 weeks (93.3%). These real-world data confirm the results previously observed in the phase 3 SOLO-CONTINUE study² and support the use of maintenance dosing of dupilumab at prolonged intervals, though such use would technically be considered off-label.

Let’s also review some new data for abrocitinib, a once-daily oral preferential Janus kinase (JAK) 1 inhibitor. Reich and colleagues reported results from a phase 3 trial of adults with moderate-to-severe AD that compared the safety and efficacy of oral abrocitinib at the higher 200 mg dose vs subcutaneous dupilumab over 26 weeks. They found that more patients achieved ≥ 4-point improvement in the Peak Pruritus Numerical Rating Scale score at week 2 with 200 mg abrocitinib compared with 300 mg dupilumab every other week (48% vs 26%). There were also improved EASI-90 responses at week 4 (29% vs 15%). A dose of 200 mg abrocitinib was also significantly more effective than dupilumab for a number of additional investigator- and patient-reported outcomes. In general, abrocitinib had a faster onset of treatment benefit than dupilumab. However, treatment-emergent adverse events were more common with abrocitinib compared with dupilumab (74% vs 65%). Dupilumab was associated with more ocular adverse events (eg, conjunctivitis), whereas abrocitinib was associated with more headaches, nausea, and herpes zoster infections. These results provide important insights into the comparative effectiveness of treatments in moderate-to-severe AD. Of note, this study compared the higher dose of abrocitinib (200 mg) vs dupilumab. However, in the United States, the FDA-approved label recommends initiating abrocitinib therapy with the lower 100 mg dose and increasing to 200 mg only in those who had an inadequate response to 100 mg.

Additional References

1. Silverberg JI, Toth D, Bieber T, et al, for the ECZTRA 3 study investigators. Tralokinumab plus topical corticosteroids for the treatment of moderate-to-severe atopic dermatitis: Results from the double-blind, randomized, multicentre, placebo-controlled phase III ECZTRA 3 trial. Br J Dermatol. 2021;184(3):450-463. Doi: 10.1111/bjd.19573

2. Worm M, Simpson EL, Thaçi D, et al. Efficacy and safety of multiple dupilumab dose regimens after initial successful treatment in patients with atopic dermatitis: A randomized clinical trial. JAMA Dermatol. 2020;156(2):131-143. Doi: 10.1001/jamadermatol.2019.3617

Many sodium-glucose cotransporter-2 (SGLT2) inhibitors are approved for use at two doses, but there are few clinical data regarding the metabolic impact of uptitrating an SGLT2 inhibitor from the lower to the higher dose in clinical practice. Matsumura and colleagues published the results of a retrospective, longitudinal study at a single institution in Japan. A total of 52 participants who were treated with 10 mg empagliflozin once daily were analyzed at 26 weeks after the dose had been increased to 25 mg once daily. The researchers reported a 0.6 kg weight reduction, a 0.15% reduction in A1c, and a 22.1 mg/dL reduction in triglycerides in the participants on the higher dose of empagliflozin. Although the benefits of the higher dose were rather small, this study does aid the clinician regarding the clinical impact of increasing the dose of empagliflozin.

Outcome studies with SGLT2 inhibitors have shown reductions in major adverse cardiovascular events (MACE), heart failure hospitalization, and mortality. However, clinicians may be reluctant to initiate SGLT2 inhibitors in frail individuals as they are often excluded from randomized trials and may be more likely to have side effects from this class of medications. Wood and colleagues conducted a cohort study in Australia, comparing the effectiveness of SGLT2 inhibitors to that of dipeptidyl peptidase-4 (DPP-4) inhibitors. The study was done with individuals with type 2 diabetes who were initiated on these agents within 60 days of a hospital discharge. It was noted that SGLT2 inhibitors significantly reduced MACE, heart failure hospitalization, and mortality compared with DPP-4 inhibitors, and this benefit was present in both frail and nonfrail individuals. The study did not report on tolerability issues and is limited by the cohort design, but it does suggest a cardiovascular benefit among frail patients with type 2 diabetes who are treated with SGLT2 inhibitors, and it may be reassuring when considering an SGLT2 inhibitor in a frail person.

In my July 2022 commentary, I discussed the results of AWARD-PEDS, which demonstrated a significant A1c reduction but no weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide in youth with type 2 diabetes. Tamborlane and colleagues have now reported the results of a randomized trial that studied the efficacy and safety of 2 mg exenatide once weekly in youth with type 2 diabetes. Similarly to the AWARD-PEDS study, A1c was significantly reduced compared with placebo, with a difference of -0.85% at 24 weeks. Also similarly to AWARD-PEDS, there was no significant difference in body weight between the GLP-1RA and placebo groups. There are now three studies showing glycemic benefits but little weight loss with GLP-1RA treatment in youth with type 2 diabetes, and while the glycemic benefits are encouraging, it remains perplexing why these studies have not demonstrated the weight loss that has consistently been demonstrated in adult studies of GLP-1RA.

Clinicians often choose a second-generation basal insulin analog (glargine U300, degludec) over a first-generation basal analog (glargine U100, detemir) because of lower rates of hypoglycemia. Randomized clinical trials and real-world evidence (RWE) studies comparing glargine U100 vs degludec have shown somewhat inconsistent results. In the newest RWE study comparing these two second-generation analogs, RESTORE-2 NAIVE, Fadini and colleagues reported that 6 months after initiating either glargine U300 or degludec in insulin-naive type 2 diabetes, there was a similar improvement in glycemia, no weight gain, and low hypoglycemia rates in each group. RESTORE-2 is another study demonstrating similar results between the two second-generation insulin analogs and helps build our understanding that these two insulins are more similar than different.

Many sodium-glucose cotransporter-2 (SGLT2) inhibitors are approved for use at two doses, but there are few clinical data regarding the metabolic impact of uptitrating an SGLT2 inhibitor from the lower to the higher dose in clinical practice. Matsumura and colleagues published the results of a retrospective, longitudinal study at a single institution in Japan. A total of 52 participants who were treated with 10 mg empagliflozin once daily were analyzed at 26 weeks after the dose had been increased to 25 mg once daily. The researchers reported a 0.6 kg weight reduction, a 0.15% reduction in A1c, and a 22.1 mg/dL reduction in triglycerides in the participants on the higher dose of empagliflozin. Although the benefits of the higher dose were rather small, this study does aid the clinician regarding the clinical impact of increasing the dose of empagliflozin.

Outcome studies with SGLT2 inhibitors have shown reductions in major adverse cardiovascular events (MACE), heart failure hospitalization, and mortality. However, clinicians may be reluctant to initiate SGLT2 inhibitors in frail individuals as they are often excluded from randomized trials and may be more likely to have side effects from this class of medications. Wood and colleagues conducted a cohort study in Australia, comparing the effectiveness of SGLT2 inhibitors to that of dipeptidyl peptidase-4 (DPP-4) inhibitors. The study was done with individuals with type 2 diabetes who were initiated on these agents within 60 days of a hospital discharge. It was noted that SGLT2 inhibitors significantly reduced MACE, heart failure hospitalization, and mortality compared with DPP-4 inhibitors, and this benefit was present in both frail and nonfrail individuals. The study did not report on tolerability issues and is limited by the cohort design, but it does suggest a cardiovascular benefit among frail patients with type 2 diabetes who are treated with SGLT2 inhibitors, and it may be reassuring when considering an SGLT2 inhibitor in a frail person.

In my July 2022 commentary, I discussed the results of AWARD-PEDS, which demonstrated a significant A1c reduction but no weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide in youth with type 2 diabetes. Tamborlane and colleagues have now reported the results of a randomized trial that studied the efficacy and safety of 2 mg exenatide once weekly in youth with type 2 diabetes. Similarly to the AWARD-PEDS study, A1c was significantly reduced compared with placebo, with a difference of -0.85% at 24 weeks. Also similarly to AWARD-PEDS, there was no significant difference in body weight between the GLP-1RA and placebo groups. There are now three studies showing glycemic benefits but little weight loss with GLP-1RA treatment in youth with type 2 diabetes, and while the glycemic benefits are encouraging, it remains perplexing why these studies have not demonstrated the weight loss that has consistently been demonstrated in adult studies of GLP-1RA.

Clinicians often choose a second-generation basal insulin analog (glargine U300, degludec) over a first-generation basal analog (glargine U100, detemir) because of lower rates of hypoglycemia. Randomized clinical trials and real-world evidence (RWE) studies comparing glargine U100 vs degludec have shown somewhat inconsistent results. In the newest RWE study comparing these two second-generation analogs, RESTORE-2 NAIVE, Fadini and colleagues reported that 6 months after initiating either glargine U300 or degludec in insulin-naive type 2 diabetes, there was a similar improvement in glycemia, no weight gain, and low hypoglycemia rates in each group. RESTORE-2 is another study demonstrating similar results between the two second-generation insulin analogs and helps build our understanding that these two insulins are more similar than different.

Many sodium-glucose cotransporter-2 (SGLT2) inhibitors are approved for use at two doses, but there are few clinical data regarding the metabolic impact of uptitrating an SGLT2 inhibitor from the lower to the higher dose in clinical practice. Matsumura and colleagues published the results of a retrospective, longitudinal study at a single institution in Japan. A total of 52 participants who were treated with 10 mg empagliflozin once daily were analyzed at 26 weeks after the dose had been increased to 25 mg once daily. The researchers reported a 0.6 kg weight reduction, a 0.15% reduction in A1c, and a 22.1 mg/dL reduction in triglycerides in the participants on the higher dose of empagliflozin. Although the benefits of the higher dose were rather small, this study does aid the clinician regarding the clinical impact of increasing the dose of empagliflozin.

Outcome studies with SGLT2 inhibitors have shown reductions in major adverse cardiovascular events (MACE), heart failure hospitalization, and mortality. However, clinicians may be reluctant to initiate SGLT2 inhibitors in frail individuals as they are often excluded from randomized trials and may be more likely to have side effects from this class of medications. Wood and colleagues conducted a cohort study in Australia, comparing the effectiveness of SGLT2 inhibitors to that of dipeptidyl peptidase-4 (DPP-4) inhibitors. The study was done with individuals with type 2 diabetes who were initiated on these agents within 60 days of a hospital discharge. It was noted that SGLT2 inhibitors significantly reduced MACE, heart failure hospitalization, and mortality compared with DPP-4 inhibitors, and this benefit was present in both frail and nonfrail individuals. The study did not report on tolerability issues and is limited by the cohort design, but it does suggest a cardiovascular benefit among frail patients with type 2 diabetes who are treated with SGLT2 inhibitors, and it may be reassuring when considering an SGLT2 inhibitor in a frail person.

In my July 2022 commentary, I discussed the results of AWARD-PEDS, which demonstrated a significant A1c reduction but no weight loss with the glucagon-like peptide-1 receptor agonist (GLP-1RA) dulaglutide in youth with type 2 diabetes. Tamborlane and colleagues have now reported the results of a randomized trial that studied the efficacy and safety of 2 mg exenatide once weekly in youth with type 2 diabetes. Similarly to the AWARD-PEDS study, A1c was significantly reduced compared with placebo, with a difference of -0.85% at 24 weeks. Also similarly to AWARD-PEDS, there was no significant difference in body weight between the GLP-1RA and placebo groups. There are now three studies showing glycemic benefits but little weight loss with GLP-1RA treatment in youth with type 2 diabetes, and while the glycemic benefits are encouraging, it remains perplexing why these studies have not demonstrated the weight loss that has consistently been demonstrated in adult studies of GLP-1RA.

Clinicians often choose a second-generation basal insulin analog (glargine U300, degludec) over a first-generation basal analog (glargine U100, detemir) because of lower rates of hypoglycemia. Randomized clinical trials and real-world evidence (RWE) studies comparing glargine U100 vs degludec have shown somewhat inconsistent results. In the newest RWE study comparing these two second-generation analogs, RESTORE-2 NAIVE, Fadini and colleagues reported that 6 months after initiating either glargine U300 or degludec in insulin-naive type 2 diabetes, there was a similar improvement in glycemia, no weight gain, and low hypoglycemia rates in each group. RESTORE-2 is another study demonstrating similar results between the two second-generation insulin analogs and helps build our understanding that these two insulins are more similar than different.

In the PD-L1 CPS ≥ 1 subgroup, however, no significant OS benefit was observed (median OS 17.6 months vs 16.0 months; HR 0.86; 95% CI 0.72-1.04; P = .1125). Additionally, in an exploratory analysis, the addition of pembrolizumab showed consistent OS benefit among patients whose tumors express PD-L1 with a CPS of 10-19 and CPS ≥ 20. The updated progression-free survival (PFS) and objective response rates (ORR) were consistent with prior interim data. No new safety signals were observed after the longer follow-up.

These data confirm that pembrolizumab plus chemotherapy should remain the first-line treatment for patients with advanced or metastatic TNBC whose tumors express PD-L1 with a CPS of ≥ 10. The treatment of metastatic TNBC with low or negative PD-L1 CPS scores remains an area of unmet clinical need, and further research is needed to explore better options for these patients.

Wang and colleagues presented results from a randomized, phase 3 trial comparing first-line nab-paclitaxel plus cisplatin (AP) with gemcitabine plus cisplatin (GP) among 254 patients with previously untreated metastatic TNBC. Median PFS (mPFS) was 9.8 months with AP vs 7.4 months with GP (HR 0.67; 95% CI 0.50-0.88; P  =  .004). Furthermore, AP had significantly higher ORR compared with GP (81.1% vs 56.3%; P  <  .001) and significantly improved median OS (26.3 months vs 22.9 months; HR 0.62; 95% CI 0.44-0.90; P  =  .010).

In the exploratory analyses of PFS by stratification factors, the mPFS was significantly longer in the AP group compared with the GP group in the majority of subgroups, except for those patients who presented with de novo stage IV disease or a disease-free interval of < 1 year. Regarding safety data, a significantly higher incidence of grade ≥ 3 neuropathy (19% vs 0%) and nausea and vomiting (6% vs 1%) was noted in the AP group compared with the GP group, while grade ≥ 3 thrombocytopenia was more common in the GP group compared with the AP group (29.4% vs 3.9%).

The AP doublet achieved superior efficacy with a manageable safety profile, compared with GP in patients with previously untreated metastatic TNBC. It is not clear, however, whether the AP doublet is superior to single-agent therapy in this setting, especially given several prior studies that showed no survival benefit and increased toxicity from combination therapy compared with sequential single-agent therapy in metastatic breast cancer. More studies are needed to establish the role of the AP doublet in combination with pembrolizumab in this cohort of patients, given that first-line pembrolizumab plus chemotherapy is considered the standard of care for patients with metastatic TNBC whose tumors express PD-L1.

Rugo and colleagues presented results from a randomized phase 3 study comparing 205 mg/m²oral paclitaxel plus 15 mg encequidar (a novel P-glycoprotein pump inhibitor that allows oral absorption of paclitaxel) on 3 consecutive days per week vs 175 mg/m² intravenous paclitaxel once every 3 weeks. The study enrolled 402 postmenopausal women from Latin America with metastatic breast cancer who were at least 1 year from their last taxane therapy. Oral paclitaxel plus encequidar (oPac + E) increased the confirmed tumor response compared with intravenous paclitaxel (IVpac) (36% vs 23%; P = .01). There was a trend toward improved PFS (8.4 vs 7.4 months; HR 0.768; 95.5% CI 0.584-1.01; P = .046) and OS (22.7 vs 16.5 months; HR 0.794; 95.5% CI 0.607-1.037; P = .08) with oPac + E compared to IVpac, respectively. Grade ≥3 adverse events were comparable with oPac + E and IVpac (55% vs 53%), although a lower incidence of grade 3 neuropathy (2% vs 15%) and alopecia (49% vs 62%) was noted with oPac + E compared with IVpac. A higher incidence of grade ≥ 3 gastrointestinal toxicity (nausea, vomiting, and diarrhea) and grade 4 neutropenic complications was noted in the oPac + E group. Patients with elevated baseline liver enzymes were particularly susceptible to early neutropenia and serious infections.

This study demonstrates that oral paclitaxel can be a possible alternative treatment option to intravenous paclitaxel in a select group of patients with metastatic breast cancer. High-grade neutropenia appears to be a major treatment-limiting toxicity with oPac + E. Therefore, careful patient selection and close monitoring are crucial for the successful management of this adverse event.

In the PD-L1 CPS ≥ 1 subgroup, however, no significant OS benefit was observed (median OS 17.6 months vs 16.0 months; HR 0.86; 95% CI 0.72-1.04; P = .1125). Additionally, in an exploratory analysis, the addition of pembrolizumab showed consistent OS benefit among patients whose tumors express PD-L1 with a CPS of 10-19 and CPS ≥ 20. The updated progression-free survival (PFS) and objective response rates (ORR) were consistent with prior interim data. No new safety signals were observed after the longer follow-up.

These data confirm that pembrolizumab plus chemotherapy should remain the first-line treatment for patients with advanced or metastatic TNBC whose tumors express PD-L1 with a CPS of ≥ 10. The treatment of metastatic TNBC with low or negative PD-L1 CPS scores remains an area of unmet clinical need, and further research is needed to explore better options for these patients.

Wang and colleagues presented results from a randomized, phase 3 trial comparing first-line nab-paclitaxel plus cisplatin (AP) with gemcitabine plus cisplatin (GP) among 254 patients with previously untreated metastatic TNBC. Median PFS (mPFS) was 9.8 months with AP vs 7.4 months with GP (HR 0.67; 95% CI 0.50-0.88; P  =  .004). Furthermore, AP had significantly higher ORR compared with GP (81.1% vs 56.3%; P  <  .001) and significantly improved median OS (26.3 months vs 22.9 months; HR 0.62; 95% CI 0.44-0.90; P  =  .010).

In the exploratory analyses of PFS by stratification factors, the mPFS was significantly longer in the AP group compared with the GP group in the majority of subgroups, except for those patients who presented with de novo stage IV disease or a disease-free interval of < 1 year. Regarding safety data, a significantly higher incidence of grade ≥ 3 neuropathy (19% vs 0%) and nausea and vomiting (6% vs 1%) was noted in the AP group compared with the GP group, while grade ≥ 3 thrombocytopenia was more common in the GP group compared with the AP group (29.4% vs 3.9%).

The AP doublet achieved superior efficacy with a manageable safety profile, compared with GP in patients with previously untreated metastatic TNBC. It is not clear, however, whether the AP doublet is superior to single-agent therapy in this setting, especially given several prior studies that showed no survival benefit and increased toxicity from combination therapy compared with sequential single-agent therapy in metastatic breast cancer. More studies are needed to establish the role of the AP doublet in combination with pembrolizumab in this cohort of patients, given that first-line pembrolizumab plus chemotherapy is considered the standard of care for patients with metastatic TNBC whose tumors express PD-L1.

Rugo and colleagues presented results from a randomized phase 3 study comparing 205 mg/m²oral paclitaxel plus 15 mg encequidar (a novel P-glycoprotein pump inhibitor that allows oral absorption of paclitaxel) on 3 consecutive days per week vs 175 mg/m² intravenous paclitaxel once every 3 weeks. The study enrolled 402 postmenopausal women from Latin America with metastatic breast cancer who were at least 1 year from their last taxane therapy. Oral paclitaxel plus encequidar (oPac + E) increased the confirmed tumor response compared with intravenous paclitaxel (IVpac) (36% vs 23%; P = .01). There was a trend toward improved PFS (8.4 vs 7.4 months; HR 0.768; 95.5% CI 0.584-1.01; P = .046) and OS (22.7 vs 16.5 months; HR 0.794; 95.5% CI 0.607-1.037; P = .08) with oPac + E compared to IVpac, respectively. Grade ≥3 adverse events were comparable with oPac + E and IVpac (55% vs 53%), although a lower incidence of grade 3 neuropathy (2% vs 15%) and alopecia (49% vs 62%) was noted with oPac + E compared with IVpac. A higher incidence of grade ≥ 3 gastrointestinal toxicity (nausea, vomiting, and diarrhea) and grade 4 neutropenic complications was noted in the oPac + E group. Patients with elevated baseline liver enzymes were particularly susceptible to early neutropenia and serious infections.

This study demonstrates that oral paclitaxel can be a possible alternative treatment option to intravenous paclitaxel in a select group of patients with metastatic breast cancer. High-grade neutropenia appears to be a major treatment-limiting toxicity with oPac + E. Therefore, careful patient selection and close monitoring are crucial for the successful management of this adverse event.

In the PD-L1 CPS ≥ 1 subgroup, however, no significant OS benefit was observed (median OS 17.6 months vs 16.0 months; HR 0.86; 95% CI 0.72-1.04; P = .1125). Additionally, in an exploratory analysis, the addition of pembrolizumab showed consistent OS benefit among patients whose tumors express PD-L1 with a CPS of 10-19 and CPS ≥ 20. The updated progression-free survival (PFS) and objective response rates (ORR) were consistent with prior interim data. No new safety signals were observed after the longer follow-up.

These data confirm that pembrolizumab plus chemotherapy should remain the first-line treatment for patients with advanced or metastatic TNBC whose tumors express PD-L1 with a CPS of ≥ 10. The treatment of metastatic TNBC with low or negative PD-L1 CPS scores remains an area of unmet clinical need, and further research is needed to explore better options for these patients.

Wang and colleagues presented results from a randomized, phase 3 trial comparing first-line nab-paclitaxel plus cisplatin (AP) with gemcitabine plus cisplatin (GP) among 254 patients with previously untreated metastatic TNBC. Median PFS (mPFS) was 9.8 months with AP vs 7.4 months with GP (HR 0.67; 95% CI 0.50-0.88; P  =  .004). Furthermore, AP had significantly higher ORR compared with GP (81.1% vs 56.3%; P  <  .001) and significantly improved median OS (26.3 months vs 22.9 months; HR 0.62; 95% CI 0.44-0.90; P  =  .010).

In the exploratory analyses of PFS by stratification factors, the mPFS was significantly longer in the AP group compared with the GP group in the majority of subgroups, except for those patients who presented with de novo stage IV disease or a disease-free interval of < 1 year. Regarding safety data, a significantly higher incidence of grade ≥ 3 neuropathy (19% vs 0%) and nausea and vomiting (6% vs 1%) was noted in the AP group compared with the GP group, while grade ≥ 3 thrombocytopenia was more common in the GP group compared with the AP group (29.4% vs 3.9%).

The AP doublet achieved superior efficacy with a manageable safety profile, compared with GP in patients with previously untreated metastatic TNBC. It is not clear, however, whether the AP doublet is superior to single-agent therapy in this setting, especially given several prior studies that showed no survival benefit and increased toxicity from combination therapy compared with sequential single-agent therapy in metastatic breast cancer. More studies are needed to establish the role of the AP doublet in combination with pembrolizumab in this cohort of patients, given that first-line pembrolizumab plus chemotherapy is considered the standard of care for patients with metastatic TNBC whose tumors express PD-L1.

Rugo and colleagues presented results from a randomized phase 3 study comparing 205 mg/m²oral paclitaxel plus 15 mg encequidar (a novel P-glycoprotein pump inhibitor that allows oral absorption of paclitaxel) on 3 consecutive days per week vs 175 mg/m² intravenous paclitaxel once every 3 weeks. The study enrolled 402 postmenopausal women from Latin America with metastatic breast cancer who were at least 1 year from their last taxane therapy. Oral paclitaxel plus encequidar (oPac + E) increased the confirmed tumor response compared with intravenous paclitaxel (IVpac) (36% vs 23%; P = .01). There was a trend toward improved PFS (8.4 vs 7.4 months; HR 0.768; 95.5% CI 0.584-1.01; P = .046) and OS (22.7 vs 16.5 months; HR 0.794; 95.5% CI 0.607-1.037; P = .08) with oPac + E compared to IVpac, respectively. Grade ≥3 adverse events were comparable with oPac + E and IVpac (55% vs 53%), although a lower incidence of grade 3 neuropathy (2% vs 15%) and alopecia (49% vs 62%) was noted with oPac + E compared with IVpac. A higher incidence of grade ≥ 3 gastrointestinal toxicity (nausea, vomiting, and diarrhea) and grade 4 neutropenic complications was noted in the oPac + E group. Patients with elevated baseline liver enzymes were particularly susceptible to early neutropenia and serious infections.

This study demonstrates that oral paclitaxel can be a possible alternative treatment option to intravenous paclitaxel in a select group of patients with metastatic breast cancer. High-grade neutropenia appears to be a major treatment-limiting toxicity with oPac + E. Therefore, careful patient selection and close monitoring are crucial for the successful management of this adverse event.

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

Recent publications on psoriatic arthritis (PsA) have focused on targeted therapies, particularly those targeting interleukin (IL) 17 and 23. Bimekizumab is a novel biologic that dually inhibits IL-17A and IL-17F. Coates and colleagues reported 3-year results from the phase 2b BE ACTIVE trial that included 206 adults with active PsA randomly assigned to receive bimekizumab or placebo for 48 weeks, of which 184 patients were enrolled in the open-label extension phase for a further 104 weeks of treatment. They report that at least 20% improvement in American College of Rheumatology score was maintained by 64.1% of patients at week 152 compared with 72.3% of patients at week 48. By week 152, 89.3% of patients had reported one or more treatment-emergent adverse event (TEAE), with serious TEAE being reported by 10.7% of patients. Fungal infections are of special interest when inhibiting both IL-17A and IL-17F. It was observed that 9.7% had fungal infections (all mild-to-moderate and localized), of which 4.6% had candidiasis. Thus, bimekizumab shows promise as a new therapy for PsA.

In addition to improving signs and symptoms, clinically meaningful improvement in health-related quality of life is an important goal of treatment. Two studies reported improvement in patient reported outcomes on treatment with IL-23 inhibitors.

An analysis of data from the phase 3 DISCOVER 2 trial included 738 biologic-naive patients with active PsA and inadequate response to standard treatments. These patients were randomly assigned to receive 100 mg guselkumab every 4 weeks (Q4W) or every 8 weeks (Q8W) or placebo. Curtis and colleagues showed that a significantly higher proportion of patients receiving guselkumab Q4W/Q8W vs placebo reported achieving minimally important differences (MID) in the EuroQol 5-Dimension 5-Level (EQ-5D-5L) Index (56.0%/56.0% vs 43.4%; P < .006) and Visual Analog Scale (EQ-VAS) score (62.8%/63.5% vs 44.4%; P < .0001) at week 24, with more than 60% of patients reporting improvements at week 52.

Similarly, analyses of data by Kristensen and colleagues from two phase 3 trials, KEEPsAKE-1 and KEEPsAKE-2, included adults with PsA and inadequate response/intolerance to disease-modifying antirheumatic drugs or biologics. The patients were randomly assigned to receive risankizumab or placebo for 24 weeks and only risankizumab during weeks 24-52. At week 24, patients receiving risankizumab vs placebo were significantly more likely to report achieving MID in Patient's Global Assessment of Disease Activity (PtGA) in both KEEPsAKE-1 (odds ratio [OR] 2.0; P < .001) and KEEPsAKE-2 (OR 1.9; P < .01) studies, with further improvement at week 52. Improvement was also seen on the Patient's Assessment of Pain, Health Assessment Questionnaire – Disability Index, Short-Form 36 Physical and Mental Component Summary scores, EQ-5D-5L, Functional Assessment of Chronic Illness Therapy – Fatigue, and Work Productivity and Activity Impairment.

An interesting insight from two studies showed the importance of nail disease in predicting treatment response. A post hoc analysis by Helliwell and colleagues of the phase 3 SEAM-PsA trial of 851 biologic/methotrexate-naive patients with active PsA who were randomly assigned to receive methotrexate monotherapy, etanercept monotherapy, or methotrexate + etanercept combination therapy showed that the presence of both dactylitis and nail disease at baseline were significantly associated with the achievement of minimal disease activity (OR 1.4; P = .0457; and OR 1.8; P = .0233, respectively), as well as low PsA Disease Activity Score (OR 1.8; P = .0014; and OR 1.8; P = .0168, respectively).

Similarly, a post hoc analysis by Baraliakos and colleagues of the phase 3b MAXIMISE trial of 473 adult patients with PsA and axial manifestations who were randomly assigned to receive secukinumab (150 or 300 mg) or placebo showed that the presence vs the absence of nail dystrophy was associated with the achievement of significantly better Assessment of SpondyloArthritis International Society 20 response in the 300 mg secukinumab group (OR 5.0; 95% CI 1.47-17.19).

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

The potential to prevent clinical rheumatoid arthritis (RA) in patients at risk of developing arthritis is of long-standing interest in the rheumatology community. Other studies have addressed the potential for early treatment with glucocorticoids, hydroxychloroquine, or biologics to prevent arthritis, with mixed results. Few published studies have assessed the efficacy of methotrexate in the prevention of arthritis. A randomized controlled trial by Krijbolder and colleagues of adults with arthralgias deemed to be at risk for progression to RA evaluated the use of a single intramuscular steroid injection combined with 1 year of oral methotrexate, compared with placebo, for preventing the development of RA according to the 2010 American College of Rheumatology classification criteria. Although no difference was seen between the groups in development of RA, those treated with methotrexate did have lower levels of joint inflammation seen on MRI and better functional status as per Health Assessment Questionnaire score.

Su and colleagues also looked at the impact of different medications on the development of RA. Using a national health insurance database in Taiwan (between 1997 and 2013), they studied the use of biguanides and sulfonylureas in patients with diabetes and the risk for incident RA. In over 90,000 patients with diabetes, a longer duration of sulfonylurea or biguanide prescription within the first 3 years of diabetes diagnosis was associated with a lower risk for RA compared with non-use. However, use of any antihyperglycemic agents was also associated with lower risk for RA incidence. Limited information is available on both the severity of diabetes and activity of RA, so even a potential mechanism in terms of reduction of blood glucose or inflammation is hard to determine, and more detailed studies are needed.

The safety of different treatments during pregnancy, as well as the effect of both RA and its treatment on pregnancy outcomes, have been areas of research interest in terms of counseling patients with RA about pregnancy planning and management of medications. Gerardi and colleagues followed 63 patients with RA prospectively during pregnancy. They found that although the general understanding is that inflammatory arthritis improves during pregnancy, the percentage of patients with moderate and high disease activity increased slightly, and 37% of patients experienced a flare. Flares were associated with elevated C-reactive protein (CRP) levels and use of multiple prior biologic disease-modifying antirheumatic drugs (bDMARD) (suggesting overall more active arthritis), as well as bDMARD discontinuation in early pregnancy. Similarly, preterm delivery was associated with elevated CRP, higher Disease Activity Score-28 scores, and flares. The study findings provide further support for the importance of controlling maternal disease activity in favoring a better RA course as well as better pregnancy outcomes.

Smeele and colleagues recently published an analysis of the PreCARA cohort study looking at birthweight in pregnant patients with RA. RA is associated with children being born small for gestational age. In this cohort study of 188 pregnant patients with RA, the treatment protocol before pregnancy included hydroxychloroquine, sulfasalazine, prednisone, and anti–tumor necrosis factor (TNF) agents (adalimumab, infliximab, etanercept, and certolizumab). Anti-TNF medications were stopped at 20, 20, 28, or 38 weeks, respectively, according to the European Alliance of Associations for Rheumatology (EULAR) recommendations. In terms of gestational age at delivery and congenital malformations, no difference was seen between patients who used anti-TNF agents during pregnancy and those who did not. Anti-TNF use during pregnancy was associated, however, with increased birthweight and a lower percentage of infants who were small for gestational age. These findings are in keeping with those of prior studies, although larger studies would be helpful in determining whether there are critical periods during pregnancy that have a significant effect on birthweight or whether overall control of inflammation is the predominant factor.

Surgical resection plays a critical role in the management of early-stage gastric cancer. Depending on the tumor stage and location, there are different surgical approaches. Complications associated with surgical resection can significantly affect quality of life and ability to receive subsequent treatment. With recent advances in minimally invasive approaches, laparoscopic resections are emerging as an attractive option for patients undergoing oncologic surgeries.

The KLASS-02 trial was a multicenter, randomized, controlled, noninferiority clinical trial, which enrolled 1050 patients with locally advanced gastric cancer. Of the enrolled patients, 974 patients underwent R0 resection either by laparoscopic (n = 492) or open (n = 482) distal gastrectomy. In the previous readout of this study with 3 years of follow-up, laparoscopic distal gastrectomy had noninferior oncologic outcomes compared with open surgery for locally advanced gastric cancer. Son and colleagues are now reporting 5-year follow-up results. Overall survival (OS; 88.9% vs 88.7%; P = .30) and relapse-free survival (79.5% vs 81.1%; P = .658) rates were similar in both surgical groups. The pattern of recurrences was similar between the two groups as well, with peroneal (42.1% of patients) and hematogenous (20.8%) being the most frequent ones. However, patients who underwent laparoscopic vs open distal gastrectomy had a significantly lower late complication rate (6.5% vs 11.0%; P = .01). This study demonstrates that laparoscopic distal gastrectomy is an appropriate alternative to open distal gastrectomy and should be offered to patients who are treated in centers with experience in performing these types of operations.

Peritoneal metastasis is a common site for the spread of gastric cancer. As such, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of this disease has been explored in a number of studies. The effectiveness of prophylactic HIPEC during resection of early-stage gastric cancer remains unknown.

Shen and colleagues conducted a propensity score-matching analysis looking at the efficacy and safety of HIPEC in this setting. The study evaluated outcomes of 395 patients with locally advanced gastric cancer who underwent resection with (n = 146) or without HIPEC (n = 248). In the HIPEC group, OS compared favorably to the surgery-only group (69.9% vs 40.8%, P = .049) and 2-year relapse-free survival was higher with HIPEC (60.7% vs 31.6%, P = .049).

Previously, the CYTO-CHIP propensity score analysis study performed in France demonstrated that HIPEC in addition to cytoreductive surgery resulted in improved OS in patients with advanced gastric cancer and peritoneal metastasis compared to cytoreduction surgery alone.¹ However, with both of these reports, interpretation of the results carries inherent limitations that are associated with retrospective study design. Prior prospective studies, on the other hand, had mixed results. An ongoing phase 3 prospective study of D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP) will hopefully provide a definitive answer regarding the benefit of HIPEC in early-stage gastric cancer management (NCT01882933). Ultimately, going forward, the role of HIPEC in early-stage disease will need to be examined in a prospective study with carefully selected patients, using the latest biomarkers and systemic therapies.

Mismatch repair protein deficient (dMMR) or microsatellite unstable gastric cancer (MSI-H) have distinct biologic behaviors and treatment responses. They are much more responsive to immune checkpoint inhibitors in the metastatic setting. In early-stage disease, exploratory analysis of patients with MSI-H tumors previously enrolled in the perioperative MAGIC trial, revealed that patients with MSI-H tumors had a better prognosis when treated with surgery alone, and they potentially experienced detrimental effects from chemotherapy.²

The GERCOR NEONIPIGA single-arm phase 2 study enrolled 32 patients with resectable dMMR/MSI-H gastric and gastroesophageal junction tumors.³ Patients were treated with 240-mg neoadjuvant nivolumab once every 2 weeks six times and 1-mg/kg ipilimumab once every 6 weeks twice, followed by surgery and 480-mg adjuvant nivolumab once every 4 weeks nine times. Twenty-nine patients underwent resection. All resections were with negative margins (R0). Pathologic complete response was seen in 17 (58.6%) of patients. As of the February 2022 data cutoff, with a median duration of follow-up of 14.9 months, 30 out of 31 patients with early-stage disease remained alive and without recurrence or progression (one evaluable patient had metastatic disease).

These results certainly support further investigation of immunotherapy use in this patient population. However, in the absence of prospective randomized data, the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) remains the standard of care in those who can tolerate it. For patients with MSI-H tumors who are not candidates for combination chemotherapy or whose tumors are progressing on chemotherapy, neoadjuvant immunotherapy is certainly a good option to consider.

Additional References

1. Bonnot P-E et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): A propensity score analysis. J Clin Oncol. 2019;37:2028-2040. Doi: 10.1200/JCO.18.01688

2. Smyth EC et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197-1203. Doi: 10.1001/jamaoncol.2016.6762

3. André T et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022 (Aug 15. Doi: 10.1200/JCO.22.00686

Surgical resection plays a critical role in the management of early-stage gastric cancer. Depending on the tumor stage and location, there are different surgical approaches. Complications associated with surgical resection can significantly affect quality of life and ability to receive subsequent treatment. With recent advances in minimally invasive approaches, laparoscopic resections are emerging as an attractive option for patients undergoing oncologic surgeries.

The KLASS-02 trial was a multicenter, randomized, controlled, noninferiority clinical trial, which enrolled 1050 patients with locally advanced gastric cancer. Of the enrolled patients, 974 patients underwent R0 resection either by laparoscopic (n = 492) or open (n = 482) distal gastrectomy. In the previous readout of this study with 3 years of follow-up, laparoscopic distal gastrectomy had noninferior oncologic outcomes compared with open surgery for locally advanced gastric cancer. Son and colleagues are now reporting 5-year follow-up results. Overall survival (OS; 88.9% vs 88.7%; P = .30) and relapse-free survival (79.5% vs 81.1%; P = .658) rates were similar in both surgical groups. The pattern of recurrences was similar between the two groups as well, with peroneal (42.1% of patients) and hematogenous (20.8%) being the most frequent ones. However, patients who underwent laparoscopic vs open distal gastrectomy had a significantly lower late complication rate (6.5% vs 11.0%; P = .01). This study demonstrates that laparoscopic distal gastrectomy is an appropriate alternative to open distal gastrectomy and should be offered to patients who are treated in centers with experience in performing these types of operations.

Peritoneal metastasis is a common site for the spread of gastric cancer. As such, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of this disease has been explored in a number of studies. The effectiveness of prophylactic HIPEC during resection of early-stage gastric cancer remains unknown.

Shen and colleagues conducted a propensity score-matching analysis looking at the efficacy and safety of HIPEC in this setting. The study evaluated outcomes of 395 patients with locally advanced gastric cancer who underwent resection with (n = 146) or without HIPEC (n = 248). In the HIPEC group, OS compared favorably to the surgery-only group (69.9% vs 40.8%, P = .049) and 2-year relapse-free survival was higher with HIPEC (60.7% vs 31.6%, P = .049).

Previously, the CYTO-CHIP propensity score analysis study performed in France demonstrated that HIPEC in addition to cytoreductive surgery resulted in improved OS in patients with advanced gastric cancer and peritoneal metastasis compared to cytoreduction surgery alone.¹ However, with both of these reports, interpretation of the results carries inherent limitations that are associated with retrospective study design. Prior prospective studies, on the other hand, had mixed results. An ongoing phase 3 prospective study of D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP) will hopefully provide a definitive answer regarding the benefit of HIPEC in early-stage gastric cancer management (NCT01882933). Ultimately, going forward, the role of HIPEC in early-stage disease will need to be examined in a prospective study with carefully selected patients, using the latest biomarkers and systemic therapies.

Mismatch repair protein deficient (dMMR) or microsatellite unstable gastric cancer (MSI-H) have distinct biologic behaviors and treatment responses. They are much more responsive to immune checkpoint inhibitors in the metastatic setting. In early-stage disease, exploratory analysis of patients with MSI-H tumors previously enrolled in the perioperative MAGIC trial, revealed that patients with MSI-H tumors had a better prognosis when treated with surgery alone, and they potentially experienced detrimental effects from chemotherapy.²

The GERCOR NEONIPIGA single-arm phase 2 study enrolled 32 patients with resectable dMMR/MSI-H gastric and gastroesophageal junction tumors.³ Patients were treated with 240-mg neoadjuvant nivolumab once every 2 weeks six times and 1-mg/kg ipilimumab once every 6 weeks twice, followed by surgery and 480-mg adjuvant nivolumab once every 4 weeks nine times. Twenty-nine patients underwent resection. All resections were with negative margins (R0). Pathologic complete response was seen in 17 (58.6%) of patients. As of the February 2022 data cutoff, with a median duration of follow-up of 14.9 months, 30 out of 31 patients with early-stage disease remained alive and without recurrence or progression (one evaluable patient had metastatic disease).

These results certainly support further investigation of immunotherapy use in this patient population. However, in the absence of prospective randomized data, the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) remains the standard of care in those who can tolerate it. For patients with MSI-H tumors who are not candidates for combination chemotherapy or whose tumors are progressing on chemotherapy, neoadjuvant immunotherapy is certainly a good option to consider.

Additional References

1. Bonnot P-E et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): A propensity score analysis. J Clin Oncol. 2019;37:2028-2040. Doi: 10.1200/JCO.18.01688

2. Smyth EC et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197-1203. Doi: 10.1001/jamaoncol.2016.6762

3. André T et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022 (Aug 15. Doi: 10.1200/JCO.22.00686

Surgical resection plays a critical role in the management of early-stage gastric cancer. Depending on the tumor stage and location, there are different surgical approaches. Complications associated with surgical resection can significantly affect quality of life and ability to receive subsequent treatment. With recent advances in minimally invasive approaches, laparoscopic resections are emerging as an attractive option for patients undergoing oncologic surgeries.

The KLASS-02 trial was a multicenter, randomized, controlled, noninferiority clinical trial, which enrolled 1050 patients with locally advanced gastric cancer. Of the enrolled patients, 974 patients underwent R0 resection either by laparoscopic (n = 492) or open (n = 482) distal gastrectomy. In the previous readout of this study with 3 years of follow-up, laparoscopic distal gastrectomy had noninferior oncologic outcomes compared with open surgery for locally advanced gastric cancer. Son and colleagues are now reporting 5-year follow-up results. Overall survival (OS; 88.9% vs 88.7%; P = .30) and relapse-free survival (79.5% vs 81.1%; P = .658) rates were similar in both surgical groups. The pattern of recurrences was similar between the two groups as well, with peroneal (42.1% of patients) and hematogenous (20.8%) being the most frequent ones. However, patients who underwent laparoscopic vs open distal gastrectomy had a significantly lower late complication rate (6.5% vs 11.0%; P = .01). This study demonstrates that laparoscopic distal gastrectomy is an appropriate alternative to open distal gastrectomy and should be offered to patients who are treated in centers with experience in performing these types of operations.

Peritoneal metastasis is a common site for the spread of gastric cancer. As such, the role of hyperthermic intraperitoneal chemotherapy (HIPEC) in the management of this disease has been explored in a number of studies. The effectiveness of prophylactic HIPEC during resection of early-stage gastric cancer remains unknown.

Shen and colleagues conducted a propensity score-matching analysis looking at the efficacy and safety of HIPEC in this setting. The study evaluated outcomes of 395 patients with locally advanced gastric cancer who underwent resection with (n = 146) or without HIPEC (n = 248). In the HIPEC group, OS compared favorably to the surgery-only group (69.9% vs 40.8%, P = .049) and 2-year relapse-free survival was higher with HIPEC (60.7% vs 31.6%, P = .049).

Previously, the CYTO-CHIP propensity score analysis study performed in France demonstrated that HIPEC in addition to cytoreductive surgery resulted in improved OS in patients with advanced gastric cancer and peritoneal metastasis compared to cytoreduction surgery alone.¹ However, with both of these reports, interpretation of the results carries inherent limitations that are associated with retrospective study design. Prior prospective studies, on the other hand, had mixed results. An ongoing phase 3 prospective study of D2 resection and HIPEC in locally advanced gastric carcinoma (GASTRICHIP) will hopefully provide a definitive answer regarding the benefit of HIPEC in early-stage gastric cancer management (NCT01882933). Ultimately, going forward, the role of HIPEC in early-stage disease will need to be examined in a prospective study with carefully selected patients, using the latest biomarkers and systemic therapies.

Mismatch repair protein deficient (dMMR) or microsatellite unstable gastric cancer (MSI-H) have distinct biologic behaviors and treatment responses. They are much more responsive to immune checkpoint inhibitors in the metastatic setting. In early-stage disease, exploratory analysis of patients with MSI-H tumors previously enrolled in the perioperative MAGIC trial, revealed that patients with MSI-H tumors had a better prognosis when treated with surgery alone, and they potentially experienced detrimental effects from chemotherapy.²

The GERCOR NEONIPIGA single-arm phase 2 study enrolled 32 patients with resectable dMMR/MSI-H gastric and gastroesophageal junction tumors.³ Patients were treated with 240-mg neoadjuvant nivolumab once every 2 weeks six times and 1-mg/kg ipilimumab once every 6 weeks twice, followed by surgery and 480-mg adjuvant nivolumab once every 4 weeks nine times. Twenty-nine patients underwent resection. All resections were with negative margins (R0). Pathologic complete response was seen in 17 (58.6%) of patients. As of the February 2022 data cutoff, with a median duration of follow-up of 14.9 months, 30 out of 31 patients with early-stage disease remained alive and without recurrence or progression (one evaluable patient had metastatic disease).

These results certainly support further investigation of immunotherapy use in this patient population. However, in the absence of prospective randomized data, the combination of fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) remains the standard of care in those who can tolerate it. For patients with MSI-H tumors who are not candidates for combination chemotherapy or whose tumors are progressing on chemotherapy, neoadjuvant immunotherapy is certainly a good option to consider.

Additional References

1. Bonnot P-E et al. Cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for gastric cancer with peritoneal metastases (CYTO-CHIP study): A propensity score analysis. J Clin Oncol. 2019;37:2028-2040. Doi: 10.1200/JCO.18.01688

2. Smyth EC et al. Mismatch repair deficiency, microsatellite instability, and survival: An exploratory analysis of the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. JAMA Oncol. 2017;3:1197-1203. Doi: 10.1001/jamaoncol.2016.6762

3. André T et al. Neoadjuvant nivolumab plus ipilimumab and adjuvant nivolumab in localized deficient mismatch repair/microsatellite instability-high gastric or esophagogastric junction adenocarcinoma: The GERCOR NEONIPIGA phase II study. J Clin Oncol. 2022 (Aug 15. Doi: 10.1200/JCO.22.00686

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

This month's journal articles in the field of colorectal cancer research lack the cachet of some of the high-profile dispatches we discussed in previous editions of Clinical Edge. Nonetheless, there are several interesting reports this month.

The first is a clinical trial report that came out of China investigating the possible synergistic effect of high-dose vitamin C with chemotherapy in the first-line treatment of metastatic colorectal cancer (mCRC). The study was based on preclinical data that showed a synergistic increase in cancer cell death with chemotherapy plus high-dose vitamin C in in vitro models. Wang and colleagues randomly assigned 442 treatment-naive patients with mCRC to receive folinic acid, fluorouracil, and oxaliplatin (FOLFOX) and bevacizumab with or without 1.5 g/kg vitamin C intravenously on days 1-3 of each chemotherapy cycle.

The study's primary endpoint was progression-free survival (PFS), and patients were stratified on the basis of tumor sidedness and use of bevacizumab. PFS for the intention-to-treat group was unaffected by use of vitamin C (hazard ratio [HR] 0.86; 95% CI 0.70-1.05; P = .1). However, patients whose tumors harbored RAS mutations had a PFS that was significantly improved in the vitamin C arm (9.2 vs 7.8 months; HR 0.67; 95% CI 0.50-0.91; P = .01). Additionally, treatment-related adverse events were no more common in the treatment arm than in the control arm. Although I seldom draw clinical conclusions from subgroup analyses, I find it comforting to know that high-dose vitamin C is at least safe and potentially helpful for some patients. Many of my patients through the years have asked me about the utility of high-dose vitamin C. At least I can now inform them that the treatment is unlikely to cause physical harm or substantially decrease the efficacy of chemotherapy.

The second article I will discuss focuses on dietary fat intake and its potential effects on mortality and cancer progression in patients with mCRC. Using a food-frequency questionnaire, the authors of the study assessed the diets of 1194 patients who had been part of a previous cooperative group study for patients with treatment-naive mCRC (Van Blarigan et al). Over a median follow-up of 6.1 years, patients with the highest median intake of vegetable fats (23.5% kcal/d; interquartile range [IQR] 21.6%-25.7% kcal/d) vs the lowest intake (11.6% kcal/d; IQR 10.1%-12.7% kcal/d) showed a lower risk for all-cause mortality (adjusted HR 0.79; 95% CI 0.63-1.00) and cancer progression or death (adjusted HR 0.71; 95% CI 0.57-0.88). Although this study's results were not unexpected given data that have been published in the past, it builds on previous work as it shows the specific benefits of vegetable fats vis-à-vis animal fats, which are detrimental to survival. Oncologists continue to benefit from these studies because they allow us to give more specific dietary recommendations for high fat-containing vegan foods, such as avocados, olives, and nuts.

Liver transplantation has the opportunity to cure both localized HCC as well as underlying liver cirrhosis. Donor organ shortage has led to the implementation of the Milan criteria as a way to identify patients whose tumor burden is low enough to predict a good outcome. Downstaging liver cancer to fit within Milan criteria has been controversial.

Tabrizian and colleagues undertook a retrospective cohort analysis of 2645 adult patients with HCC who underwent liver transplant. Out of those, 2122 patients always had disease that was within the Milan criteria, 341 patients had HCC that was downstaged to fit within the Milan criteria, and 182 patients had HCC that was outside the Milan criteria at the time of liver transplantation. The authors report that the 10-year post-transplant survival and recurrence rates were 61.5% and 13.3%, respectively, in those always within the Milan criteria, 52.1% and 20.6% among those whose disease was downstaged, and 43.3% and 41.1% in those whose disease was never downstaged. Characteristics that predicted recurrence after downstaging were tumor size > 7 cm at diagnosis (odds ratio [OR] 2.62; 95% CI 1.20-5.75; P = .02), more than three tumors at diagnosis (OR 2.34; 95% CI 1.22-4.50; P = .01), and alpha-fetoprotein (AFP) response ≥ 20 ng/mL with < 50% improvement from maximum AFP before transplantation (OR 1.99; 95% CI 1.14-3.46; P = .02). Additionally, patients with recurrent tumors that were surgically resected had improved 5-year post-recurrence survival (31.6% vs 7.3%; P < .001). The conclusion was that the national downstaging policies were valid and should continue.

For patients who have unresectable HCC, systemic therapy is the mainstay of treatment. Peng and colleagues reported the results of the LAUNCH phase 3 clinical trial that randomized patients to receive lenvatinib alone or lenvatinib plus transarterial chemoembolization (TACE). Out of 338 patients, 170 received lenvatinib plus TACE. Unsurprisingly, the response rate was higher with the combination (54.1% vs 25.0%; P < .001); however, so was the median overall survival (17.8 vs 11.5 months; hazard ratio 0.45; P < .001), and median progression-free survival (10.6 vs 6.4 months; hazard ratio 0.43; P < .001). The investigators concluded that the addition of TACE to lenvatinib had manageable toxicities, improved clinical outcomes, and could be used as a potential first-line treatment for some patients with unresectable HCC.

Finally, in patients whose HCC progressed after a single TACE treatment, the question remains whether repeated TACE is worthwhile. Zhao and colleagues retrospectively reviewed the outcomes of 94 patients who underwent at least one TACE. Of these, 28 (29.8%) had a response to the first TACE, and these patients tended to have a longer OS compared with nonresponders (36.7 vs 21.5 months; P = .071). Of the 43 initial nonresponders who underwent a second TACE, 15 of 43 (34.9%) achieved a response and had an improved median overall survival (47.8 v. 13.6 months; P = .01), suggesting that repeat TACE may offer a benefit to some patients, even after no response to the initial treatment.

Liver transplantation has the opportunity to cure both localized HCC as well as underlying liver cirrhosis. Donor organ shortage has led to the implementation of the Milan criteria as a way to identify patients whose tumor burden is low enough to predict a good outcome. Downstaging liver cancer to fit within Milan criteria has been controversial.

Tabrizian and colleagues undertook a retrospective cohort analysis of 2645 adult patients with HCC who underwent liver transplant. Out of those, 2122 patients always had disease that was within the Milan criteria, 341 patients had HCC that was downstaged to fit within the Milan criteria, and 182 patients had HCC that was outside the Milan criteria at the time of liver transplantation. The authors report that the 10-year post-transplant survival and recurrence rates were 61.5% and 13.3%, respectively, in those always within the Milan criteria, 52.1% and 20.6% among those whose disease was downstaged, and 43.3% and 41.1% in those whose disease was never downstaged. Characteristics that predicted recurrence after downstaging were tumor size > 7 cm at diagnosis (odds ratio [OR] 2.62; 95% CI 1.20-5.75; P = .02), more than three tumors at diagnosis (OR 2.34; 95% CI 1.22-4.50; P = .01), and alpha-fetoprotein (AFP) response ≥ 20 ng/mL with < 50% improvement from maximum AFP before transplantation (OR 1.99; 95% CI 1.14-3.46; P = .02). Additionally, patients with recurrent tumors that were surgically resected had improved 5-year post-recurrence survival (31.6% vs 7.3%; P < .001). The conclusion was that the national downstaging policies were valid and should continue.

For patients who have unresectable HCC, systemic therapy is the mainstay of treatment. Peng and colleagues reported the results of the LAUNCH phase 3 clinical trial that randomized patients to receive lenvatinib alone or lenvatinib plus transarterial chemoembolization (TACE). Out of 338 patients, 170 received lenvatinib plus TACE. Unsurprisingly, the response rate was higher with the combination (54.1% vs 25.0%; P < .001); however, so was the median overall survival (17.8 vs 11.5 months; hazard ratio 0.45; P < .001), and median progression-free survival (10.6 vs 6.4 months; hazard ratio 0.43; P < .001). The investigators concluded that the addition of TACE to lenvatinib had manageable toxicities, improved clinical outcomes, and could be used as a potential first-line treatment for some patients with unresectable HCC.

Finally, in patients whose HCC progressed after a single TACE treatment, the question remains whether repeated TACE is worthwhile. Zhao and colleagues retrospectively reviewed the outcomes of 94 patients who underwent at least one TACE. Of these, 28 (29.8%) had a response to the first TACE, and these patients tended to have a longer OS compared with nonresponders (36.7 vs 21.5 months; P = .071). Of the 43 initial nonresponders who underwent a second TACE, 15 of 43 (34.9%) achieved a response and had an improved median overall survival (47.8 v. 13.6 months; P = .01), suggesting that repeat TACE may offer a benefit to some patients, even after no response to the initial treatment.

Liver transplantation has the opportunity to cure both localized HCC as well as underlying liver cirrhosis. Donor organ shortage has led to the implementation of the Milan criteria as a way to identify patients whose tumor burden is low enough to predict a good outcome. Downstaging liver cancer to fit within Milan criteria has been controversial.

Tabrizian and colleagues undertook a retrospective cohort analysis of 2645 adult patients with HCC who underwent liver transplant. Out of those, 2122 patients always had disease that was within the Milan criteria, 341 patients had HCC that was downstaged to fit within the Milan criteria, and 182 patients had HCC that was outside the Milan criteria at the time of liver transplantation. The authors report that the 10-year post-transplant survival and recurrence rates were 61.5% and 13.3%, respectively, in those always within the Milan criteria, 52.1% and 20.6% among those whose disease was downstaged, and 43.3% and 41.1% in those whose disease was never downstaged. Characteristics that predicted recurrence after downstaging were tumor size > 7 cm at diagnosis (odds ratio [OR] 2.62; 95% CI 1.20-5.75; P = .02), more than three tumors at diagnosis (OR 2.34; 95% CI 1.22-4.50; P = .01), and alpha-fetoprotein (AFP) response ≥ 20 ng/mL with < 50% improvement from maximum AFP before transplantation (OR 1.99; 95% CI 1.14-3.46; P = .02). Additionally, patients with recurrent tumors that were surgically resected had improved 5-year post-recurrence survival (31.6% vs 7.3%; P < .001). The conclusion was that the national downstaging policies were valid and should continue.

For patients who have unresectable HCC, systemic therapy is the mainstay of treatment. Peng and colleagues reported the results of the LAUNCH phase 3 clinical trial that randomized patients to receive lenvatinib alone or lenvatinib plus transarterial chemoembolization (TACE). Out of 338 patients, 170 received lenvatinib plus TACE. Unsurprisingly, the response rate was higher with the combination (54.1% vs 25.0%; P < .001); however, so was the median overall survival (17.8 vs 11.5 months; hazard ratio 0.45; P < .001), and median progression-free survival (10.6 vs 6.4 months; hazard ratio 0.43; P < .001). The investigators concluded that the addition of TACE to lenvatinib had manageable toxicities, improved clinical outcomes, and could be used as a potential first-line treatment for some patients with unresectable HCC.

Finally, in patients whose HCC progressed after a single TACE treatment, the question remains whether repeated TACE is worthwhile. Zhao and colleagues retrospectively reviewed the outcomes of 94 patients who underwent at least one TACE. Of these, 28 (29.8%) had a response to the first TACE, and these patients tended to have a longer OS compared with nonresponders (36.7 vs 21.5 months; P = .071). Of the 43 initial nonresponders who underwent a second TACE, 15 of 43 (34.9%) achieved a response and had an improved median overall survival (47.8 v. 13.6 months; P = .01), suggesting that repeat TACE may offer a benefit to some patients, even after no response to the initial treatment.