LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – When it comes to lupus nephritis, the guidelines – and prevailing wisdom – don’t always get it quite right, according to Michelle A. Petri, MD.

Mitchel L. Zoler/MDedge News

During an update at the annual meeting of the Florida Society of Rheumatology, she outlined five key components of lupus nephritis treatment, and the status of the evidence for each.

Antihypertensive therapy

Antihypertensive therapy isn’t just for hypertension in patients with lupus nephritis – it’s for reducing proteinuria and preventing renal fibrosis, said Dr. Petri, professor of medicine and director of the Hopkins Lupus Center at Johns Hopkins University, Baltimore.

“I get a lot of push-back on this,” she added, explaining that other physicians often will stop the treatment as she prescribed it, because they believe it’s unnecessary.

She described a case involving a 33-year-old African American man with blood pressure of 132/86 mm Hg and grade 3+ ankle edema. Laboratory tests were remarkable for hematocrit (33.4%), white blood cell count (3.1), erythrocyte sedimentation rate (67 mm/hr) and urinalysis (2+ protein by dipstick, 3 red cells/high-power field, no casts). Additionally, 24-hour urine protein showed 400 mg of microalbumin, and he had a positive antinuclear antibody test, positive anti–double stranded DNA, and low complement.

“I’m going to argue really strenuously that he has to be on an ACE inhibitor or an ARB [angiotensin receptor blocker],” she said, explaining that even before an immunosuppressant therapy is started, optimizing ACE inhibitor or ARB therapy can reduce proteinuria by 50%.

The “sweet spot” for blood pressure in these patients is between 110 and 129, she said.

“You don’t want it too low, because you might hurt renal perfusion, but you sure don’t want it above 130,” she said.

The problem is that many physicians think 110 or 112 is too low.

“Not for a lupus nephritis patient,” she said. “It’s really where we want to be.”

ACE inhibitors and ARBs are preferable for reaching this goal, she said, noting that calcium channel blockers have been linked with shorter time to renal failure.

Hydroxychloroquine

Everyone with lupus nephritis should be on hydroxychloroquine, Dr. Petri argued.

“It improves renal outcomes,” she said. “It more than triples the chance that a patient will have a complete renal response.”

Guidelines from the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) are in agreement on this, she said.

Even the renal guidelines for lupus nephritis now include hydroxychloroquine as mandatory, she added, noting that it is not necessary to check glucose-6-phosphate dehydrogenase (G6PD) before starting treatment.

In fact, a recent study showed that only 2 of 11 patients with G6PD deficiency had episodes of hemolysis, and those episodes did not occur during hydroxychloroquine therapy. The authors concluded that the routine measurement of G6PD levels and withholding therapy among African American patients with G6PD deficiency is not supported, she said (Arthritis Care Res. 2018;70[3]:481-5).

“Of course, if your patient has renal insufficiency you’re going to have to reduce the dose in half,” she noted.
 

Vitamin D

Modestly increasing 25-hydroxyvitamin D can “greatly, significantly reduce the urine protein – with no cost, with no toxicity,” Dr. Petri said.

In a 2013 study, she and her colleagues showed that a 20‐ng/mL increase in the 25(OH)vitamin D level was associated with a 21% decrease in the odds of having a high disease-activity score, and with a 15% decrease in the odds of having clinically important proteinuria (Arthritis Rheumatol. 2013;65[7]:1865-71).

“But you’ll be fascinated to hear that vitamin D may be an antifibrotic drug, as well,” she noted. “This has been proven in animal models of pulmonary fibrosis ... and although we don’t have proof in lupus nephritis, the animal models are so strong that I think absolutely everybody with lupus nephritis needs to be on vitamin D, both to reduce proteinuria and then, hopefully, as a very cheap antifibrotic drug.”
 

Mycophenolate mofetil

The case Dr. Petri presented involved a patient with International Society of Nephrology class IV disease.

Left untreated, he would be in end-stage renal disease within a year, she said.

“But even with my maximal treatment he has a 23% chance of being in end-stage renal disease in 20 years,” she noted.

This patient had a high National Institutes of Health activity index, but low chronicity, and there were no crescents.

“The reason I mention this is because crescents mean rapidly progressive [glomerular nephritis],” she said. “That’s very urgent; it’s one of the situations where even I will dump on the steroids, because you’ve got to do something fast.”

In this case, however, the best induction therapy is mycophenolate mofetil, she said.

“Boy, our guidelines are wishy-washy on this, and they shouldn’t be,” she said, explaining that “because he’s African American, there are very clear data that mycophenolate is better than cyclophosphamide – our guidelines need to make that very clear.”

In fact, mycophenolate should be the first choice of induction therapy in all cases, except those involving rapidly progressive glomerulonephritis (RPGN), for which cyclophosphamide should be given for at least 3 months before trying to transition to mycophenolate, she stressed.

After about 1 year of treatment, 50% of patients will be complete renal responders, she noted, adding that “in Caucasians, mycophenolate is as good as cyclophosphamide, and in African Americans, mycophenolate is much better.”

“So mycophenolate has won, and for good reason. But is it sufficient to have 50% of patients be complete renal responders at 1 year?” she asked, noting the risk for renal fibrosis in those who respond late in that year or not at all.

“So we really need something that’s much more successful.”
 

Steroids

How much prednisone should lupus nephritis patients get?

As little as possible, according to Dr. Petri.

“I want you to think back to all those times you were taught during you fellowship about dumping on as much prednisone as possible,” she said. “[They] probably aren’t correct.”

She also pulled no punches when it comes to the ACR and EULAR guidelines on prednisone use.

“Both ... are wrong,” she said, explaining that the ACR guidelines are “top-heavy” on prednisone in calling for 0.5-1 mg/kg/day.

“One mg/kg? Like everybody’s the same? I do not object to 1 mg/kg if it’s RPGN, but not for everybody else,” she said.

EULAR guidelines are “less generous,” calling for 0.5 mg/kg/day for 4 weeks, and they make it clear that “you better taper that stuff off.”

“I like that part,” she said. “But still, you’re starting out with a lot of steroid.”

Why the objection? Data show that prednisone is directly or indirectly responsible for 80% of organ damage over 15 years, she said (J Rheumatol. 2003;30[9]:1955-9).

“It’s bad enough to have lupus nephritis; why should you have to be poisoned with prednisone, as well?” she asked. “Now, if the people on prednisone did better, of course I’d have to back off, wouldn’t I?”

Recent data, however, suggest that lupus nephritis patients who are treated with prednisone end up doing worse, and studies being performed outside the United States are beginning to use lower doses of prednisone, she said.

“The rest of the world is lowering the prednisone; our guidelines need to catch up,” she said, adding that she sees no reason why this shouldn’t apply in lupus nephritis.

“Their prednisone should be less than 6 mg, and doses above that level increase organ damage by 50%,” she said, citing a 2009 study in which she and her colleagues found that the hazard ratio for organ damage with prednisone vs. no prednisone was 1.50 for cumulative average doses of 180-360 mg/month, compared with 1.16 for doses up to 180 mg/month (J Rheumatol. 2009;36[3]:560-4).

Even a 20-mg dose has been linked with a fivefold increase the risk of a vascular incident, she added, citing another such study (Am J Epidemiol. 2012;176:708-19).

Dr. Petri is a consultant for GlaxoSmithKline, Merck EMD Serono, Lilly, Janssen, Amgen, Novartis, Exagen, Inova Diagnostics, AstraZeneca, Blackrock Pharma, Glenmark, and UCB.

[email protected]

LAKE BUENA VISTA, FLA. – “Crude and uninformed.”

That’s how Leonard H. Calabrese, DO, described the general approach to managing immune-related adverse events (irAEs) in cancer patients treated with checkpoint inhibitor therapy.

Rheumatologists have the expertise to change that, he said during a presentation at the annual meeting of the Florida Society of Rheumatology.

“The therapy is where it’s at – this is where rheumatologists come into play,” said Dr. Calabrese, professor of medicine and chair of clinical immunology at the Cleveland Clinic.

According to relevant guidelines, such as those recently developed by the American Society of Clinical Oncology/National Comprehensive Cancer Network and the Society for the Immunotherapy of Cancer, irAEs are graded on a severity-based scale. Grade 1 events are mild and generally require observation; grade 2 events may include arthralgias and myalgias that are typically treated with symptomatic therapy; grade 3 events involve more serious conditions and may require hospitalization; and grade 4 events are life-threatening and may require targeted therapies.

“Grade 3 – these would be people with profound polyarthritis, vasculitis, myositis – rely heavily on glucocorticoids, and if patients don’t tolerate glucocorticoids or don’t respond to tapering doses, consider the use of [disease-modifying antirheumatic drugs],” he said, noting that the guidelines are vaguely written and refer to both conventional and biologic DMARDs.

“This is all anecdotal at the present time; this is a story to be discovered as we move along,” he explained.

A recommendation for the use of targeted therapies, such as tumor necrosis factor inhibitors, anti-interleukin (IL)-6, and antimetabolites, in patients with the most advanced disease is similarly vague and just represents “the beginning of the beginning,” he said.

The “crude and uninformed” nature of the current approach to irAEs, as he described it, is related to a failure to consider the immunopathogenesis of specific conditions.

“The oncologists, who have done such an incredible job with this – learning about derm[atitis] and colitis that respond to steroids and infliximab, immediately extrapolated that steroids and infliximab are for everything,” he said. “They give it for pneumonitis, they give it for [central nervous system] disease, they give it for everything.”

However, there’s no pathophysiologic basis for doing so, and not surprisingly, some patients don’t respond.

“Here we are sitting on this amazing armamentarium of targeted therapies and only now just starting to ask the questions: ‘Do they offer benefit for these irAEs? Do they offer risk? Will they blunt the antitumoral response of this?’ ” he said.

A “Personal View” published in Lancet Oncology in January 2019 was among the first from the oncology arena to pose these questions (20[1]:PE54-64. doi: 10.1016/S1470-2045[18]30828-3).

“It said, ‘well maybe we should look at the immunopathogenesis of each of these diseases and then pick the therapy – if it’s IL-17 mediated, we’ve got drugs for that; if it’s IL-1 mediated, we’ve got drugs for that; if it’s interferon-mediated, we can deal with that,’ ” he said. “The problem is we don’t yet have detailed immunopathogenic knowledge of these diseases, but it’s coming.”

Data needed to define best treatments

Data also are emerging to define the roles of various targeted therapies for treating irAEs, but most of the evidence remains anecdotal, he said.

For example, anecdotal reports suggest that rituximab has some efficacy in cytopenias, arthritis, and myositis, and a case report suggests that secukinumab and other IL-17 inhibitors may have benefit in psoriasis and inflammatory bowel disease with tumoral progression, he said.

A reasonable question has been whether attacking T cells might be worthwhile given that “these things are all T-cell mediated,” but until very recently, “no one has had the temerity to actually do this,” he said.

However, two cases reported in the June 13 issue of the New England Journal of Medicine described “very successful” treatment of checkpoint inhibitor-associated myocarditis. One case described the use of alemtuzumab in a 71-year-old woman being treated with first-line pembrolizumab for stage IV melanoma, and another case involved the use of abatacept for severe, glucocorticoid-refractory myocarditis in a 66-year-old woman who had been treated with nivolumab for metastatic lung cancer (2019;380:2375-6 and 2377-79).Dr. Calabrese urged rheumatologists who are interested in addressing the treatment of irAEs to “get involved.”

“People need good rheumatologists, and I will tell you that whoever your oncologists are who you refer patients to for cancer – they’re seeing this and they need help,” he said. “Particularly outside of these big major centers, just having someone to lean on is very important.”

Keep in mind, however, that triage is very important, he said, stressing that patients with irAEs “actually need to be seen.”

Between three and five new irAE patients are being seen each week at the Cleveland Clinic, he noted.
 

Need for multidisciplinary collaboration

Collaboration was the focus of an article in the June 2019 issue of the Journal of the National Comprehensive Cancer Network, which looked at the value of a virtual “multidisciplinary toxicity team” for managing cancer irAEs. The investigators found that such an approach was feasible, used by oncology providers, and effective for facilitating toxicity identification and management.

A number of other recent studies have attempted to assess confidence and knowledge of rheumatologists and others with respect to the treatment of irAEs in cancer patients, and the findings highlight the need for education at the oncologist, specialist, generalist, and advanced practitioner level, Dr. Calabrese said, adding that the findings also highlight a need for assistance from “big pharma, which makes these drugs,” in supporting this type of education.

The need for “novel venues for such educational interchange” also was the topic of a study on a new Cleveland Clinic irAE tumor board that he and his colleagues presented at the 2018 annual meeting of the American College of Rheumatology.

The study showed that the tumor board, which is now “one of the most popular conferences at the clinic,” has educational value for participants, and “may increase skill and confidence in patient management.”

“We just present case after case of new things. Last week was autoimmune lipodystrophy from checkpoint inhibitors,” he said, noting that the rheumatologists and oncologists at the clinic co-chair the events.

In another 2018 article, he and coauthor Xavier Mariette, MD, further highlighted the “evolving role of the rheumatologist” in managing cancer treatment–related irAEs.

“We think that rheumatologists have a lot to offer here,” he said. “We understand these drugs better than all of these guys, and as we gain more knowledge in this field, we have guidance, and counsel, and experience to add to this.”

He encouraged rheumatologists to “stay tuned on this, follow this along,” adding that their help is needed.

“It’s really simple – talk to your oncologists and say, ‘Hey, what are you doing with these patients?’ – and I think you’ll have something new, exciting, and invigorating.”

Dr. Calabrese reported serving as a consultant and/or speaker for Bristol-Myers Squibb, Genentech, AbbVie, Pfizer, Crescendo Bioscience, UCB, Janssen, Gilead, Sanofi-Regeneron, Novartis, AstraZeneca, and Amgen.

[email protected]

LAKE BUENA VISTA, FLA. – “Crude and uninformed.”

That’s how Leonard H. Calabrese, DO, described the general approach to managing immune-related adverse events (irAEs) in cancer patients treated with checkpoint inhibitor therapy.

Rheumatologists have the expertise to change that, he said during a presentation at the annual meeting of the Florida Society of Rheumatology.

“The therapy is where it’s at – this is where rheumatologists come into play,” said Dr. Calabrese, professor of medicine and chair of clinical immunology at the Cleveland Clinic.

According to relevant guidelines, such as those recently developed by the American Society of Clinical Oncology/National Comprehensive Cancer Network and the Society for the Immunotherapy of Cancer, irAEs are graded on a severity-based scale. Grade 1 events are mild and generally require observation; grade 2 events may include arthralgias and myalgias that are typically treated with symptomatic therapy; grade 3 events involve more serious conditions and may require hospitalization; and grade 4 events are life-threatening and may require targeted therapies.

“Grade 3 – these would be people with profound polyarthritis, vasculitis, myositis – rely heavily on glucocorticoids, and if patients don’t tolerate glucocorticoids or don’t respond to tapering doses, consider the use of [disease-modifying antirheumatic drugs],” he said, noting that the guidelines are vaguely written and refer to both conventional and biologic DMARDs.

“This is all anecdotal at the present time; this is a story to be discovered as we move along,” he explained.

A recommendation for the use of targeted therapies, such as tumor necrosis factor inhibitors, anti-interleukin (IL)-6, and antimetabolites, in patients with the most advanced disease is similarly vague and just represents “the beginning of the beginning,” he said.

The “crude and uninformed” nature of the current approach to irAEs, as he described it, is related to a failure to consider the immunopathogenesis of specific conditions.

“The oncologists, who have done such an incredible job with this – learning about derm[atitis] and colitis that respond to steroids and infliximab, immediately extrapolated that steroids and infliximab are for everything,” he said. “They give it for pneumonitis, they give it for [central nervous system] disease, they give it for everything.”

However, there’s no pathophysiologic basis for doing so, and not surprisingly, some patients don’t respond.

“Here we are sitting on this amazing armamentarium of targeted therapies and only now just starting to ask the questions: ‘Do they offer benefit for these irAEs? Do they offer risk? Will they blunt the antitumoral response of this?’ ” he said.

A “Personal View” published in Lancet Oncology in January 2019 was among the first from the oncology arena to pose these questions (20[1]:PE54-64. doi: 10.1016/S1470-2045[18]30828-3).

“It said, ‘well maybe we should look at the immunopathogenesis of each of these diseases and then pick the therapy – if it’s IL-17 mediated, we’ve got drugs for that; if it’s IL-1 mediated, we’ve got drugs for that; if it’s interferon-mediated, we can deal with that,’ ” he said. “The problem is we don’t yet have detailed immunopathogenic knowledge of these diseases, but it’s coming.”

Data needed to define best treatments

Data also are emerging to define the roles of various targeted therapies for treating irAEs, but most of the evidence remains anecdotal, he said.

For example, anecdotal reports suggest that rituximab has some efficacy in cytopenias, arthritis, and myositis, and a case report suggests that secukinumab and other IL-17 inhibitors may have benefit in psoriasis and inflammatory bowel disease with tumoral progression, he said.

A reasonable question has been whether attacking T cells might be worthwhile given that “these things are all T-cell mediated,” but until very recently, “no one has had the temerity to actually do this,” he said.

However, two cases reported in the June 13 issue of the New England Journal of Medicine described “very successful” treatment of checkpoint inhibitor-associated myocarditis. One case described the use of alemtuzumab in a 71-year-old woman being treated with first-line pembrolizumab for stage IV melanoma, and another case involved the use of abatacept for severe, glucocorticoid-refractory myocarditis in a 66-year-old woman who had been treated with nivolumab for metastatic lung cancer (2019;380:2375-6 and 2377-79).Dr. Calabrese urged rheumatologists who are interested in addressing the treatment of irAEs to “get involved.”

“People need good rheumatologists, and I will tell you that whoever your oncologists are who you refer patients to for cancer – they’re seeing this and they need help,” he said. “Particularly outside of these big major centers, just having someone to lean on is very important.”

Keep in mind, however, that triage is very important, he said, stressing that patients with irAEs “actually need to be seen.”

Between three and five new irAE patients are being seen each week at the Cleveland Clinic, he noted.
 

Need for multidisciplinary collaboration

Collaboration was the focus of an article in the June 2019 issue of the Journal of the National Comprehensive Cancer Network, which looked at the value of a virtual “multidisciplinary toxicity team” for managing cancer irAEs. The investigators found that such an approach was feasible, used by oncology providers, and effective for facilitating toxicity identification and management.

A number of other recent studies have attempted to assess confidence and knowledge of rheumatologists and others with respect to the treatment of irAEs in cancer patients, and the findings highlight the need for education at the oncologist, specialist, generalist, and advanced practitioner level, Dr. Calabrese said, adding that the findings also highlight a need for assistance from “big pharma, which makes these drugs,” in supporting this type of education.

The need for “novel venues for such educational interchange” also was the topic of a study on a new Cleveland Clinic irAE tumor board that he and his colleagues presented at the 2018 annual meeting of the American College of Rheumatology.

The study showed that the tumor board, which is now “one of the most popular conferences at the clinic,” has educational value for participants, and “may increase skill and confidence in patient management.”

“We just present case after case of new things. Last week was autoimmune lipodystrophy from checkpoint inhibitors,” he said, noting that the rheumatologists and oncologists at the clinic co-chair the events.

In another 2018 article, he and coauthor Xavier Mariette, MD, further highlighted the “evolving role of the rheumatologist” in managing cancer treatment–related irAEs.

“We think that rheumatologists have a lot to offer here,” he said. “We understand these drugs better than all of these guys, and as we gain more knowledge in this field, we have guidance, and counsel, and experience to add to this.”

He encouraged rheumatologists to “stay tuned on this, follow this along,” adding that their help is needed.

“It’s really simple – talk to your oncologists and say, ‘Hey, what are you doing with these patients?’ – and I think you’ll have something new, exciting, and invigorating.”

Dr. Calabrese reported serving as a consultant and/or speaker for Bristol-Myers Squibb, Genentech, AbbVie, Pfizer, Crescendo Bioscience, UCB, Janssen, Gilead, Sanofi-Regeneron, Novartis, AstraZeneca, and Amgen.

[email protected]

LAKE BUENA VISTA, FLA. – “Crude and uninformed.”

That’s how Leonard H. Calabrese, DO, described the general approach to managing immune-related adverse events (irAEs) in cancer patients treated with checkpoint inhibitor therapy.

Rheumatologists have the expertise to change that, he said during a presentation at the annual meeting of the Florida Society of Rheumatology.

“The therapy is where it’s at – this is where rheumatologists come into play,” said Dr. Calabrese, professor of medicine and chair of clinical immunology at the Cleveland Clinic.

According to relevant guidelines, such as those recently developed by the American Society of Clinical Oncology/National Comprehensive Cancer Network and the Society for the Immunotherapy of Cancer, irAEs are graded on a severity-based scale. Grade 1 events are mild and generally require observation; grade 2 events may include arthralgias and myalgias that are typically treated with symptomatic therapy; grade 3 events involve more serious conditions and may require hospitalization; and grade 4 events are life-threatening and may require targeted therapies.

“Grade 3 – these would be people with profound polyarthritis, vasculitis, myositis – rely heavily on glucocorticoids, and if patients don’t tolerate glucocorticoids or don’t respond to tapering doses, consider the use of [disease-modifying antirheumatic drugs],” he said, noting that the guidelines are vaguely written and refer to both conventional and biologic DMARDs.

“This is all anecdotal at the present time; this is a story to be discovered as we move along,” he explained.

A recommendation for the use of targeted therapies, such as tumor necrosis factor inhibitors, anti-interleukin (IL)-6, and antimetabolites, in patients with the most advanced disease is similarly vague and just represents “the beginning of the beginning,” he said.

The “crude and uninformed” nature of the current approach to irAEs, as he described it, is related to a failure to consider the immunopathogenesis of specific conditions.

“The oncologists, who have done such an incredible job with this – learning about derm[atitis] and colitis that respond to steroids and infliximab, immediately extrapolated that steroids and infliximab are for everything,” he said. “They give it for pneumonitis, they give it for [central nervous system] disease, they give it for everything.”

However, there’s no pathophysiologic basis for doing so, and not surprisingly, some patients don’t respond.

“Here we are sitting on this amazing armamentarium of targeted therapies and only now just starting to ask the questions: ‘Do they offer benefit for these irAEs? Do they offer risk? Will they blunt the antitumoral response of this?’ ” he said.

A “Personal View” published in Lancet Oncology in January 2019 was among the first from the oncology arena to pose these questions (20[1]:PE54-64. doi: 10.1016/S1470-2045[18]30828-3).

“It said, ‘well maybe we should look at the immunopathogenesis of each of these diseases and then pick the therapy – if it’s IL-17 mediated, we’ve got drugs for that; if it’s IL-1 mediated, we’ve got drugs for that; if it’s interferon-mediated, we can deal with that,’ ” he said. “The problem is we don’t yet have detailed immunopathogenic knowledge of these diseases, but it’s coming.”

Data needed to define best treatments

Data also are emerging to define the roles of various targeted therapies for treating irAEs, but most of the evidence remains anecdotal, he said.

For example, anecdotal reports suggest that rituximab has some efficacy in cytopenias, arthritis, and myositis, and a case report suggests that secukinumab and other IL-17 inhibitors may have benefit in psoriasis and inflammatory bowel disease with tumoral progression, he said.

A reasonable question has been whether attacking T cells might be worthwhile given that “these things are all T-cell mediated,” but until very recently, “no one has had the temerity to actually do this,” he said.

However, two cases reported in the June 13 issue of the New England Journal of Medicine described “very successful” treatment of checkpoint inhibitor-associated myocarditis. One case described the use of alemtuzumab in a 71-year-old woman being treated with first-line pembrolizumab for stage IV melanoma, and another case involved the use of abatacept for severe, glucocorticoid-refractory myocarditis in a 66-year-old woman who had been treated with nivolumab for metastatic lung cancer (2019;380:2375-6 and 2377-79).Dr. Calabrese urged rheumatologists who are interested in addressing the treatment of irAEs to “get involved.”

“People need good rheumatologists, and I will tell you that whoever your oncologists are who you refer patients to for cancer – they’re seeing this and they need help,” he said. “Particularly outside of these big major centers, just having someone to lean on is very important.”

Keep in mind, however, that triage is very important, he said, stressing that patients with irAEs “actually need to be seen.”

Between three and five new irAE patients are being seen each week at the Cleveland Clinic, he noted.
 

Need for multidisciplinary collaboration

Collaboration was the focus of an article in the June 2019 issue of the Journal of the National Comprehensive Cancer Network, which looked at the value of a virtual “multidisciplinary toxicity team” for managing cancer irAEs. The investigators found that such an approach was feasible, used by oncology providers, and effective for facilitating toxicity identification and management.

A number of other recent studies have attempted to assess confidence and knowledge of rheumatologists and others with respect to the treatment of irAEs in cancer patients, and the findings highlight the need for education at the oncologist, specialist, generalist, and advanced practitioner level, Dr. Calabrese said, adding that the findings also highlight a need for assistance from “big pharma, which makes these drugs,” in supporting this type of education.

The need for “novel venues for such educational interchange” also was the topic of a study on a new Cleveland Clinic irAE tumor board that he and his colleagues presented at the 2018 annual meeting of the American College of Rheumatology.

The study showed that the tumor board, which is now “one of the most popular conferences at the clinic,” has educational value for participants, and “may increase skill and confidence in patient management.”

“We just present case after case of new things. Last week was autoimmune lipodystrophy from checkpoint inhibitors,” he said, noting that the rheumatologists and oncologists at the clinic co-chair the events.

In another 2018 article, he and coauthor Xavier Mariette, MD, further highlighted the “evolving role of the rheumatologist” in managing cancer treatment–related irAEs.

“We think that rheumatologists have a lot to offer here,” he said. “We understand these drugs better than all of these guys, and as we gain more knowledge in this field, we have guidance, and counsel, and experience to add to this.”

He encouraged rheumatologists to “stay tuned on this, follow this along,” adding that their help is needed.

“It’s really simple – talk to your oncologists and say, ‘Hey, what are you doing with these patients?’ – and I think you’ll have something new, exciting, and invigorating.”

Dr. Calabrese reported serving as a consultant and/or speaker for Bristol-Myers Squibb, Genentech, AbbVie, Pfizer, Crescendo Bioscience, UCB, Janssen, Gilead, Sanofi-Regeneron, Novartis, AstraZeneca, and Amgen.

[email protected]

LAKE BUENA VISTA, FLA. – Wellness is an antidote to burnout.

That was the message from psychotherapist and author Saundra Jain, PsyD, during a talk focused on “reigniting the flame” in both professional and personal life.

©stanciuc/thinkstockphotos.com

“Wellness is not an afterthought. It simply cannot be,” she said at the annual meeting of the Florida Society of Rheumatology. The “data demand that wellness be elevated.”

That’s true both for patient care and for self care, she stressed, noting that by “wellness” she is referring to the 1948 World Health Organization definition: “... a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity.”

Wellness-enhancing practices – she discussed five that have “the most robust dataset”: exercise, nutrition, mindfulness, social connectedness, and sleep – can improve well-being and reduce burnout through a number of mechanisms, not the least of which are reduced inflammation and reduced depression and anxiety, said Dr. Jain, adjunct clinical affiliate for the School of Nursing at the University of Texas at Austin.

For example, regular exercise is known to reduce chronic inflammation, and the effect has been shown to be independent of weight loss, she noted (Sports Med. 2013;43[4]:243-56).

Mindfulness also has been shown to reduce cortisol production in response to a psychological stressor, and thus may positively affect inflammatory responses, she said (Brain Behav Immun. 2013;27:174-184).

People struggle with the concept of mindfulness, because for many it is a bit foreign to their experience, she said, adding that “what we don’t know, we’re sometimes a little bit afraid of.

“But the data around mindfulness, honestly, is robust – it really, really is,” she said, adding that “you can take people who have not meditated at all, and in 8 weeks impact their inflammation.

“So you don’t have to be a long-term meditator – you do not have to meditate for 18 hours a day sitting in a lotus position in a serene, beautiful location.”

There is no right or wrong way to meditate; it’s all about the practice, she added.

In an effort to help her own patients find wellness, Dr. Jain cofounded the WILD 5 Wellness program and coauthored a related workbook and program called KickStart30 designed to help kick-start the wellness journey.

WILD stands for Wellness Interventions for Life’s Demands, and the program combines the five key evidence-based wellness elements into an easy-to-follow program, she said.

The KickStart30 workbook is available for purchase, with all profits benefiting mental health charities. The approach is as applicable for physician wellness as for patient wellness, she said. The program is simple, prescriptive, trackable, and self-contained, she added.

Wellness-enhancing practices as recommended in the program include:

• 30 minutes of exercise daily for 30 days, with an aim of at least moderate intensity.
• 10 minutes of mindfulness practice each day for 30 days. (Free guided meditations, which she and her colleagues use in their studies of the program, are available at www.WILD5Meditations.com, but a number of other guided meditation apps are available online, she said.) “Of the apps that are available, Headspace, without a doubt, is my favorite,” she said. It requires a paid subscription, but “is so worth it.”
• Implementation of at least four of six sleep hygiene practices each day for 30 days.
• Meeting or calling a minimum of two friends or family members each day for 30 days.
• Logging meals/snacks/beverages/alcohol consumption each day for 30 days, following the Mediterranean-DASH intervention for Neurodegenerative Delay (MIND) diet principles as closely as possible.

Program success requires effort, not perfection, in following the recommendations, and measurement and tracking are essential, Dr. Jain said, noting that a simple tracking tool – the KickStart30–HERO Wellness Scale – was validated in a recent study that has been accepted for publication in Annals of Psychology in the coming months).

A prior study of 82 participants, which she presented in 2016 in a poster at the 29th Annual U.S. Psychiatric and Mental Health Congress, showed that completion of the KickStart30 program was associated with improvements on a variety of wellness measures, including happiness (30%), enthusiasm (51%), resilience 63%, and optimism (45%), she said.

Participants also experienced important improvements in disease markers, including depression (43% based on the 9-item Patient Health Questionnaire), anxiety (40% as measured by the 7-item Generalized Anxiety Disorder scale), and sleep quality (29% based on the 9-item Pittsburgh Sleep Quality Index).

“The one thing I want when you leave and you think about this session is a feeling ... that ‘there are actually things that I can do to improve my wellness.’ There’s something about the power, the synergy between the elements ... it’s reigniting the flame, the interest in wellness,” she said, adding that taking care of others requires “learning to take better care of ourselves.”

“We have to walk the walk of wellness; we cannot simply sit in the ivory tower and talk about it,” she said. “To be genuine and to really engage our patients, we have to walk the walk.”

Dr. Jain is cofounder of the WILD 5 Wellness program, and has served on advisory boards or panels for numerous pharmaceutical companies and other organizations.

[email protected]

LAKE BUENA VISTA, FLA. – Wellness is an antidote to burnout.

That was the message from psychotherapist and author Saundra Jain, PsyD, during a talk focused on “reigniting the flame” in both professional and personal life.

©stanciuc/thinkstockphotos.com

“Wellness is not an afterthought. It simply cannot be,” she said at the annual meeting of the Florida Society of Rheumatology. The “data demand that wellness be elevated.”

That’s true both for patient care and for self care, she stressed, noting that by “wellness” she is referring to the 1948 World Health Organization definition: “... a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity.”

Wellness-enhancing practices – she discussed five that have “the most robust dataset”: exercise, nutrition, mindfulness, social connectedness, and sleep – can improve well-being and reduce burnout through a number of mechanisms, not the least of which are reduced inflammation and reduced depression and anxiety, said Dr. Jain, adjunct clinical affiliate for the School of Nursing at the University of Texas at Austin.

For example, regular exercise is known to reduce chronic inflammation, and the effect has been shown to be independent of weight loss, she noted (Sports Med. 2013;43[4]:243-56).

Mindfulness also has been shown to reduce cortisol production in response to a psychological stressor, and thus may positively affect inflammatory responses, she said (Brain Behav Immun. 2013;27:174-184).

People struggle with the concept of mindfulness, because for many it is a bit foreign to their experience, she said, adding that “what we don’t know, we’re sometimes a little bit afraid of.

“But the data around mindfulness, honestly, is robust – it really, really is,” she said, adding that “you can take people who have not meditated at all, and in 8 weeks impact their inflammation.

“So you don’t have to be a long-term meditator – you do not have to meditate for 18 hours a day sitting in a lotus position in a serene, beautiful location.”

There is no right or wrong way to meditate; it’s all about the practice, she added.

In an effort to help her own patients find wellness, Dr. Jain cofounded the WILD 5 Wellness program and coauthored a related workbook and program called KickStart30 designed to help kick-start the wellness journey.

WILD stands for Wellness Interventions for Life’s Demands, and the program combines the five key evidence-based wellness elements into an easy-to-follow program, she said.

The KickStart30 workbook is available for purchase, with all profits benefiting mental health charities. The approach is as applicable for physician wellness as for patient wellness, she said. The program is simple, prescriptive, trackable, and self-contained, she added.

Wellness-enhancing practices as recommended in the program include:

• 30 minutes of exercise daily for 30 days, with an aim of at least moderate intensity.
• 10 minutes of mindfulness practice each day for 30 days. (Free guided meditations, which she and her colleagues use in their studies of the program, are available at www.WILD5Meditations.com, but a number of other guided meditation apps are available online, she said.) “Of the apps that are available, Headspace, without a doubt, is my favorite,” she said. It requires a paid subscription, but “is so worth it.”
• Implementation of at least four of six sleep hygiene practices each day for 30 days.
• Meeting or calling a minimum of two friends or family members each day for 30 days.
• Logging meals/snacks/beverages/alcohol consumption each day for 30 days, following the Mediterranean-DASH intervention for Neurodegenerative Delay (MIND) diet principles as closely as possible.

Program success requires effort, not perfection, in following the recommendations, and measurement and tracking are essential, Dr. Jain said, noting that a simple tracking tool – the KickStart30–HERO Wellness Scale – was validated in a recent study that has been accepted for publication in Annals of Psychology in the coming months).

A prior study of 82 participants, which she presented in 2016 in a poster at the 29th Annual U.S. Psychiatric and Mental Health Congress, showed that completion of the KickStart30 program was associated with improvements on a variety of wellness measures, including happiness (30%), enthusiasm (51%), resilience 63%, and optimism (45%), she said.

Participants also experienced important improvements in disease markers, including depression (43% based on the 9-item Patient Health Questionnaire), anxiety (40% as measured by the 7-item Generalized Anxiety Disorder scale), and sleep quality (29% based on the 9-item Pittsburgh Sleep Quality Index).

“The one thing I want when you leave and you think about this session is a feeling ... that ‘there are actually things that I can do to improve my wellness.’ There’s something about the power, the synergy between the elements ... it’s reigniting the flame, the interest in wellness,” she said, adding that taking care of others requires “learning to take better care of ourselves.”

“We have to walk the walk of wellness; we cannot simply sit in the ivory tower and talk about it,” she said. “To be genuine and to really engage our patients, we have to walk the walk.”

Dr. Jain is cofounder of the WILD 5 Wellness program, and has served on advisory boards or panels for numerous pharmaceutical companies and other organizations.

[email protected]

LAKE BUENA VISTA, FLA. – Wellness is an antidote to burnout.

That was the message from psychotherapist and author Saundra Jain, PsyD, during a talk focused on “reigniting the flame” in both professional and personal life.

©stanciuc/thinkstockphotos.com

“Wellness is not an afterthought. It simply cannot be,” she said at the annual meeting of the Florida Society of Rheumatology. The “data demand that wellness be elevated.”

That’s true both for patient care and for self care, she stressed, noting that by “wellness” she is referring to the 1948 World Health Organization definition: “... a state of complete physical, mental, and social well-being and not merely the absence of disease or infirmity.”

Wellness-enhancing practices – she discussed five that have “the most robust dataset”: exercise, nutrition, mindfulness, social connectedness, and sleep – can improve well-being and reduce burnout through a number of mechanisms, not the least of which are reduced inflammation and reduced depression and anxiety, said Dr. Jain, adjunct clinical affiliate for the School of Nursing at the University of Texas at Austin.

For example, regular exercise is known to reduce chronic inflammation, and the effect has been shown to be independent of weight loss, she noted (Sports Med. 2013;43[4]:243-56).

Mindfulness also has been shown to reduce cortisol production in response to a psychological stressor, and thus may positively affect inflammatory responses, she said (Brain Behav Immun. 2013;27:174-184).

People struggle with the concept of mindfulness, because for many it is a bit foreign to their experience, she said, adding that “what we don’t know, we’re sometimes a little bit afraid of.

“But the data around mindfulness, honestly, is robust – it really, really is,” she said, adding that “you can take people who have not meditated at all, and in 8 weeks impact their inflammation.

“So you don’t have to be a long-term meditator – you do not have to meditate for 18 hours a day sitting in a lotus position in a serene, beautiful location.”

There is no right or wrong way to meditate; it’s all about the practice, she added.

In an effort to help her own patients find wellness, Dr. Jain cofounded the WILD 5 Wellness program and coauthored a related workbook and program called KickStart30 designed to help kick-start the wellness journey.

WILD stands for Wellness Interventions for Life’s Demands, and the program combines the five key evidence-based wellness elements into an easy-to-follow program, she said.

The KickStart30 workbook is available for purchase, with all profits benefiting mental health charities. The approach is as applicable for physician wellness as for patient wellness, she said. The program is simple, prescriptive, trackable, and self-contained, she added.

Wellness-enhancing practices as recommended in the program include:

• 30 minutes of exercise daily for 30 days, with an aim of at least moderate intensity.
• 10 minutes of mindfulness practice each day for 30 days. (Free guided meditations, which she and her colleagues use in their studies of the program, are available at www.WILD5Meditations.com, but a number of other guided meditation apps are available online, she said.) “Of the apps that are available, Headspace, without a doubt, is my favorite,” she said. It requires a paid subscription, but “is so worth it.”
• Implementation of at least four of six sleep hygiene practices each day for 30 days.
• Meeting or calling a minimum of two friends or family members each day for 30 days.
• Logging meals/snacks/beverages/alcohol consumption each day for 30 days, following the Mediterranean-DASH intervention for Neurodegenerative Delay (MIND) diet principles as closely as possible.

Program success requires effort, not perfection, in following the recommendations, and measurement and tracking are essential, Dr. Jain said, noting that a simple tracking tool – the KickStart30–HERO Wellness Scale – was validated in a recent study that has been accepted for publication in Annals of Psychology in the coming months).

A prior study of 82 participants, which she presented in 2016 in a poster at the 29th Annual U.S. Psychiatric and Mental Health Congress, showed that completion of the KickStart30 program was associated with improvements on a variety of wellness measures, including happiness (30%), enthusiasm (51%), resilience 63%, and optimism (45%), she said.

Participants also experienced important improvements in disease markers, including depression (43% based on the 9-item Patient Health Questionnaire), anxiety (40% as measured by the 7-item Generalized Anxiety Disorder scale), and sleep quality (29% based on the 9-item Pittsburgh Sleep Quality Index).

“The one thing I want when you leave and you think about this session is a feeling ... that ‘there are actually things that I can do to improve my wellness.’ There’s something about the power, the synergy between the elements ... it’s reigniting the flame, the interest in wellness,” she said, adding that taking care of others requires “learning to take better care of ourselves.”

“We have to walk the walk of wellness; we cannot simply sit in the ivory tower and talk about it,” she said. “To be genuine and to really engage our patients, we have to walk the walk.”

Dr. Jain is cofounder of the WILD 5 Wellness program, and has served on advisory boards or panels for numerous pharmaceutical companies and other organizations.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

The Food and Drug Administration Arthritis Advisory Committee recommended approval of nintedanib for the treatment of interstitial lung disease in patients with systemic sclerosis by a 10-7 vote on July 25, 2019. If the FDA acts in accord with the panel’s recommendation, it would make nintedanib (Ofev) the first drug to receive marketing approval for this indication.

Nintedanib has had FDA approval for treating idiopathic pulmonary fibrosis since 2014, and the manufacturer, Boehringer Ingelheim, designed the current pivotal trial with 576 patients to broaden the indication to patients with a different but similar fibrotic lung disease, interstitial lung disease (ILD), that is a common and eventually lethal complication of systemic sclerosis. The results of the pivotal study, the SENSCIS (Safety and Efficacy of Nintedanib in Systemic Sclerosis) trial, recently appeared in print and showed that patients randomized to receive 150 mg of nintedanib orally twice daily had an average 41-mL cut in the rate of loss of forced vital capacity (FVC) during 52 weeks on treatment, compared with those randomized to placebo. This was a 44% relative reduction in rate of FVC loss that was statistically significant for the study’s primary endpoint (N Engl J Med. 2019 June 27;380[26]:2518-28).

Votes in favor of FDA approval for many on the panel seemed to stem from a combination of the fact that nintedanib met the pivotal trial’s primary endpoint; which had been developed in consultation with the FDA, as well as the absence of any new safety signals when compared with prior experience using the drug; the lack of any treatment specifically recognized as beneficial to systemic sclerosis patients who develop the terminal complication of ILD; and the challenge of running a second trial in an orphan disease with an estimated U.S. prevalence of no more than 100,000 patients. Several committee members who voted in favor of nintedanib’s approval also voiced concern that the case in favor of its benefit/risk balance was not open and shut.

“I have a fair amount of apprehension,” admitted the committee’s chair, Daniel H. Solomon, MD, a rheumatologist and professor of medicine at Harvard Medical School, Boston. “I support the needs of patients, but we don’t want to give them false hope. We need to be able to say who will benefit, and the single study [SENSCIS] results don’t tell us how to use the drug. I want to understand which patient subgroups benefit.” He suggested that the FDA mandate further data collection through postmarketing studies.

Comments from panel members who voted against recommending approval generally focused on what was generally agreed to be a very modest treatment effect with a 41-mL average difference in FVC decline that has marginal clinical meaningfulness. Although the SENSCIS results met the study’s primary endpoint it was neutral for all prespecified secondary endpoints, including a measure of quality of life, although many on the panel agreed that a good measure of quality of life in the target patient population is lacking. Some sensitivity analyses run by FDA staffers also failed to confirm the primary result. Fewer questions arose about safety, although some panelists expressed concern about gastrointestinal effects, especially diarrhea, that seemed to link with treatment, as well as a signal for an increased incidence of pneumonia among patients on nintedanib. The data also showed a possible signal of reduced efficacy among patients who also received treatment with the immunosuppressive agent mycophenolate mofetil, often used off label to treat systemic sclerosis patients with ILD. However, a statistician involved in the discussion warned against overinterpreting this or other subgroup analyses.

Dr. Solomon has received research support from AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Janssen, and Pfizer.

[email protected]

Clinical question: In patients with hypertension, chronic kidney disease, or heart failure presenting with a musculoskeletal disorder, how frequently are prescription NSAIDs dispensed and are there associated short-term (between 7-38 days of visit) safety-related outcomes?

Background: Multiple expert panels recommend against the use of NSAIDs in patients with hypertension (HTN), chronic kidney disease (CKD), or heart failure (HF). Previous studies have demonstrated an increased risk of cardiovascular events and renal injury with long-term NSAID use.

Study design: Retrospective cohort study.

Setting: Population-based administrative claims database identified primary care visits in Ontario.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: In patients with hypertension, chronic kidney disease, or heart failure presenting with a musculoskeletal disorder, how frequently are prescription NSAIDs dispensed and are there associated short-term (between 7-38 days of visit) safety-related outcomes?

Background: Multiple expert panels recommend against the use of NSAIDs in patients with hypertension (HTN), chronic kidney disease (CKD), or heart failure (HF). Previous studies have demonstrated an increased risk of cardiovascular events and renal injury with long-term NSAID use.

Study design: Retrospective cohort study.

Setting: Population-based administrative claims database identified primary care visits in Ontario.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Clinical question: In patients with hypertension, chronic kidney disease, or heart failure presenting with a musculoskeletal disorder, how frequently are prescription NSAIDs dispensed and are there associated short-term (between 7-38 days of visit) safety-related outcomes?

Background: Multiple expert panels recommend against the use of NSAIDs in patients with hypertension (HTN), chronic kidney disease (CKD), or heart failure (HF). Previous studies have demonstrated an increased risk of cardiovascular events and renal injury with long-term NSAID use.

Study design: Retrospective cohort study.

Setting: Population-based administrative claims database identified primary care visits in Ontario.

Dr. Stanley is assistant professor of medicine at Northwestern University Feinberg School of Medicine and a hospitalist at Northwestern Memorial Hospital, both in Chicago.

Pediatric non-Hodgkin lymphomas should be added to the list of cancers associated with BRCA2 mutations, and survivors of childhood NHL should be considered for genetic counseling, investigators suggest.

Among 1,380 survivors of childhood lymphomas, those who were retrospectively found to be carriers of BRCA2 mutations had a fivefold higher risk for non-Hodgkin lymphoma than controls without cancer, reported Zhaoming Wang, PhD, and colleagues from St. Jude Children’s Research Hospital in Memphis.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” they wrote in JAMA Oncology.

The investigators had previously reported that BRCA2 was the third-most frequently mutated gene among 3006 survivors of childhood cancers, with the highest number of mutations seen in lymphoma survivors. In that study, 7 of 586 survivors of Hodgkin and non-Hodgkin lymphoma (1.2%) were found to carry BRCA2 mutations.

In the current study, the investigators performed germline whole-genome sequencing on samples from 815 survivors of childhood Hodgkin lymphoma and 748 survivors of non-Hodgkin lymphoma from the St. Jude Lifetime Cohort and Childhood Cancer Survivor studies and compared the data with those of controls without cancer from the Genome Aggregation Database.

They identified mutations in five Hodgkin lymphoma survivors (0.6%) and eight non-Hodgkin lymphoma survivors.

A comparison of cancer risk among lymphoma survivors and controls found that non-Hodgkin lymphoma survivors and BRCA2 carriers had an odds ratio for cancer of 5.0, compared with controls who were not BRCA2 carriers (P less than .001). Among Hodgkin lymphoma survivors the OR for carriers vs. controls was 2.1, but was not statistically significant.

Available family histories for seven of the eight non-Hodgkin lymphoma BRCA2 mutation carriers showed histories of BRCA2-linked cancers, including breast, prostate, and pancreas tumors and malignant melanoma.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages,” the investigators wrote.

“This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants to St Jude Children’s Research Hospital from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Wang Z et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2203.

Pediatric non-Hodgkin lymphomas should be added to the list of cancers associated with BRCA2 mutations, and survivors of childhood NHL should be considered for genetic counseling, investigators suggest.

Among 1,380 survivors of childhood lymphomas, those who were retrospectively found to be carriers of BRCA2 mutations had a fivefold higher risk for non-Hodgkin lymphoma than controls without cancer, reported Zhaoming Wang, PhD, and colleagues from St. Jude Children’s Research Hospital in Memphis.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” they wrote in JAMA Oncology.

The investigators had previously reported that BRCA2 was the third-most frequently mutated gene among 3006 survivors of childhood cancers, with the highest number of mutations seen in lymphoma survivors. In that study, 7 of 586 survivors of Hodgkin and non-Hodgkin lymphoma (1.2%) were found to carry BRCA2 mutations.

In the current study, the investigators performed germline whole-genome sequencing on samples from 815 survivors of childhood Hodgkin lymphoma and 748 survivors of non-Hodgkin lymphoma from the St. Jude Lifetime Cohort and Childhood Cancer Survivor studies and compared the data with those of controls without cancer from the Genome Aggregation Database.

They identified mutations in five Hodgkin lymphoma survivors (0.6%) and eight non-Hodgkin lymphoma survivors.

A comparison of cancer risk among lymphoma survivors and controls found that non-Hodgkin lymphoma survivors and BRCA2 carriers had an odds ratio for cancer of 5.0, compared with controls who were not BRCA2 carriers (P less than .001). Among Hodgkin lymphoma survivors the OR for carriers vs. controls was 2.1, but was not statistically significant.

Available family histories for seven of the eight non-Hodgkin lymphoma BRCA2 mutation carriers showed histories of BRCA2-linked cancers, including breast, prostate, and pancreas tumors and malignant melanoma.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages,” the investigators wrote.

“This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants to St Jude Children’s Research Hospital from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Wang Z et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2203.

Pediatric non-Hodgkin lymphomas should be added to the list of cancers associated with BRCA2 mutations, and survivors of childhood NHL should be considered for genetic counseling, investigators suggest.

Among 1,380 survivors of childhood lymphomas, those who were retrospectively found to be carriers of BRCA2 mutations had a fivefold higher risk for non-Hodgkin lymphoma than controls without cancer, reported Zhaoming Wang, PhD, and colleagues from St. Jude Children’s Research Hospital in Memphis.

“Genetic counseling and the option of BRCA2 genetic testing should be offered to survivors of pediatric or adolescent non–Hodgkin lymphoma, particularly those with a family history of BRCA2-associated cancers,” they wrote in JAMA Oncology.

The investigators had previously reported that BRCA2 was the third-most frequently mutated gene among 3006 survivors of childhood cancers, with the highest number of mutations seen in lymphoma survivors. In that study, 7 of 586 survivors of Hodgkin and non-Hodgkin lymphoma (1.2%) were found to carry BRCA2 mutations.

In the current study, the investigators performed germline whole-genome sequencing on samples from 815 survivors of childhood Hodgkin lymphoma and 748 survivors of non-Hodgkin lymphoma from the St. Jude Lifetime Cohort and Childhood Cancer Survivor studies and compared the data with those of controls without cancer from the Genome Aggregation Database.

They identified mutations in five Hodgkin lymphoma survivors (0.6%) and eight non-Hodgkin lymphoma survivors.

A comparison of cancer risk among lymphoma survivors and controls found that non-Hodgkin lymphoma survivors and BRCA2 carriers had an odds ratio for cancer of 5.0, compared with controls who were not BRCA2 carriers (P less than .001). Among Hodgkin lymphoma survivors the OR for carriers vs. controls was 2.1, but was not statistically significant.

Available family histories for seven of the eight non-Hodgkin lymphoma BRCA2 mutation carriers showed histories of BRCA2-linked cancers, including breast, prostate, and pancreas tumors and malignant melanoma.

“Survivors whose test results are positive for mutation should be offered surveillance for BRCA2-associated cancers, such as breast and ovarian, and counseled about cancer risk–reducing strategies. Currently, it remains unclear whether surveillance for non–Hodgkin lymphoma is associated with early detection of lymphomas or with other medical advantages,” the investigators wrote.

“This study was funded by a grant to St Jude Children’s Research Hospital from the American Lebanese Syrian Associated Charities and by grants to St Jude Children’s Research Hospital from the National Institutes of Health. The authors reported having no conflicts of interest.

SOURCE: Wang Z et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2203.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

The first-in-class antiretroviral therapy islatravir (Merck) was well tolerated and had promising efficacy in a phase 2B study including treatment-naive adults with HIV-1 infection, supporting plans to initiate a phase 3 trial, an investigator said at the International AIDS Society Conference on HIV Science.

MattZ90/Thinkstock.com

The proportion of patients achieving viral suppression at week 48 with combinations including the nucleoside transcriptase translocation inhibitor (NRTTI) was comparable to what was achieved with a standard triple regimen, said investigator Jean-Michel Molina, MD, professor of infectious diseases at the University of Paris Diderot, and head of the infectious diseases department at the Saint-Louis Hospital in Paris

The treatment was effective not only as part of a three-drug combination of islatravir, doravirine, and lamivudine over 24 weeks, but also over an additional 24 weeks in patients who achieved viral suppression and were switched to dual therapy with islatravir and doravirine, according to Dr. Molina.

“These are promising data that will encourage the company to move to a phase 3 trial to see how these results can be confirmed in a larger study set, and also to assess the potency of the dual combination for maintenance therapy in the future, providing also novel options for people with a drug that has a high genetic barrier to resistance and efficacy that seems to be quite interesting,” Dr. Molina said in an IAS press conference in Mexico City.

This drug has very potent activity not only against wild-type HIV-1 viruses, but also multiresistant viruses, according to Dr. Molina.

“It has a high inhibitory quotient at a very low dose, so you give people a tiny amount of drug – in the range of 1 milligram per day, instead of a few hundred milligrams with other, regular drugs,” he said.

Another attribute of islatravir is its long half-life of approximately 120 hours, allowing not only for once-daily dosing, but potentially for evaluation as once-weekly or once-monthly dosing in the future, he said, adding that a subdermal islatravir-eluting implant under investigation for preexposure prophylaxis has potential as a once-yearly option.

The international, multicenter, 121-patient clinical trial that Dr. Molina described included adults with HIV-1 infection naive to antiretroviral therapy randomized to islatravir (in one of three doses) plus doravirine and lamivudine, or to the combination of doravirine, lamivudine, and tenofovir (Delstrigo, Merck).

After at least 24 weeks of treatment, subjects in the islatravir treatment groups were transitioned to the two-drug combination of islatravir and doravirine if they had HIV-1 RNA levels less than 50 copies/mL and did not meet any protocol-defined criteria for virologic failure.

Those participants in the islatravir arms who received 48 weeks of treatment had “very good response” and safety that was comparable to the control arm, according to Dr. Molina.

At 48 weeks, the proportion of patients with HIV-1 RNA less than 50 copies/mL were 89.7%, 90%, and 77.4% for regimens containing islatravir 0.25 mg, 0.75 mg, and 2.25 mg, respectively, and 83.9% for those receiving the standard triple therapy, according to reported data.

All patients with protocol-defined virologic failure (greater than or equal to 50 copies/mL) in the study actually had very low viral load, below 80 copies/mL, Dr. Molina said.

The study was supported by Merck. Dr. Molina has been on the Merck advisory board and speaker’s bureau.

SOURCE: Molina J-M et al. IAS 2019, Abstract WEAB0402LB.

The first-in-class antiretroviral therapy islatravir (Merck) was well tolerated and had promising efficacy in a phase 2B study including treatment-naive adults with HIV-1 infection, supporting plans to initiate a phase 3 trial, an investigator said at the International AIDS Society Conference on HIV Science.

MattZ90/Thinkstock.com

The proportion of patients achieving viral suppression at week 48 with combinations including the nucleoside transcriptase translocation inhibitor (NRTTI) was comparable to what was achieved with a standard triple regimen, said investigator Jean-Michel Molina, MD, professor of infectious diseases at the University of Paris Diderot, and head of the infectious diseases department at the Saint-Louis Hospital in Paris

The treatment was effective not only as part of a three-drug combination of islatravir, doravirine, and lamivudine over 24 weeks, but also over an additional 24 weeks in patients who achieved viral suppression and were switched to dual therapy with islatravir and doravirine, according to Dr. Molina.

“These are promising data that will encourage the company to move to a phase 3 trial to see how these results can be confirmed in a larger study set, and also to assess the potency of the dual combination for maintenance therapy in the future, providing also novel options for people with a drug that has a high genetic barrier to resistance and efficacy that seems to be quite interesting,” Dr. Molina said in an IAS press conference in Mexico City.

This drug has very potent activity not only against wild-type HIV-1 viruses, but also multiresistant viruses, according to Dr. Molina.

“It has a high inhibitory quotient at a very low dose, so you give people a tiny amount of drug – in the range of 1 milligram per day, instead of a few hundred milligrams with other, regular drugs,” he said.

Another attribute of islatravir is its long half-life of approximately 120 hours, allowing not only for once-daily dosing, but potentially for evaluation as once-weekly or once-monthly dosing in the future, he said, adding that a subdermal islatravir-eluting implant under investigation for preexposure prophylaxis has potential as a once-yearly option.

The international, multicenter, 121-patient clinical trial that Dr. Molina described included adults with HIV-1 infection naive to antiretroviral therapy randomized to islatravir (in one of three doses) plus doravirine and lamivudine, or to the combination of doravirine, lamivudine, and tenofovir (Delstrigo, Merck).

After at least 24 weeks of treatment, subjects in the islatravir treatment groups were transitioned to the two-drug combination of islatravir and doravirine if they had HIV-1 RNA levels less than 50 copies/mL and did not meet any protocol-defined criteria for virologic failure.

Those participants in the islatravir arms who received 48 weeks of treatment had “very good response” and safety that was comparable to the control arm, according to Dr. Molina.

At 48 weeks, the proportion of patients with HIV-1 RNA less than 50 copies/mL were 89.7%, 90%, and 77.4% for regimens containing islatravir 0.25 mg, 0.75 mg, and 2.25 mg, respectively, and 83.9% for those receiving the standard triple therapy, according to reported data.

All patients with protocol-defined virologic failure (greater than or equal to 50 copies/mL) in the study actually had very low viral load, below 80 copies/mL, Dr. Molina said.

The study was supported by Merck. Dr. Molina has been on the Merck advisory board and speaker’s bureau.

SOURCE: Molina J-M et al. IAS 2019, Abstract WEAB0402LB.

The first-in-class antiretroviral therapy islatravir (Merck) was well tolerated and had promising efficacy in a phase 2B study including treatment-naive adults with HIV-1 infection, supporting plans to initiate a phase 3 trial, an investigator said at the International AIDS Society Conference on HIV Science.

MattZ90/Thinkstock.com

The proportion of patients achieving viral suppression at week 48 with combinations including the nucleoside transcriptase translocation inhibitor (NRTTI) was comparable to what was achieved with a standard triple regimen, said investigator Jean-Michel Molina, MD, professor of infectious diseases at the University of Paris Diderot, and head of the infectious diseases department at the Saint-Louis Hospital in Paris

The treatment was effective not only as part of a three-drug combination of islatravir, doravirine, and lamivudine over 24 weeks, but also over an additional 24 weeks in patients who achieved viral suppression and were switched to dual therapy with islatravir and doravirine, according to Dr. Molina.

“These are promising data that will encourage the company to move to a phase 3 trial to see how these results can be confirmed in a larger study set, and also to assess the potency of the dual combination for maintenance therapy in the future, providing also novel options for people with a drug that has a high genetic barrier to resistance and efficacy that seems to be quite interesting,” Dr. Molina said in an IAS press conference in Mexico City.

This drug has very potent activity not only against wild-type HIV-1 viruses, but also multiresistant viruses, according to Dr. Molina.

“It has a high inhibitory quotient at a very low dose, so you give people a tiny amount of drug – in the range of 1 milligram per day, instead of a few hundred milligrams with other, regular drugs,” he said.

Another attribute of islatravir is its long half-life of approximately 120 hours, allowing not only for once-daily dosing, but potentially for evaluation as once-weekly or once-monthly dosing in the future, he said, adding that a subdermal islatravir-eluting implant under investigation for preexposure prophylaxis has potential as a once-yearly option.

The international, multicenter, 121-patient clinical trial that Dr. Molina described included adults with HIV-1 infection naive to antiretroviral therapy randomized to islatravir (in one of three doses) plus doravirine and lamivudine, or to the combination of doravirine, lamivudine, and tenofovir (Delstrigo, Merck).

After at least 24 weeks of treatment, subjects in the islatravir treatment groups were transitioned to the two-drug combination of islatravir and doravirine if they had HIV-1 RNA levels less than 50 copies/mL and did not meet any protocol-defined criteria for virologic failure.

Those participants in the islatravir arms who received 48 weeks of treatment had “very good response” and safety that was comparable to the control arm, according to Dr. Molina.

At 48 weeks, the proportion of patients with HIV-1 RNA less than 50 copies/mL were 89.7%, 90%, and 77.4% for regimens containing islatravir 0.25 mg, 0.75 mg, and 2.25 mg, respectively, and 83.9% for those receiving the standard triple therapy, according to reported data.

All patients with protocol-defined virologic failure (greater than or equal to 50 copies/mL) in the study actually had very low viral load, below 80 copies/mL, Dr. Molina said.

The study was supported by Merck. Dr. Molina has been on the Merck advisory board and speaker’s bureau.

SOURCE: Molina J-M et al. IAS 2019, Abstract WEAB0402LB.

Trastuzumab emtansine (T-DM1) is a suitable first-line therapy for patients with HER2-positive, advanced breast cancer who cannot receive taxane-based therapy, according to researchers.

Final results from the phase 3 MARIANNE trial revealed similar overall survival (OS) in patients who received T-DM1, T-DM1 plus pertuzumab, or trastuzumab plus a taxane (HT). All three regimens resulted in a median OS exceeding 50 months.

The incidence of grade 3 or higher adverse events (AEs) was highest in patients who received HT.

Edith A. Perez, MD, of Mayo Clinic Cancer Center in Jacksonville, Fla., and colleagues reported these results in Cancer.

The MARIANNE trial (NCT01120184) enrolled 1,095 adults with HER2-positive, advanced breast cancer. They were randomized to receive HT, T-DM1, or T-DM1 plus pertuzumab. Patients in the HT arm received trastuzumab plus paclitaxel or docetaxel according to the investigator’s discretion.

In all, 352 patients received HT (257 on docetaxel and 96 on paclitaxel), 361 patients received T-DM1 plus placebo, and 366 received T-DM1 plus pertuzumab.
 

Response and OS

In the primary analysis, the median OS was not reached in any treatment arm at a median follow-up of 35 months. The rate of objective response was 67.9% in the HT arm, 64.2% in the T-DM1 plus pertuzumab arm, and 59.7% in the T-DM1 arm. The median duration of response was 12.5 months, 21.2 months, and 20.7 months, respectively.

For the final OS analysis, the median duration of follow-up was 54 months. Roughly 70% of patients in each arm had received at least one treatment regimen during follow-up.

The final median OS was similar across the treatment arms – 50.9 months in the HT arm, 53.7 months in the T-DM1 arm, and 51.8 months in the T-DM1 plus pertuzumab arm. With the HT arm as a reference, the stratified hazard ratio was 0.93 for the T-DM1 arm and 0.86 for the T-DM1 plus pertuzumab arm.

OS results were consistent across subgroups. Although there were some differences in hazard ratios, “none of the examined subgroups showed a clear benefit with one treatment regimen in comparison with the others,” the researchers wrote.

The researchers also analyzed OS by response status at 6.5 months after randomization. Among nonresponders, the median OS was 41.9 months in the T-DM1 plus pertuzumab arm, 45.7 months in the T-DM1 arm, and 48.1 months in the HT arm. Among responders, the median OS was not reached in the T-DM1 plus pertuzumab arm, 64.4 months, and 56.3 months, respectively.

There were no baseline characteristics or biomarkers that were strongly associated with response by treatment group. However, in the HT and T-DM1 arms, patients with above-median HER2 messenger RNA expression were more likely to respond.
 

Safety

Rates of grade 3 or higher AEs were 55.8% in the HT arm, 47.1% in the T-DM1 arm, and 48.6% in the T-DM1 plus pertuzumab arm. The most common grade 3 or higher AEs were as follows:

• HT arm – neutropenia (19.3%), febrile neutropenia (6.5%), and diarrhea (4.2%).
• T-DM1 arm – increased aspartate aminotransferase (6.9%), thrombocytopenia (6.6%), and anemia (5.0%).
• T-DM1 plus pertuzumab arm – thrombocytopenia (9.0%), anemia (7.1%), and increased alanine aminotransferase (6.0%).

Rates of AE-related treatment discontinuation were 20.8% in the T-DM1 arm, 23.0% in the T-DM1 plus pertuzumab arm, and 30.6% in the HT arm. Rates of AE-related death were 1.4%, 1.9%, and 2.0%, respectively.

This study was funded by F. Hoffmann–La Roche. Dr. Perez was previously employed by Genentech/Roche. Her fellow authors disclosed relationships with Roche and many other companies.

SOURCE: Perez EA et al. Cancer. 2019 Jul 18. doi: 10.1002/cncr.32392.

Trastuzumab emtansine (T-DM1) is a suitable first-line therapy for patients with HER2-positive, advanced breast cancer who cannot receive taxane-based therapy, according to researchers.

Final results from the phase 3 MARIANNE trial revealed similar overall survival (OS) in patients who received T-DM1, T-DM1 plus pertuzumab, or trastuzumab plus a taxane (HT). All three regimens resulted in a median OS exceeding 50 months.

The incidence of grade 3 or higher adverse events (AEs) was highest in patients who received HT.

Edith A. Perez, MD, of Mayo Clinic Cancer Center in Jacksonville, Fla., and colleagues reported these results in Cancer.

The MARIANNE trial (NCT01120184) enrolled 1,095 adults with HER2-positive, advanced breast cancer. They were randomized to receive HT, T-DM1, or T-DM1 plus pertuzumab. Patients in the HT arm received trastuzumab plus paclitaxel or docetaxel according to the investigator’s discretion.

In all, 352 patients received HT (257 on docetaxel and 96 on paclitaxel), 361 patients received T-DM1 plus placebo, and 366 received T-DM1 plus pertuzumab.
 

Response and OS

In the primary analysis, the median OS was not reached in any treatment arm at a median follow-up of 35 months. The rate of objective response was 67.9% in the HT arm, 64.2% in the T-DM1 plus pertuzumab arm, and 59.7% in the T-DM1 arm. The median duration of response was 12.5 months, 21.2 months, and 20.7 months, respectively.

For the final OS analysis, the median duration of follow-up was 54 months. Roughly 70% of patients in each arm had received at least one treatment regimen during follow-up.

The final median OS was similar across the treatment arms – 50.9 months in the HT arm, 53.7 months in the T-DM1 arm, and 51.8 months in the T-DM1 plus pertuzumab arm. With the HT arm as a reference, the stratified hazard ratio was 0.93 for the T-DM1 arm and 0.86 for the T-DM1 plus pertuzumab arm.

OS results were consistent across subgroups. Although there were some differences in hazard ratios, “none of the examined subgroups showed a clear benefit with one treatment regimen in comparison with the others,” the researchers wrote.

The researchers also analyzed OS by response status at 6.5 months after randomization. Among nonresponders, the median OS was 41.9 months in the T-DM1 plus pertuzumab arm, 45.7 months in the T-DM1 arm, and 48.1 months in the HT arm. Among responders, the median OS was not reached in the T-DM1 plus pertuzumab arm, 64.4 months, and 56.3 months, respectively.

There were no baseline characteristics or biomarkers that were strongly associated with response by treatment group. However, in the HT and T-DM1 arms, patients with above-median HER2 messenger RNA expression were more likely to respond.
 

Safety

Rates of grade 3 or higher AEs were 55.8% in the HT arm, 47.1% in the T-DM1 arm, and 48.6% in the T-DM1 plus pertuzumab arm. The most common grade 3 or higher AEs were as follows:

• HT arm – neutropenia (19.3%), febrile neutropenia (6.5%), and diarrhea (4.2%).
• T-DM1 arm – increased aspartate aminotransferase (6.9%), thrombocytopenia (6.6%), and anemia (5.0%).
• T-DM1 plus pertuzumab arm – thrombocytopenia (9.0%), anemia (7.1%), and increased alanine aminotransferase (6.0%).

Rates of AE-related treatment discontinuation were 20.8% in the T-DM1 arm, 23.0% in the T-DM1 plus pertuzumab arm, and 30.6% in the HT arm. Rates of AE-related death were 1.4%, 1.9%, and 2.0%, respectively.

This study was funded by F. Hoffmann–La Roche. Dr. Perez was previously employed by Genentech/Roche. Her fellow authors disclosed relationships with Roche and many other companies.

SOURCE: Perez EA et al. Cancer. 2019 Jul 18. doi: 10.1002/cncr.32392.

Trastuzumab emtansine (T-DM1) is a suitable first-line therapy for patients with HER2-positive, advanced breast cancer who cannot receive taxane-based therapy, according to researchers.

Final results from the phase 3 MARIANNE trial revealed similar overall survival (OS) in patients who received T-DM1, T-DM1 plus pertuzumab, or trastuzumab plus a taxane (HT). All three regimens resulted in a median OS exceeding 50 months.

The incidence of grade 3 or higher adverse events (AEs) was highest in patients who received HT.

Edith A. Perez, MD, of Mayo Clinic Cancer Center in Jacksonville, Fla., and colleagues reported these results in Cancer.

The MARIANNE trial (NCT01120184) enrolled 1,095 adults with HER2-positive, advanced breast cancer. They were randomized to receive HT, T-DM1, or T-DM1 plus pertuzumab. Patients in the HT arm received trastuzumab plus paclitaxel or docetaxel according to the investigator’s discretion.

In all, 352 patients received HT (257 on docetaxel and 96 on paclitaxel), 361 patients received T-DM1 plus placebo, and 366 received T-DM1 plus pertuzumab.
 

Response and OS

In the primary analysis, the median OS was not reached in any treatment arm at a median follow-up of 35 months. The rate of objective response was 67.9% in the HT arm, 64.2% in the T-DM1 plus pertuzumab arm, and 59.7% in the T-DM1 arm. The median duration of response was 12.5 months, 21.2 months, and 20.7 months, respectively.

For the final OS analysis, the median duration of follow-up was 54 months. Roughly 70% of patients in each arm had received at least one treatment regimen during follow-up.

The final median OS was similar across the treatment arms – 50.9 months in the HT arm, 53.7 months in the T-DM1 arm, and 51.8 months in the T-DM1 plus pertuzumab arm. With the HT arm as a reference, the stratified hazard ratio was 0.93 for the T-DM1 arm and 0.86 for the T-DM1 plus pertuzumab arm.

OS results were consistent across subgroups. Although there were some differences in hazard ratios, “none of the examined subgroups showed a clear benefit with one treatment regimen in comparison with the others,” the researchers wrote.

The researchers also analyzed OS by response status at 6.5 months after randomization. Among nonresponders, the median OS was 41.9 months in the T-DM1 plus pertuzumab arm, 45.7 months in the T-DM1 arm, and 48.1 months in the HT arm. Among responders, the median OS was not reached in the T-DM1 plus pertuzumab arm, 64.4 months, and 56.3 months, respectively.

There were no baseline characteristics or biomarkers that were strongly associated with response by treatment group. However, in the HT and T-DM1 arms, patients with above-median HER2 messenger RNA expression were more likely to respond.
 

Safety

Rates of grade 3 or higher AEs were 55.8% in the HT arm, 47.1% in the T-DM1 arm, and 48.6% in the T-DM1 plus pertuzumab arm. The most common grade 3 or higher AEs were as follows:

• HT arm – neutropenia (19.3%), febrile neutropenia (6.5%), and diarrhea (4.2%).
• T-DM1 arm – increased aspartate aminotransferase (6.9%), thrombocytopenia (6.6%), and anemia (5.0%).
• T-DM1 plus pertuzumab arm – thrombocytopenia (9.0%), anemia (7.1%), and increased alanine aminotransferase (6.0%).

Rates of AE-related treatment discontinuation were 20.8% in the T-DM1 arm, 23.0% in the T-DM1 plus pertuzumab arm, and 30.6% in the HT arm. Rates of AE-related death were 1.4%, 1.9%, and 2.0%, respectively.

This study was funded by F. Hoffmann–La Roche. Dr. Perez was previously employed by Genentech/Roche. Her fellow authors disclosed relationships with Roche and many other companies.

SOURCE: Perez EA et al. Cancer. 2019 Jul 18. doi: 10.1002/cncr.32392.