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BRAF/MEK combo shows long-term efficacy in melanoma
, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.
The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).
There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.
The new study was published online in the Journal of Clinical Oncology.
In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.
Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
BRAF inhibitors as second- or later-line therapy
Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.
To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.
Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.
The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.
The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.
Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.
, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.
The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).
There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.
The new study was published online in the Journal of Clinical Oncology.
In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.
Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
BRAF inhibitors as second- or later-line therapy
Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.
To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.
Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.
The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.
The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.
Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.
, according to 5-year follow-up data from the COLUMBUS trial. Among patients with advanced unresectable or metastatic disease who were untreated or who had progressed following immunotherapy, the regimen of encorafenib plus binimetinib produced impressive gains in progression-free and overall survival, compared with historical controls, and are in line with other BRAF/MEK inhibitor combinations. It also outperformed encorafenib and vemurafenib monotherapy regimens.
The findings present good news, but the combination still doesn’t represent the best first-line option, according to Ryan Sullivan, MD, who wrote an accompanying editorial. He pointed out that the previously published DREAMSeq trial showed that a combination of immune checkpoint inhibitors (ICIs) ipilimumab and nivolumab produced a 2-year survival of 72%, compared with 52% for a BRAF inhibitor combination of dabrafenib plus trametinib (P = .0095).
There are three combinations of BRAF and MEK inhibitors that are approved for BRAF mutant melanoma, and any of the seven individual agents and six combinations that are approved by the U.S. Food and Drug Administration- for melanoma can be used in BRAFV600 patients. “The standard of care for most patients with newly diagnosed BRAF mutant melanoma is ... immune checkpoint inhibition, either with anti–PD-1 inhibitor or a combination of immunotherapy with an anti–PD-1 inhibitor. The optimal use of BRAF targeted therapy is unknown but some data supports its use earlier in the disease course (adjuvant setting) or after progression following anti–PD-1 therapy in the advanced disease setting,” wrote Dr. Sullivan in an email. He is associate director of the melanoma program at Massachusetts General Hospital, Boston.
The new study was published online in the Journal of Clinical Oncology.
In his editorial, Dr. Sullivan wrote that anti–PD-1 monoclonal antibodies alone or in combination with anti-CTLA4 receptor therapies is likely the best front-line therapy for BRAFV600 mutant advanced melanoma, with long-term survival ranging from 40% to 50%.
Still, the efficacy of BRAF-targeted therapy makes it important to explore ways to strengthen it further. One possibility is to use it in the front-line setting when a patient is at high risk of rapid progression and death, since analysis from DREAMSeq showed that BRAF-targeted therapy had a better overall survival than immunotherapy during the first 10 months after random assignment. It was only after this time point that the curves reversed and pointed to greater efficacy for immunotherapy. An option would be to treat to maximum tumor regression with BRAF-targeted therapy and then switch to immunotherapy, according to Dr. Sullivan. That point was echoed by study author Paolo Ascierto, MD, in an email exchange. “For patients with symptomatic disease or very high tumor burden, BRAF/MEK inhibitor should be used first,” said Dr. Ascierto, who is director of the melanoma cancer immunotherapy innovative therapy unit of the National Tumor Institute in Naples, Italy.
BRAF inhibitors as second- or later-line therapy
Aside from that exception, BRAF inhibitors should generally be reserved for second- or later-line therapy, according to Dr. Sullivan. Retrospective data indicate that response to BRAF inhibitors is preserved following immunotherapy, although the duration of benefit is reduced. Unfortunately, that strategy limits BRAF inhibitors to a setting in which they’re less likely to be maximally effective.
To improve matters, Dr. Sullivan suggested that they could be used in the adjuvant setting, where disease burden is lower. He noted that dabrafenib and trametinib are approved for resected stage 3 melanoma and showed similar efficacy to immunotherapy in that setting. Immunotherapy retains efficacy after BRAF-targeted therapy.
Another potential strategy is to come up with 3- or even 4-drug combinations employing BRAF/MEK inhibitors in the second-line setting. A few trials have already begun to investigate this possibility.
The COLUMBUS trial included 192 patients who received encorafenib plus binimetinib (E+B), 191 who received vemurafenib and 194 who received encorafenib. Five-year progression-free survival (PFS) was 23% in the E+B group, and 31% in those with normal lactate dehydrogenase levels. Five-year PFS was 10% with vemurafenib alone (12% with normal lactate dehydrogenase). Progression free survival (PFS) was 19% in the encorafenib group. Five-year overall survival (OS) followed a similar trend: 35% (45% with normal lactate dehydrogenase) in the E+B group, and 21% (28%) in the vemurafenib group. E+B had a median duration of response of 18.6 months, and a disease control rate of 92.2%, compared with 12.3 months and 81.2% with vemurafenib. Median duration of response was 15.5 months in the encorafenib monotherapy group.
The COLUMBUS trial was sponsored by Array BioPharma, which was acquired by Pfizer in July 2019.
Dr. Sullivan has consulted or advised Novartis, Merck, Replimune, Asana Biosciences, Alkermes, Eisai, Pfizer, Iovance Biotherapeutics, OncoSec, AstraZeneca, and Bristol Myers Squibb. Dr. Ascierto has stock or an ownership position in PrimeVax. He has consulted or advised for Bristol Myers Squibb, Roche/Genentech, Merck Sharp & Dohme, Novartis, Array BioPharma, Merck Serono, Pierre Fabre, Incyte, MedImmune, AstraZeneca, Sun Pharma, Sanofi, Idera, Ultimovacs, Sandoz, Immunocore, 4SC, Alkermes, Italfarmaco, Nektar, Boehringer Ingelheim, Eisai, Regeneron, Daiichi Sankyo, Pfizer, OncoSec, Nouscom, Takis Biotech, Lunaphore Technologies, Seattle Genetics, ITeos Therapeutics, Medicenna, and Bio-Al Health.
FROM JOURNAL OF CLINICAL ONCOLOGY
Sustained response at 2 years reported for newly approved oral psoriasis agent
MILAN – The day after deucravacitinib became the first TYK2 inhibitor approved for the treatment of moderate to severe psoriasis, long-term data were presented at the annual congress of the European Academy of Dermatology and Venereology, suggesting that a high degree of benefit persists for at least 2 years, making this oral drug a potential competitor for biologics.
,” said Mark G. Lebwohl, MD, professor of dermatology and dean of clinical therapeutics, Icahn School of Medicine at Mount Sinai, New York.
Just 2 months after the 52-week data from the phase 3 POETYK PSO-1 trial were published online in the Journal of the American Academy of Dermatology, a long-term extension study found essentially no loss of benefit at 112 weeks, according to Dr. Lebwohl.
One of the two co-primary endpoints was a 75% clearance on the Psoriasis and Severity Index (PASI75) score. At 52 weeks, 80.2% of patients on deucravacitinib had met this criterion of benefit. At 112 weeks, the proportion was 84.4%.
The other primary endpoint was a static Physician’s Global Assessment (sPGA) score of clear or almost clear skin. The proportion of patients meeting this criterion at weeks 52 and 112 weeks were 65.6% and 67.6%, respectively.
When assessed by Treatment Failure Rule (TFR) or modified nonresponder imputation (mNRI), results were similar. For both, the primary endpoints at every time interval were just one or two percentage points lower but not clinically meaningfully different, according to Dr. Lebwohl.
The same type of sustained response out to 112 weeks was observed in multiple analyses. When the researchers isolated the subgroup of patients who had achieved a PASI 75 response at 16 weeks (100%), there was a modest decline in the PASI 75 rate at week 52 (90.2%) but then no additional decline at week 112 (91.3%).
There were essentially no changes in the PASI 90 rates at week 16 (63%), week 52 (65.3%), and week 112 (63.1%), Dr. Lebwohl reported. PASI 100 rates, once achieved, were sustained long term.
The target, TYK2, is one of four Janus kinase (JAK) inhibitors. Until now, almost all JAK inhibitors have had greater relative specificity for JAK 1, JAK 2, and JAK 3, but several inhibitors of TYK2 inhibitors other than deucravacitinib are in development for inflammatory diseases. Deucravacitinib (Sotyktu), approved by the Food and Drug Administration on Sept. 9, is the only TYK2 inhibitor with regulatory approval for plaque psoriasis.
In the POETYK PSO-1 trial, 666 patients were initially randomized in a 2:1:1 ratio to 6 mg deucravacitinib (now the approved dose), placebo, or the oral phosphodiesterase 4 inhibitor apremilast. At week 16, patients on placebo were switched over to deucravacitinib. At week 24, patients who did not achieve a PASI 50 on apremilast (which had been titrated to 10 mg daily to 30 mg twice a day over the first 5 days of dosing) were switched to deucravacitinib.
In the previously reported data, deucravacitinib was superior for all efficacy endpoints at week 16, including an analysis of quality of life when compared with placebo (P < .0001) or apremilast (P = .0088). At week 52, after having been switched to deucravacitinib at week 16, patients on placebo achieved comparable responses on the efficacy measures in this study, including PASI75.
Relative to JAK inhibitors commonly used in rheumatoid arthritis and other inflammatory diseases, the greater specificity of deucravacitinib for TYK2 appears to have meaningful safety advantages, according to Dr. Lebwohl. Targeted mostly on the TYK2 regulatory domain, deucravacitinib largely avoids inhibition of the JAK 1, 2, and 3 subtypes. Dr. Lebwohl said this explains why deucravacitinib labeling does not share the boxed warnings about off-target effects, such as those on the cardiovascular system, that can be found in the labeling of other JAK inhibitors.
In the published 52-week data, the discontinuation rate for adverse events was lower in the group randomized to deucravacitinib arm than in the placebo arm. In the extended follow-up, there were no new signals for adverse events, including those involving the CV system or immune function.
The key message so far from the long-term follow-up, which is ongoing, is that “continuous treatment with deucravacitinib is associated with durable efficacy,” Dr. Lebwohl said. It is this combination of sustained efficacy and safety that led Dr. Lebwohl to suggest it as a reasonable oral competitor to injectable biologics.
“Patients now have a choice,” he said.
Jashin J. Wu, MD, a board member of the National Psoriasis Foundation and an associate professor in the department of dermatology, University of Miami, has been following the development of deucravacitinib. He said that the recent FDA approval validates the clinical evidence of benefit and safety, while the long-term data presented at the EADV congress support its role in expanding treatment options.
“Deucravacitinib is a very effective oral agent for moderate to severe plaque psoriasis with strong maintenance of effect through week 112,” he said. Differentiating it from other JAK inhibitors, the FDA approval “confirms the safety of this agent as there is no boxed warning,” he added.
Dr. Lebwohl reports financial relationships with more than 30 pharmaceutical companies, including Bristol-Myers Squibb, the manufacturer of deucravacitinib. Dr. Wu has financial relationships with 14 pharmaceutical companies, including Bristol-Myers Squibb, but he was not an investigator for the phase 3 trials of deucravacitinib.
MILAN – The day after deucravacitinib became the first TYK2 inhibitor approved for the treatment of moderate to severe psoriasis, long-term data were presented at the annual congress of the European Academy of Dermatology and Venereology, suggesting that a high degree of benefit persists for at least 2 years, making this oral drug a potential competitor for biologics.
,” said Mark G. Lebwohl, MD, professor of dermatology and dean of clinical therapeutics, Icahn School of Medicine at Mount Sinai, New York.
Just 2 months after the 52-week data from the phase 3 POETYK PSO-1 trial were published online in the Journal of the American Academy of Dermatology, a long-term extension study found essentially no loss of benefit at 112 weeks, according to Dr. Lebwohl.
One of the two co-primary endpoints was a 75% clearance on the Psoriasis and Severity Index (PASI75) score. At 52 weeks, 80.2% of patients on deucravacitinib had met this criterion of benefit. At 112 weeks, the proportion was 84.4%.
The other primary endpoint was a static Physician’s Global Assessment (sPGA) score of clear or almost clear skin. The proportion of patients meeting this criterion at weeks 52 and 112 weeks were 65.6% and 67.6%, respectively.
When assessed by Treatment Failure Rule (TFR) or modified nonresponder imputation (mNRI), results were similar. For both, the primary endpoints at every time interval were just one or two percentage points lower but not clinically meaningfully different, according to Dr. Lebwohl.
The same type of sustained response out to 112 weeks was observed in multiple analyses. When the researchers isolated the subgroup of patients who had achieved a PASI 75 response at 16 weeks (100%), there was a modest decline in the PASI 75 rate at week 52 (90.2%) but then no additional decline at week 112 (91.3%).
There were essentially no changes in the PASI 90 rates at week 16 (63%), week 52 (65.3%), and week 112 (63.1%), Dr. Lebwohl reported. PASI 100 rates, once achieved, were sustained long term.
The target, TYK2, is one of four Janus kinase (JAK) inhibitors. Until now, almost all JAK inhibitors have had greater relative specificity for JAK 1, JAK 2, and JAK 3, but several inhibitors of TYK2 inhibitors other than deucravacitinib are in development for inflammatory diseases. Deucravacitinib (Sotyktu), approved by the Food and Drug Administration on Sept. 9, is the only TYK2 inhibitor with regulatory approval for plaque psoriasis.
In the POETYK PSO-1 trial, 666 patients were initially randomized in a 2:1:1 ratio to 6 mg deucravacitinib (now the approved dose), placebo, or the oral phosphodiesterase 4 inhibitor apremilast. At week 16, patients on placebo were switched over to deucravacitinib. At week 24, patients who did not achieve a PASI 50 on apremilast (which had been titrated to 10 mg daily to 30 mg twice a day over the first 5 days of dosing) were switched to deucravacitinib.
In the previously reported data, deucravacitinib was superior for all efficacy endpoints at week 16, including an analysis of quality of life when compared with placebo (P < .0001) or apremilast (P = .0088). At week 52, after having been switched to deucravacitinib at week 16, patients on placebo achieved comparable responses on the efficacy measures in this study, including PASI75.
Relative to JAK inhibitors commonly used in rheumatoid arthritis and other inflammatory diseases, the greater specificity of deucravacitinib for TYK2 appears to have meaningful safety advantages, according to Dr. Lebwohl. Targeted mostly on the TYK2 regulatory domain, deucravacitinib largely avoids inhibition of the JAK 1, 2, and 3 subtypes. Dr. Lebwohl said this explains why deucravacitinib labeling does not share the boxed warnings about off-target effects, such as those on the cardiovascular system, that can be found in the labeling of other JAK inhibitors.
In the published 52-week data, the discontinuation rate for adverse events was lower in the group randomized to deucravacitinib arm than in the placebo arm. In the extended follow-up, there were no new signals for adverse events, including those involving the CV system or immune function.
The key message so far from the long-term follow-up, which is ongoing, is that “continuous treatment with deucravacitinib is associated with durable efficacy,” Dr. Lebwohl said. It is this combination of sustained efficacy and safety that led Dr. Lebwohl to suggest it as a reasonable oral competitor to injectable biologics.
“Patients now have a choice,” he said.
Jashin J. Wu, MD, a board member of the National Psoriasis Foundation and an associate professor in the department of dermatology, University of Miami, has been following the development of deucravacitinib. He said that the recent FDA approval validates the clinical evidence of benefit and safety, while the long-term data presented at the EADV congress support its role in expanding treatment options.
“Deucravacitinib is a very effective oral agent for moderate to severe plaque psoriasis with strong maintenance of effect through week 112,” he said. Differentiating it from other JAK inhibitors, the FDA approval “confirms the safety of this agent as there is no boxed warning,” he added.
Dr. Lebwohl reports financial relationships with more than 30 pharmaceutical companies, including Bristol-Myers Squibb, the manufacturer of deucravacitinib. Dr. Wu has financial relationships with 14 pharmaceutical companies, including Bristol-Myers Squibb, but he was not an investigator for the phase 3 trials of deucravacitinib.
MILAN – The day after deucravacitinib became the first TYK2 inhibitor approved for the treatment of moderate to severe psoriasis, long-term data were presented at the annual congress of the European Academy of Dermatology and Venereology, suggesting that a high degree of benefit persists for at least 2 years, making this oral drug a potential competitor for biologics.
,” said Mark G. Lebwohl, MD, professor of dermatology and dean of clinical therapeutics, Icahn School of Medicine at Mount Sinai, New York.
Just 2 months after the 52-week data from the phase 3 POETYK PSO-1 trial were published online in the Journal of the American Academy of Dermatology, a long-term extension study found essentially no loss of benefit at 112 weeks, according to Dr. Lebwohl.
One of the two co-primary endpoints was a 75% clearance on the Psoriasis and Severity Index (PASI75) score. At 52 weeks, 80.2% of patients on deucravacitinib had met this criterion of benefit. At 112 weeks, the proportion was 84.4%.
The other primary endpoint was a static Physician’s Global Assessment (sPGA) score of clear or almost clear skin. The proportion of patients meeting this criterion at weeks 52 and 112 weeks were 65.6% and 67.6%, respectively.
When assessed by Treatment Failure Rule (TFR) or modified nonresponder imputation (mNRI), results were similar. For both, the primary endpoints at every time interval were just one or two percentage points lower but not clinically meaningfully different, according to Dr. Lebwohl.
The same type of sustained response out to 112 weeks was observed in multiple analyses. When the researchers isolated the subgroup of patients who had achieved a PASI 75 response at 16 weeks (100%), there was a modest decline in the PASI 75 rate at week 52 (90.2%) but then no additional decline at week 112 (91.3%).
There were essentially no changes in the PASI 90 rates at week 16 (63%), week 52 (65.3%), and week 112 (63.1%), Dr. Lebwohl reported. PASI 100 rates, once achieved, were sustained long term.
The target, TYK2, is one of four Janus kinase (JAK) inhibitors. Until now, almost all JAK inhibitors have had greater relative specificity for JAK 1, JAK 2, and JAK 3, but several inhibitors of TYK2 inhibitors other than deucravacitinib are in development for inflammatory diseases. Deucravacitinib (Sotyktu), approved by the Food and Drug Administration on Sept. 9, is the only TYK2 inhibitor with regulatory approval for plaque psoriasis.
In the POETYK PSO-1 trial, 666 patients were initially randomized in a 2:1:1 ratio to 6 mg deucravacitinib (now the approved dose), placebo, or the oral phosphodiesterase 4 inhibitor apremilast. At week 16, patients on placebo were switched over to deucravacitinib. At week 24, patients who did not achieve a PASI 50 on apremilast (which had been titrated to 10 mg daily to 30 mg twice a day over the first 5 days of dosing) were switched to deucravacitinib.
In the previously reported data, deucravacitinib was superior for all efficacy endpoints at week 16, including an analysis of quality of life when compared with placebo (P < .0001) or apremilast (P = .0088). At week 52, after having been switched to deucravacitinib at week 16, patients on placebo achieved comparable responses on the efficacy measures in this study, including PASI75.
Relative to JAK inhibitors commonly used in rheumatoid arthritis and other inflammatory diseases, the greater specificity of deucravacitinib for TYK2 appears to have meaningful safety advantages, according to Dr. Lebwohl. Targeted mostly on the TYK2 regulatory domain, deucravacitinib largely avoids inhibition of the JAK 1, 2, and 3 subtypes. Dr. Lebwohl said this explains why deucravacitinib labeling does not share the boxed warnings about off-target effects, such as those on the cardiovascular system, that can be found in the labeling of other JAK inhibitors.
In the published 52-week data, the discontinuation rate for adverse events was lower in the group randomized to deucravacitinib arm than in the placebo arm. In the extended follow-up, there were no new signals for adverse events, including those involving the CV system or immune function.
The key message so far from the long-term follow-up, which is ongoing, is that “continuous treatment with deucravacitinib is associated with durable efficacy,” Dr. Lebwohl said. It is this combination of sustained efficacy and safety that led Dr. Lebwohl to suggest it as a reasonable oral competitor to injectable biologics.
“Patients now have a choice,” he said.
Jashin J. Wu, MD, a board member of the National Psoriasis Foundation and an associate professor in the department of dermatology, University of Miami, has been following the development of deucravacitinib. He said that the recent FDA approval validates the clinical evidence of benefit and safety, while the long-term data presented at the EADV congress support its role in expanding treatment options.
“Deucravacitinib is a very effective oral agent for moderate to severe plaque psoriasis with strong maintenance of effect through week 112,” he said. Differentiating it from other JAK inhibitors, the FDA approval “confirms the safety of this agent as there is no boxed warning,” he added.
Dr. Lebwohl reports financial relationships with more than 30 pharmaceutical companies, including Bristol-Myers Squibb, the manufacturer of deucravacitinib. Dr. Wu has financial relationships with 14 pharmaceutical companies, including Bristol-Myers Squibb, but he was not an investigator for the phase 3 trials of deucravacitinib.
AT THE EADV CONGRESS
Pembro/chemo combo fails to improve event-free survival in head and neck cancer
PARIS – compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.
Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.
Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.
“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.
He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.
The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.
KEYNOTE-412 details
The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.
In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.
Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.
A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.
As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.
In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.
The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.
Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
Benefit still to be proven
In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.
He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.
He also pointed to the numerically superior 2-year EFS and overall rates.
In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.
“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.
“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.
Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.
“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.
The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.
PARIS – compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.
Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.
Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.
“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.
He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.
The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.
KEYNOTE-412 details
The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.
In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.
Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.
A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.
As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.
In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.
The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.
Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
Benefit still to be proven
In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.
He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.
He also pointed to the numerically superior 2-year EFS and overall rates.
In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.
“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.
“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.
Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.
“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.
The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.
PARIS – compared with CRT plus placebo as first-line therapy for patients with locally advanced head and neck squamous cell cancers (HNSCC), reported investigators of the KEYNOTE-412 trial.
Among 804 patients with newly diagnosed, pathologically proven, unresected locally advanced head and neck squamous cell carcinomas who were followed for a median of 47.7 months, the event-free survival (EFS) rate with the pembrolizumab/CRT combination followed by maintenance pembrolizumab was 63.2%, compared with 56.2% for CRT plus placebo. This translated into a nonsignificant hazard ratio of 0.83, said Jean-Pascal Machiels, MD, PhD, at the annual meeting of the European Society for Medical Oncology.
Despite the trial failing to meet its primary endpoint, Dr. Machiels expressed optimism about the results.
“Pembrolizumab with chemoradiation was associated with a favorable trend toward improved event-free survival versus placebo plus chemoradiation in patients with locally advanced head and neck cancer,” he said.
He noted that the 2-year EFS rate was 63% with pembrolizumab, compared with 56% with placebo.
The data also support the hypothesis that programmed death–ligand 1 (PD-L1) expression as measured by a combined positive score (CPS) could be a predictive biomarker for identifying those patients most likely to respond to the immune checkpoint inhibitor, he added.
KEYNOTE-412 details
The rationale for combining the checkpoint inhibitors pembrolizumab with chemoradiotherapy comes from the KEYNOTE-048 trial results of which showed a survival improvement for the use of pembrolizumab plus a platinum-containing regimen as a first-line therapy for recurrent or metastatic HNSCC, as well as pembrolizumab monotherapy for patients with PD-L1 CPS of 1 or greater.
In the current study, Dr. Machiels and colleagues studied whether adding pembrolizumab to CRT could benefit patients with treatment-naive unresected, locally advanced HNSCC.
Eligible patients included those with stage T3 or T4, N0-N3 or any N2a-3 (T1-T4) cancers of the larynx, hypopharynx, or oral cavity, and either p16-negative oropharynx cancers or T4 or N3 p16-positive oropharynx cancer. Patients were required to be eligible for high-dose cisplatin-based CRT.
A total of 804 patients were randomized, 402 in each arm, to receive either pembrolizumab 200 mg intravenously every 3 weeks for 3 cycles plus CRT followed by maintenance pembrolizumab for 14 cycles, or to placebo plus CRT followed by placebo maintenance.
As noted before, there was no significant difference between the study arms for the primary endpoint of EFS. The 24-month EFS rate was 63.2% for the pembrolizumab group, compared with 56.2% for controls. The respective 6-month EFS rates were 57.4% versus 52.1%.
In a post hoc analysis, both EFS and overall survival were numerically with pembrolizumab among patients with PD-L1 CPS of 20 or greater. The respective 2- and 3-year EFS rates were 71.2% versus 62.6%, and 66.7% versus 57.2%.
The 24-months overall survival rates were 83.3% with pembrolizumab and 79.9% with placebo, and 36-month rates were 79.1% and 73%, respectively.
Neither EFS rates nor OS rates among patients in this subgroup differed significantly; however, there were no new safety signals with the combination, Dr. Machiels said. The incidence of grade 3 or greater adverse events was 92.2% in the pembrolizumab arm versus 88.4% in the placebo arm. Four patients in the pembrolizumab arm and six in the control arm died from treatment-related causes.
Benefit still to be proven
In a media briefing held prior to his presentation, Dr. Machiels was asked how he could justify his conclusions about a benefit for adding pembrolizumab given that there was no difference between the treatment groups for the primary endpoint.
He said that when the investigators designed the trial 7 years ago, the CPS score for PD-L1 expression had not yet been developed, and that if it had been they might have designed the trial to explore the effect of the pembrolizumab chemoradiation combination according to CPS subgroups.
He also pointed to the numerically superior 2-year EFS and overall rates.
In the presidential symposium, James Larkin, MD, PhD, an invited discussant from the Royal Marsden Hospital, London, said that chemotherapy and anti–PD-1 therapies are known to offer benefit in advanced cancers despite the trial’s failure.
“There is a signal, particularly as we’ve seen in the high PD-L1 group,” he said, noting that the signal was consistent with that seen in the JAVELIN 100 study, which was also a negative trial. He cautioned against relying too heavily on the comparison, however, as JAVELIN 100 was conducted with avelumab, a PD-L1 inhibitor, whereas pembrolizumab is a PD-1 inhibitor.
“Could there be an issue here with treatment schedule? An example and a comparison might be the PACIFIC study in non–small cell lung cancer, which is a positive trial, where actually the checkpoint inhibit with durvalumab was given immediately after the chemoradiotherapy, leading to benefit, rather than being concurrent,” he said.
Dr. Larkin also questioned whether, as codiscussant Sherene Loi, MD, PhD, from the Peter MacCallum Cancer Center, Melbourne, suggested radiotherapy to lymph nodes might alter the immune response to checkpoint inhibitors.
“Clearly radiotherapy is the central component of treatment in this setting, so it would be quite difficult to scale too much on that, but the question is: ‘Could it be modified?’ For example, just to irradiate the primary tumor and involved lymph nodes and potentially spare noninvolved lymph nodes,” he said.
The KEYNOTE-412 study was funded by Merck Sharp & Dohme. Dr. Machiels reported uncompensated consulting to the company. Dr. Larkin reported consulting for and receiving honoraria from Merck and others. Dr. Loi reported uncompensated advisory board activity for Merck and others.
AT ESMO CONGRESS 2022
Heparin pretreatment may safely open arteries before STEMI cath
, suggests a large registry study.
An open infarct-related artery (IRA) at angiography on cath-lab arrival presents STEMI patients an opportunity for earlier reperfusion and a chance, in theory at least, for smaller infarcts and maybe improved clinical outcomes.
In the new analysis, which covers more than 40,000 patients with STEMI in Sweden, the 38% who received heparin before cath-lab arrival were 11% less likely to show IRA occlusion at angiography prior to direct percutaneous coronary intervention (PCI). They also showed a 13% lower 30-day mortality compared with patients who were started on heparin in the cath lab. Importantly, their risk of major bleeding in the hospital did not increase.
The “early reperfusion” associated with IRA patency at angiography “could have long-term benefit due to smaller infarct size,” potentially explaining the observed 30-day survival gain in the pretreatment group, Oskar Love Emilsson, Lund (Sweden) University, said in an interview.
Mr. Emilsson, a third-year medical student, reported the analysis at the annual congress of the European Society of Cardiology, and is lead author on its same-day publication in the journal EuroIntervention.
He mentioned a few cautions in interpreting the study, which is based primarily on data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). It included several sensitivity analyses that continued to back pretreatment heparin as a significant predictor of an unoccluded IRA but didn’t consistently support the 30-day mortality benefit seen in the primary analysis.
And, although the pretreatment group overall didn’t have more major bleeds, the risk did go up significantly for those older than 75 or those who weighed less than 60 kg (132 pounds) or underwent catheterization with an access route other than the radial artery. Extra caution should be exercised in such patients who receive heparin before cath-lab arrival for PCI, Mr. Emilsson observed.
“Our results suggest that heparin pretreatment might be a good option to improve patency of infarct related arteries in STEMI,” and potentially clinical outcomes, he said. “However, a definite answer would require a randomized controlled trial.”
Meanwhile, the current study may be the largest yet to look at clinical outcomes after pretreatment with unfractionated heparin before PCI for acute STEMI, the report states. There have been some observational studies, subanalyses of STEMI trials, and even a few limited randomized trials – including the HEAP trial published in 2000 – to weigh in on the subject. Some have supported the strategy, others have not.
“With rapid door-to-balloon times in STEMI, it can be challenging to show a significant difference between a prehospital heparin approach and heparin given in the lab,” observed Sunil V. Rao, MD, NYU Langone Health System, New York, who is not connected with the current study.
Many EDs in the United States have “a STEMI protocol that calls for an IV bolus of heparin. It would be tougher in the U.S. to give it in the ambulance but again, it’s not clear how much advantage that would really provide,” he told this news organization.
Support from randomized trials would be needed before the practice could be formally recommended. “The SCAAR registries have set the standard for how registries should be conducted,” Dr. Rao said. “This is a very well done observational study, but it is observational.”
The priority for STEMI patients, he added, “really should be to get them to the lab as fast as possible. If the ED protocol includes heparin before the cath lab, that’s great, but I don’t think we should delay getting these patients to the lab to accommodate pre–cath-lab heparin.”
The current analysis covered 41,631 patients with STEMI from 2008 through to 2016, of whom 38% were pretreated with heparin in an ambulance or the ED. The remaining 62% initiated heparin in the cath lab.
About one-third of the group had an open IRA at angiography. The adjusted risk ratio (RR) for IRA occlusion at angiography for patients pretreated vs. not pretreated with heparin was 0.89 (95% confidence interval [CI], 0.87-0.90).
The corresponding RR for death within 30 days was 0.87 (95% CI, 0.77-0.99), and for major in-hospital bleeding it was 1.01 (95% CI, 0.86-1.18).
The analysis was adjusted for other medications received before cath-lab arrival, especially a long list of antiplatelets and non-heparin antithrombins. That strengthens the case for heparin pretreatment as an independent predictor of an open IRA at initial angiography, Mr. Emilsson said.
Comparisons of propensity-score–matched subgroups of the total cohort, conducted separately for the IRA-occlusion endpoint and the endpoints of 30-day mortality and major bleeding, produced similar results.
Some observational data suggest that antiplatelet pretreatment with a P2Y12 inhibitor may promote IRA patency on angiography after cath lab arrival, Dr. Rao observed. “This indicates that there probably is a role of earlier antithrombotic therapy in STEMI patients, but the randomized trials have not shown a consistent benefit,” he said, referring in particular to the ATLANTIC trial.
Mr. Emilsson and Dr. Rao disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests a large registry study.
An open infarct-related artery (IRA) at angiography on cath-lab arrival presents STEMI patients an opportunity for earlier reperfusion and a chance, in theory at least, for smaller infarcts and maybe improved clinical outcomes.
In the new analysis, which covers more than 40,000 patients with STEMI in Sweden, the 38% who received heparin before cath-lab arrival were 11% less likely to show IRA occlusion at angiography prior to direct percutaneous coronary intervention (PCI). They also showed a 13% lower 30-day mortality compared with patients who were started on heparin in the cath lab. Importantly, their risk of major bleeding in the hospital did not increase.
The “early reperfusion” associated with IRA patency at angiography “could have long-term benefit due to smaller infarct size,” potentially explaining the observed 30-day survival gain in the pretreatment group, Oskar Love Emilsson, Lund (Sweden) University, said in an interview.
Mr. Emilsson, a third-year medical student, reported the analysis at the annual congress of the European Society of Cardiology, and is lead author on its same-day publication in the journal EuroIntervention.
He mentioned a few cautions in interpreting the study, which is based primarily on data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). It included several sensitivity analyses that continued to back pretreatment heparin as a significant predictor of an unoccluded IRA but didn’t consistently support the 30-day mortality benefit seen in the primary analysis.
And, although the pretreatment group overall didn’t have more major bleeds, the risk did go up significantly for those older than 75 or those who weighed less than 60 kg (132 pounds) or underwent catheterization with an access route other than the radial artery. Extra caution should be exercised in such patients who receive heparin before cath-lab arrival for PCI, Mr. Emilsson observed.
“Our results suggest that heparin pretreatment might be a good option to improve patency of infarct related arteries in STEMI,” and potentially clinical outcomes, he said. “However, a definite answer would require a randomized controlled trial.”
Meanwhile, the current study may be the largest yet to look at clinical outcomes after pretreatment with unfractionated heparin before PCI for acute STEMI, the report states. There have been some observational studies, subanalyses of STEMI trials, and even a few limited randomized trials – including the HEAP trial published in 2000 – to weigh in on the subject. Some have supported the strategy, others have not.
“With rapid door-to-balloon times in STEMI, it can be challenging to show a significant difference between a prehospital heparin approach and heparin given in the lab,” observed Sunil V. Rao, MD, NYU Langone Health System, New York, who is not connected with the current study.
Many EDs in the United States have “a STEMI protocol that calls for an IV bolus of heparin. It would be tougher in the U.S. to give it in the ambulance but again, it’s not clear how much advantage that would really provide,” he told this news organization.
Support from randomized trials would be needed before the practice could be formally recommended. “The SCAAR registries have set the standard for how registries should be conducted,” Dr. Rao said. “This is a very well done observational study, but it is observational.”
The priority for STEMI patients, he added, “really should be to get them to the lab as fast as possible. If the ED protocol includes heparin before the cath lab, that’s great, but I don’t think we should delay getting these patients to the lab to accommodate pre–cath-lab heparin.”
The current analysis covered 41,631 patients with STEMI from 2008 through to 2016, of whom 38% were pretreated with heparin in an ambulance or the ED. The remaining 62% initiated heparin in the cath lab.
About one-third of the group had an open IRA at angiography. The adjusted risk ratio (RR) for IRA occlusion at angiography for patients pretreated vs. not pretreated with heparin was 0.89 (95% confidence interval [CI], 0.87-0.90).
The corresponding RR for death within 30 days was 0.87 (95% CI, 0.77-0.99), and for major in-hospital bleeding it was 1.01 (95% CI, 0.86-1.18).
The analysis was adjusted for other medications received before cath-lab arrival, especially a long list of antiplatelets and non-heparin antithrombins. That strengthens the case for heparin pretreatment as an independent predictor of an open IRA at initial angiography, Mr. Emilsson said.
Comparisons of propensity-score–matched subgroups of the total cohort, conducted separately for the IRA-occlusion endpoint and the endpoints of 30-day mortality and major bleeding, produced similar results.
Some observational data suggest that antiplatelet pretreatment with a P2Y12 inhibitor may promote IRA patency on angiography after cath lab arrival, Dr. Rao observed. “This indicates that there probably is a role of earlier antithrombotic therapy in STEMI patients, but the randomized trials have not shown a consistent benefit,” he said, referring in particular to the ATLANTIC trial.
Mr. Emilsson and Dr. Rao disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
, suggests a large registry study.
An open infarct-related artery (IRA) at angiography on cath-lab arrival presents STEMI patients an opportunity for earlier reperfusion and a chance, in theory at least, for smaller infarcts and maybe improved clinical outcomes.
In the new analysis, which covers more than 40,000 patients with STEMI in Sweden, the 38% who received heparin before cath-lab arrival were 11% less likely to show IRA occlusion at angiography prior to direct percutaneous coronary intervention (PCI). They also showed a 13% lower 30-day mortality compared with patients who were started on heparin in the cath lab. Importantly, their risk of major bleeding in the hospital did not increase.
The “early reperfusion” associated with IRA patency at angiography “could have long-term benefit due to smaller infarct size,” potentially explaining the observed 30-day survival gain in the pretreatment group, Oskar Love Emilsson, Lund (Sweden) University, said in an interview.
Mr. Emilsson, a third-year medical student, reported the analysis at the annual congress of the European Society of Cardiology, and is lead author on its same-day publication in the journal EuroIntervention.
He mentioned a few cautions in interpreting the study, which is based primarily on data from the Swedish Coronary Angiography and Angioplasty Registry (SCAAR). It included several sensitivity analyses that continued to back pretreatment heparin as a significant predictor of an unoccluded IRA but didn’t consistently support the 30-day mortality benefit seen in the primary analysis.
And, although the pretreatment group overall didn’t have more major bleeds, the risk did go up significantly for those older than 75 or those who weighed less than 60 kg (132 pounds) or underwent catheterization with an access route other than the radial artery. Extra caution should be exercised in such patients who receive heparin before cath-lab arrival for PCI, Mr. Emilsson observed.
“Our results suggest that heparin pretreatment might be a good option to improve patency of infarct related arteries in STEMI,” and potentially clinical outcomes, he said. “However, a definite answer would require a randomized controlled trial.”
Meanwhile, the current study may be the largest yet to look at clinical outcomes after pretreatment with unfractionated heparin before PCI for acute STEMI, the report states. There have been some observational studies, subanalyses of STEMI trials, and even a few limited randomized trials – including the HEAP trial published in 2000 – to weigh in on the subject. Some have supported the strategy, others have not.
“With rapid door-to-balloon times in STEMI, it can be challenging to show a significant difference between a prehospital heparin approach and heparin given in the lab,” observed Sunil V. Rao, MD, NYU Langone Health System, New York, who is not connected with the current study.
Many EDs in the United States have “a STEMI protocol that calls for an IV bolus of heparin. It would be tougher in the U.S. to give it in the ambulance but again, it’s not clear how much advantage that would really provide,” he told this news organization.
Support from randomized trials would be needed before the practice could be formally recommended. “The SCAAR registries have set the standard for how registries should be conducted,” Dr. Rao said. “This is a very well done observational study, but it is observational.”
The priority for STEMI patients, he added, “really should be to get them to the lab as fast as possible. If the ED protocol includes heparin before the cath lab, that’s great, but I don’t think we should delay getting these patients to the lab to accommodate pre–cath-lab heparin.”
The current analysis covered 41,631 patients with STEMI from 2008 through to 2016, of whom 38% were pretreated with heparin in an ambulance or the ED. The remaining 62% initiated heparin in the cath lab.
About one-third of the group had an open IRA at angiography. The adjusted risk ratio (RR) for IRA occlusion at angiography for patients pretreated vs. not pretreated with heparin was 0.89 (95% confidence interval [CI], 0.87-0.90).
The corresponding RR for death within 30 days was 0.87 (95% CI, 0.77-0.99), and for major in-hospital bleeding it was 1.01 (95% CI, 0.86-1.18).
The analysis was adjusted for other medications received before cath-lab arrival, especially a long list of antiplatelets and non-heparin antithrombins. That strengthens the case for heparin pretreatment as an independent predictor of an open IRA at initial angiography, Mr. Emilsson said.
Comparisons of propensity-score–matched subgroups of the total cohort, conducted separately for the IRA-occlusion endpoint and the endpoints of 30-day mortality and major bleeding, produced similar results.
Some observational data suggest that antiplatelet pretreatment with a P2Y12 inhibitor may promote IRA patency on angiography after cath lab arrival, Dr. Rao observed. “This indicates that there probably is a role of earlier antithrombotic therapy in STEMI patients, but the randomized trials have not shown a consistent benefit,” he said, referring in particular to the ATLANTIC trial.
Mr. Emilsson and Dr. Rao disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM ESC CONGRESS 2022
Clozapine may be best choice for cutting SUD risk in schizophrenia
results of a real-world study show.
“Our findings are in line with a recent meta-analysis showing superior efficacy of clozapine in schizophrenia and comorbid SUD and other studies pointing toward clozapine’s superiority over other antipsychotics in the treatment of individuals with schizophrenia and comorbid SUD,” the investigators, led by Jari Tiihonen MD, PhD, department of clinical neuroscience, Karolinska Institutet, Stockholm, write.
“The results on polypharmacy are in line with previous results from nationwide cohorts showing a favorable outcome, compared with oral monotherapies among persons with schizophrenia in general,” they add.
The study was published online Aug. 25 in The British Journal of Psychiatry.
Research gap
Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid SUD is “very sparse, and more importantly, non-existent on the prevention of the development of SUDs in patients with schizophrenia,” the researchers note.
To investigate, they analyzed data on more than 45,000 patients with schizophrenia from Finnish and Swedish national registries, with follow-up lasting 22 years in Finland and 11 years in Sweden.
In patients with schizophrenia without SUD, treatment with clozapine was associated with lowest risk for an initial SUD in both Finland (adjusted hazard ratio, 0.20; 95% confidence interval, 0.16-0.24) and Sweden (aHR, 0.35; 95% CI, 0.24-0.50), compared with no use or use of other antipsychotics.
In Finland, aripiprazole was associated with the second lowest risk for an initial SUD (aHR, 0.36; 95% CI, 0.24-0.55) and antipsychotic polytherapy the third lowest risk (aHR, 0.47; 95% CI, 0.42-0.53).
In Sweden, antipsychotic polytherapy was associated with second lowest risk for an initial SUD (aHR, 0.54; 95% CI, 0.44-0.66) and olanzapine the third lowest risk (aHR, 0.67; 95% CI, 0.53-0.84).
In both countries, the risk for relapse as indicated by psychiatric hospital admission and SUD-related hospital admission were lowest for clozapine, antipsychotic polytherapy and long-acting injectables, the investigators report.
Interpret with caution
Reached for comment, Christoph U. Correll, MD, professor of psychiatry and molecular medicine, the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, urged caution in interpreting the results.
“While the authors are experts in national database analyses and the study was conducted with state-of-the-art methodology, the onset of SUD analyses favoring clozapine are subject to survival bias and order effects,” Dr. Correll said.
“Since clozapine is generally used later in the illness and treatment course, after multiple other antipsychotics have been used, and since SUDs generally occur early in the illness course, most SUDs will already have arisen by the time that clozapine is considered and used,” Dr. Correll said.
“A similar potential bias exists for long-acting injectables (LAIs), as these have generally also been used late in the treatment algorithm,” he noted.
In terms of the significant reduction of SUD-related hospitalizations observed with clozapine, the “order effect” could also be relevant, Dr. Correll said, because over time, patients are less likely to be nonadherent and hospitalized and clozapine is systematically used later in life than other antipsychotics.
“Why antipsychotic polytherapy came out as the second-best treatment is much less clear. Clearly head-to-head randomized trials are needed to follow up on these interesting and intriguing naturalistic database study data,” said Dr. Correll.
This study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Dr. Tiihonen and three co-authors have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their institution. Dr. Correll reports having been a consultant and/or advisor to or receiving honoraria from many companies. He has also provided expert testimony for Janssen and Otsuka; served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic.
A version of this article first appeared on Medscape.com.
results of a real-world study show.
“Our findings are in line with a recent meta-analysis showing superior efficacy of clozapine in schizophrenia and comorbid SUD and other studies pointing toward clozapine’s superiority over other antipsychotics in the treatment of individuals with schizophrenia and comorbid SUD,” the investigators, led by Jari Tiihonen MD, PhD, department of clinical neuroscience, Karolinska Institutet, Stockholm, write.
“The results on polypharmacy are in line with previous results from nationwide cohorts showing a favorable outcome, compared with oral monotherapies among persons with schizophrenia in general,” they add.
The study was published online Aug. 25 in The British Journal of Psychiatry.
Research gap
Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid SUD is “very sparse, and more importantly, non-existent on the prevention of the development of SUDs in patients with schizophrenia,” the researchers note.
To investigate, they analyzed data on more than 45,000 patients with schizophrenia from Finnish and Swedish national registries, with follow-up lasting 22 years in Finland and 11 years in Sweden.
In patients with schizophrenia without SUD, treatment with clozapine was associated with lowest risk for an initial SUD in both Finland (adjusted hazard ratio, 0.20; 95% confidence interval, 0.16-0.24) and Sweden (aHR, 0.35; 95% CI, 0.24-0.50), compared with no use or use of other antipsychotics.
In Finland, aripiprazole was associated with the second lowest risk for an initial SUD (aHR, 0.36; 95% CI, 0.24-0.55) and antipsychotic polytherapy the third lowest risk (aHR, 0.47; 95% CI, 0.42-0.53).
In Sweden, antipsychotic polytherapy was associated with second lowest risk for an initial SUD (aHR, 0.54; 95% CI, 0.44-0.66) and olanzapine the third lowest risk (aHR, 0.67; 95% CI, 0.53-0.84).
In both countries, the risk for relapse as indicated by psychiatric hospital admission and SUD-related hospital admission were lowest for clozapine, antipsychotic polytherapy and long-acting injectables, the investigators report.
Interpret with caution
Reached for comment, Christoph U. Correll, MD, professor of psychiatry and molecular medicine, the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, urged caution in interpreting the results.
“While the authors are experts in national database analyses and the study was conducted with state-of-the-art methodology, the onset of SUD analyses favoring clozapine are subject to survival bias and order effects,” Dr. Correll said.
“Since clozapine is generally used later in the illness and treatment course, after multiple other antipsychotics have been used, and since SUDs generally occur early in the illness course, most SUDs will already have arisen by the time that clozapine is considered and used,” Dr. Correll said.
“A similar potential bias exists for long-acting injectables (LAIs), as these have generally also been used late in the treatment algorithm,” he noted.
In terms of the significant reduction of SUD-related hospitalizations observed with clozapine, the “order effect” could also be relevant, Dr. Correll said, because over time, patients are less likely to be nonadherent and hospitalized and clozapine is systematically used later in life than other antipsychotics.
“Why antipsychotic polytherapy came out as the second-best treatment is much less clear. Clearly head-to-head randomized trials are needed to follow up on these interesting and intriguing naturalistic database study data,” said Dr. Correll.
This study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Dr. Tiihonen and three co-authors have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their institution. Dr. Correll reports having been a consultant and/or advisor to or receiving honoraria from many companies. He has also provided expert testimony for Janssen and Otsuka; served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic.
A version of this article first appeared on Medscape.com.
results of a real-world study show.
“Our findings are in line with a recent meta-analysis showing superior efficacy of clozapine in schizophrenia and comorbid SUD and other studies pointing toward clozapine’s superiority over other antipsychotics in the treatment of individuals with schizophrenia and comorbid SUD,” the investigators, led by Jari Tiihonen MD, PhD, department of clinical neuroscience, Karolinska Institutet, Stockholm, write.
“The results on polypharmacy are in line with previous results from nationwide cohorts showing a favorable outcome, compared with oral monotherapies among persons with schizophrenia in general,” they add.
The study was published online Aug. 25 in The British Journal of Psychiatry.
Research gap
Research on the effectiveness of pharmacotherapies for schizophrenia and comorbid SUD is “very sparse, and more importantly, non-existent on the prevention of the development of SUDs in patients with schizophrenia,” the researchers note.
To investigate, they analyzed data on more than 45,000 patients with schizophrenia from Finnish and Swedish national registries, with follow-up lasting 22 years in Finland and 11 years in Sweden.
In patients with schizophrenia without SUD, treatment with clozapine was associated with lowest risk for an initial SUD in both Finland (adjusted hazard ratio, 0.20; 95% confidence interval, 0.16-0.24) and Sweden (aHR, 0.35; 95% CI, 0.24-0.50), compared with no use or use of other antipsychotics.
In Finland, aripiprazole was associated with the second lowest risk for an initial SUD (aHR, 0.36; 95% CI, 0.24-0.55) and antipsychotic polytherapy the third lowest risk (aHR, 0.47; 95% CI, 0.42-0.53).
In Sweden, antipsychotic polytherapy was associated with second lowest risk for an initial SUD (aHR, 0.54; 95% CI, 0.44-0.66) and olanzapine the third lowest risk (aHR, 0.67; 95% CI, 0.53-0.84).
In both countries, the risk for relapse as indicated by psychiatric hospital admission and SUD-related hospital admission were lowest for clozapine, antipsychotic polytherapy and long-acting injectables, the investigators report.
Interpret with caution
Reached for comment, Christoph U. Correll, MD, professor of psychiatry and molecular medicine, the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, urged caution in interpreting the results.
“While the authors are experts in national database analyses and the study was conducted with state-of-the-art methodology, the onset of SUD analyses favoring clozapine are subject to survival bias and order effects,” Dr. Correll said.
“Since clozapine is generally used later in the illness and treatment course, after multiple other antipsychotics have been used, and since SUDs generally occur early in the illness course, most SUDs will already have arisen by the time that clozapine is considered and used,” Dr. Correll said.
“A similar potential bias exists for long-acting injectables (LAIs), as these have generally also been used late in the treatment algorithm,” he noted.
In terms of the significant reduction of SUD-related hospitalizations observed with clozapine, the “order effect” could also be relevant, Dr. Correll said, because over time, patients are less likely to be nonadherent and hospitalized and clozapine is systematically used later in life than other antipsychotics.
“Why antipsychotic polytherapy came out as the second-best treatment is much less clear. Clearly head-to-head randomized trials are needed to follow up on these interesting and intriguing naturalistic database study data,” said Dr. Correll.
This study was funded by the Finnish Ministry of Social Affairs and Health through the developmental fund for Niuvanniemi Hospital. Dr. Tiihonen and three co-authors have participated in research projects funded by grants from Janssen-Cilag and Eli Lilly to their institution. Dr. Correll reports having been a consultant and/or advisor to or receiving honoraria from many companies. He has also provided expert testimony for Janssen and Otsuka; served on a Data Safety Monitoring Board for Lundbeck, Relmada, Reviva, Rovi, Supernus, and Teva; received royalties from UpToDate; and is a stock option holder of Cardio Diagnostics, Mindpax, LB Pharma, and Quantic.
A version of this article first appeared on Medscape.com.
FROM THE BRITISH JOURNAL OF PSYCHIATRY
Cabozantinib boosts dual immunotherapy in advanced RCC
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
PARIS – (PFS) in advanced renal cell carcinoma (aRCC), particularly in intermediate-risk patients, suggest results from the COSMIC-313 trial.
At present, dual checkpoint inhibition with nivolumab and ipilimumab is a standard of care for first-line treatment of aRCC that is deemed to be of intermediate or poor risk on the International Metastatic RCC Database Consortium (IMDC) risk score.
Cabozantinib, a tyrosine kinase inhibitor (TKI), is also a standard of care in aRCC, both as a single agent and in combination with nivolumab.
The new study investigated the use of the three drugs together as upfront first-line treatment and suggests that this triplet may become a new standard of care, especially in patients with intermediate-risk disease.
The research was presented at the European Society for Medical Oncology Congress in Paris.
The trial involved 855 previously untreated patients with aRCC, all of whom received dual immunotherapy with nivolumab and ipilimumab, who were randomly assigned to also receive either cabozantinib or matched placebo.
Patients given the triplet therapy had a significant 27% reduction in the risk for progression versus the doublet in the overall patient population.
The difference increased to 37% in patients with intermediate-risk disease on the IMDC risk score.
However, patients with poor-risk disease appeared not to derive any benefit from adding cabozantinib to nivolumab plus ipilimumab.
In addition, grade 3 or 4 treatment-related adverse events were more common with the triplet therapy.
The results suggest that adding cabozantinib results in a “statistically significant and clinically meaningful” PFS benefit, study presenter Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology at the Dana-Farber Cancer Institute, Boston, told a press conference.
He added that the safety profile of the triplet therapy was “generally manageable” and “consistent with the profiles of the treatment components.”
“The study will continue to the next analysis of overall survival, as this secondary endpoint was not met at first interim analysis,” Dr. Choueiri commented.
He told this news organization that, based on the current results, the triplet combination “may end up in intermediate-risk” patients, although it is not clear why there is a difference in response between risk groups, and the finding is “quite intriguing.”
Asked which therapy to choose now for first-line treatment of aRCC, given that there are now so many options, he said that there is now such “an embarrassment of riches of trials in the first-line” that it is perhaps easier to talk about which therapies “not to use.”
“We cannot use single TKIs anymore, so you have to use doublets and possibly now triplets,” he said.
“In my practice, patients that are progressing rapidly ... need a VEGF [vascular endothelial growth factor]–based combination. In patients that can wait and ... do not have a heavy disease burden, I still believe in nivolumab and ipilimumab, which has the longest follow-up, and the responses are durable.”
Approached for comment, Dominik Berthold, MD, Centre hospitalier universitaire vaudois, Lausanne, Switzerland, said that this is a “really important study” because it has a “modern” study comparator in the control arm.
He said in an interview, however, that the question now is “obviously” how much treatment should be escalated to triple therapy “upfront versus the sequencing of active drugs.” The answer, he said, is currently unclear, and overall survival data are awaited.
Alongside the potential “challenge” of the toxicity to patients of the triplet therapy, Dr. Berthold also highlighted that it is “currently a challenge for health systems to imagine giving such expensive combinations.”
So though it is “really interesting data” and potentially represents a “step forward” in the field, the combination of cabozantinib and nivolumab plus ipilimumab is “not for everybody.”
Dr. Choueiri said that he does “agree” that adding a third drug to an already expensive doublet therapy can mean that the costs end up being “exorbitant.”
However, he noted that in aRCC, “the paradigm is sequential, so if we’re able to delay the second line, and give drugs later, especially if there is some quality of life [benefit], I’m not sure it is more expensive” to give the three-drug combination.
Commenting for ESMO, Viktor Grünwald, MD, West German Cancer Center, University Hospital Essen, Germany, noted that this is the “first study” to report “successful treatment intensification” in metastatic RCC through the use of triple therapy.
“However, treatment intensification is rarely seen without additional risks. Patients experienced the benefit of superior disease control but also additional toxicities, treatment pauses and discontinuations,” he pointed out.
“The triplet may compete in the clinical landscape with recommended life-prolonging immune doublets but mature overall survival data is needed for it to become a novel standard of care,” Dr. Grünwald commented.
Details of the new results
The phase 3 COSMIC-313 trial enrolled intermediate- or poor-risk patients with aRCC and good performance status who had received no prior systemic therapy and had a clear cell component on histology, which, Dr. Choueiri noted, represents around 80% of patients.
They were randomly assigned to cabozantinib or a matched placebo against a background of four cycles of nivolumab plus ipilimumab followed by nivolumab for up to 2 years. No crossover was allowed between the two arms. Tumor assessment was performed every 8 weeks.
Overall, 855 patients were randomly assigned, 75% of whom had an intermediate risk on the IDMC risk score, and 25% had a poor risk. The median age of the patients was around 60 years, and between 73% and 76% were men. Prior nephrectomy had been performed in 65%.
The study met its primary endpoint of a significant improvement in PFS as assessed by blinded independent central review. The median PFS was not reached for the triplet versus 11.3 months for patients given the doublet, at a hazard ratio of 0.73 (P = 0.013).
At 12 months, 57% of patients in the triplet-therapy arm remained disease-free versus 49% of those on dual immunotherapy.
Moreover, there was a higher objective response rate with the triplet therapy, at 43% versus 36% for the doublet, and the median duration of response was not reached in either group.
Prespecified subgroup analysis suggested that most subgroups responded similarly to the overall patient population.
However, breaking the results down by IMDC risk group, Dr. Choueiri showed that PFS benefit was even greater in intermediate-risk patients, at an HR for the triplet versus the doublet therapy of 0.63 (95% confidence interval, 047-0.85), and a similar response rate as in the overall analysis.
But the benefit of adding cabozantinib to nivolumab plus ipilimumab appeared to be lost in poor-risk patients, at an HR for the triplet versus the doublet of 1.04 (95% CI, 0.65-1.69). And in this subgroup, the objective response rates were similar: 37% with the triplet and 38% with the doublet.
Also, the triplet had a higher rate of adverse events. Grade 3 or 4 treatment-related adverse events were observed in 73% of patients on the triplet versus 41% with the doublet; 1% of patients in each group had a grade 5 event.
Treatment-related adverse events leading to discontinuation of all treatment components occurred in 12% of patients receiving triplet therapy and in 5% of those assigned to placebo and nivolumab plus ipilimumab.
Dr. Choueiri highlighted that some adverse events, including elevated liver transaminases, diarrhea, and skin toxicity, were markedly more frequent with cabozantinib and nivolumab plus ipilimumab than with the doublet therapy. Discussing the study, Sumanta K. Pal, MD, co-director of the Kidney Cancer Program at City of Hope, Irvine, Calif., said that ESMO Congress 2022 has been a “high watermark” for trials in the RCC field and congratulated the researchers of COSMIC-313 for the number of “firsts” that it achieved.
However, he continued, the “elephant in the room” is the current lack of overall survival, and he pointed out that those hotly anticipated results could have a major impact on the future use of the triplet combination.
Dr. Pal questioned whether, in the meantime, it is even possible to make a decision about the combination and urged investigators of all trials to make overall survival data available sooner.
He also highlighted the high rates of elevated liver transaminases, and the apparent overlapping toxicities between the TKI and the immune checkpoint inhibitors, asking: “Does toxicity stand in the way of treatment?”
In conclusion, Dr. Pal acknowledged that the study did meet its PFS primary endpoint but asked whether a risk-adapted approach could be used to optimize delivery of triplet therapy.
He also called for investment into biomarker studies for regimens that are “actually used in the clinic” and wondered whether there could be a shift toward using drugs with novel modes of action that do not yield overlapping toxicities.
The study was funded by Exelixis.
Dr. Choueiri reports relationships with Bristol-Myers Squibb; Pfizer; Lilly; Merck; Exelixis; AstraZeneca; EMD Serono; Calithera; Ipsen; Infinity; Surface Oncology; Analysis Group; ww2.peerview.com; gotoper.com; researchtopractice.com; ResearchToPractice; National Association of Managed Care; Orien Network; Aptitude Health; Advent health; UAE Society of Onc; MJH life sciences; MDACC; Cancernet; Kidney Cancer Association; Springer; WebMed; ASiM, Caribou Publishing; Aravive; Roche, and others.
A version of this article first appeared on Medscape.com.
FDA approves oral TYK2 inhibitor deucravacitinib for treating psoriasis
the manufacturer announced on Sept. 9.
Deucravacitinib targets TYK2, which inhibits signaling of interleukin-23, interleukin-12, and type 1 interferons, key cytokines involved in the pathogenesis of multiple immune-mediated diseases, according to Bristol Myers Squibb (BMS). This is the first approval for deucravacitinib, which will be marketed as Sotyktu, and the first drug in this class to be approved.
It is also currently under review for the same indication in Europe and Japan, and elsewhere, and for treating pustular psoriasis and erythrodermic psoriasis in Japan.
FDA approval was based on the results of POETYK PSO-1 and POETYK PSO-2, phase 3 trials of almost 1,700 adults with moderate to severe plaque psoriasis. In these studies, treatment with once-daily deucravacitinib showed significant and clinically meaningful improvements in skin clearance and symptoms, compared with placebo and with apremilast (Otezla), according to the company.
In the two studies, patients were randomly assigned to receive 6 mg daily of deucravacitinib, placebo, or a 30-mg twice-daily dose of apremilast, the oral phosphodiesterase 4 inhibitor approved for psoriasis. The primary endpoints were the percentage of patients who achieved a Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear) at 16 weeks.
At 16 weeks, 58% and 53% of patients receiving deucravacitinib in the POETYK PSO-1 and POETYK PSO-2 studies, respectively, achieved PASI 75 response, compared with 13% and 9% of those receiving placebo (P < .0001 for both) and 35% and 40% receiving apremilast (P < .0001, P = .0004, respectively), according to the company’s announcement of the approval. PASI 75 responses were maintained through 52 weeks among the patients who remained on treatment, in both studies, according to BMS.
In the POETYK PSO-1 and PSO-2 studies, respectively, 54% and 50% of those on deucravacitinib achieved an sPGA of 0/1 at 16 weeks, compared with 7% and 9% of those receiving placebo (P < .0001 for both) and 32% and 34% of those receiving apremilast (P < .0001 for both).
Across the two studies, at 16 weeks, the most common adverse events that affected at least 1% of patients on deucravacitinib and that occurred at higher rates than in the placebo group were upper respiratory infections (19.2%), increases in serum creatine phosphokinase (2.7%), herpes simplex (2%), mouth ulcers (1.9%), folliculitis (1.7%), and acne (1.4%). Adverse events resulting in discontinuation of treatment were reported in 2.4% of persons receiving deucravacitinib and 5.2% of those receiving apremilast, compared with 3.8% of those receiving placebo.
Up to 16 weeks, according to the BMS statement, 28% of persons receiving deucravacitinib had infections, most of which were mild to moderate and not serious and did not result in stopping treatment, compared with 22% of those receiving placebo. In addition, five patients treated with deucravacitinib and five patients receiving placebo had serious infections, and three patients receiving deucravacitinib had cancer (not including nonmelanoma skin cancer).
Deucravacitinib is also being evaluated in clinical trials for psoriatic arthritis, lupus, and inflammatory bowel disease. It is not recommended for use in combination with other potent immunosuppressants, according to BMS.
The prescribing information and patient medication guide are available online.
The POETYK PSO-1 and POETYK PSO-2 studies were funded by Bristol Myers Squibb.
A version of this article first appeared on Medscape.com.
the manufacturer announced on Sept. 9.
Deucravacitinib targets TYK2, which inhibits signaling of interleukin-23, interleukin-12, and type 1 interferons, key cytokines involved in the pathogenesis of multiple immune-mediated diseases, according to Bristol Myers Squibb (BMS). This is the first approval for deucravacitinib, which will be marketed as Sotyktu, and the first drug in this class to be approved.
It is also currently under review for the same indication in Europe and Japan, and elsewhere, and for treating pustular psoriasis and erythrodermic psoriasis in Japan.
FDA approval was based on the results of POETYK PSO-1 and POETYK PSO-2, phase 3 trials of almost 1,700 adults with moderate to severe plaque psoriasis. In these studies, treatment with once-daily deucravacitinib showed significant and clinically meaningful improvements in skin clearance and symptoms, compared with placebo and with apremilast (Otezla), according to the company.
In the two studies, patients were randomly assigned to receive 6 mg daily of deucravacitinib, placebo, or a 30-mg twice-daily dose of apremilast, the oral phosphodiesterase 4 inhibitor approved for psoriasis. The primary endpoints were the percentage of patients who achieved a Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear) at 16 weeks.
At 16 weeks, 58% and 53% of patients receiving deucravacitinib in the POETYK PSO-1 and POETYK PSO-2 studies, respectively, achieved PASI 75 response, compared with 13% and 9% of those receiving placebo (P < .0001 for both) and 35% and 40% receiving apremilast (P < .0001, P = .0004, respectively), according to the company’s announcement of the approval. PASI 75 responses were maintained through 52 weeks among the patients who remained on treatment, in both studies, according to BMS.
In the POETYK PSO-1 and PSO-2 studies, respectively, 54% and 50% of those on deucravacitinib achieved an sPGA of 0/1 at 16 weeks, compared with 7% and 9% of those receiving placebo (P < .0001 for both) and 32% and 34% of those receiving apremilast (P < .0001 for both).
Across the two studies, at 16 weeks, the most common adverse events that affected at least 1% of patients on deucravacitinib and that occurred at higher rates than in the placebo group were upper respiratory infections (19.2%), increases in serum creatine phosphokinase (2.7%), herpes simplex (2%), mouth ulcers (1.9%), folliculitis (1.7%), and acne (1.4%). Adverse events resulting in discontinuation of treatment were reported in 2.4% of persons receiving deucravacitinib and 5.2% of those receiving apremilast, compared with 3.8% of those receiving placebo.
Up to 16 weeks, according to the BMS statement, 28% of persons receiving deucravacitinib had infections, most of which were mild to moderate and not serious and did not result in stopping treatment, compared with 22% of those receiving placebo. In addition, five patients treated with deucravacitinib and five patients receiving placebo had serious infections, and three patients receiving deucravacitinib had cancer (not including nonmelanoma skin cancer).
Deucravacitinib is also being evaluated in clinical trials for psoriatic arthritis, lupus, and inflammatory bowel disease. It is not recommended for use in combination with other potent immunosuppressants, according to BMS.
The prescribing information and patient medication guide are available online.
The POETYK PSO-1 and POETYK PSO-2 studies were funded by Bristol Myers Squibb.
A version of this article first appeared on Medscape.com.
the manufacturer announced on Sept. 9.
Deucravacitinib targets TYK2, which inhibits signaling of interleukin-23, interleukin-12, and type 1 interferons, key cytokines involved in the pathogenesis of multiple immune-mediated diseases, according to Bristol Myers Squibb (BMS). This is the first approval for deucravacitinib, which will be marketed as Sotyktu, and the first drug in this class to be approved.
It is also currently under review for the same indication in Europe and Japan, and elsewhere, and for treating pustular psoriasis and erythrodermic psoriasis in Japan.
FDA approval was based on the results of POETYK PSO-1 and POETYK PSO-2, phase 3 trials of almost 1,700 adults with moderate to severe plaque psoriasis. In these studies, treatment with once-daily deucravacitinib showed significant and clinically meaningful improvements in skin clearance and symptoms, compared with placebo and with apremilast (Otezla), according to the company.
In the two studies, patients were randomly assigned to receive 6 mg daily of deucravacitinib, placebo, or a 30-mg twice-daily dose of apremilast, the oral phosphodiesterase 4 inhibitor approved for psoriasis. The primary endpoints were the percentage of patients who achieved a Psoriasis Area and Severity Index (PASI) 75 response and a static Physician’s Global Assessment (sPGA) score of 0 or 1 (clear or almost clear) at 16 weeks.
At 16 weeks, 58% and 53% of patients receiving deucravacitinib in the POETYK PSO-1 and POETYK PSO-2 studies, respectively, achieved PASI 75 response, compared with 13% and 9% of those receiving placebo (P < .0001 for both) and 35% and 40% receiving apremilast (P < .0001, P = .0004, respectively), according to the company’s announcement of the approval. PASI 75 responses were maintained through 52 weeks among the patients who remained on treatment, in both studies, according to BMS.
In the POETYK PSO-1 and PSO-2 studies, respectively, 54% and 50% of those on deucravacitinib achieved an sPGA of 0/1 at 16 weeks, compared with 7% and 9% of those receiving placebo (P < .0001 for both) and 32% and 34% of those receiving apremilast (P < .0001 for both).
Across the two studies, at 16 weeks, the most common adverse events that affected at least 1% of patients on deucravacitinib and that occurred at higher rates than in the placebo group were upper respiratory infections (19.2%), increases in serum creatine phosphokinase (2.7%), herpes simplex (2%), mouth ulcers (1.9%), folliculitis (1.7%), and acne (1.4%). Adverse events resulting in discontinuation of treatment were reported in 2.4% of persons receiving deucravacitinib and 5.2% of those receiving apremilast, compared with 3.8% of those receiving placebo.
Up to 16 weeks, according to the BMS statement, 28% of persons receiving deucravacitinib had infections, most of which were mild to moderate and not serious and did not result in stopping treatment, compared with 22% of those receiving placebo. In addition, five patients treated with deucravacitinib and five patients receiving placebo had serious infections, and three patients receiving deucravacitinib had cancer (not including nonmelanoma skin cancer).
Deucravacitinib is also being evaluated in clinical trials for psoriatic arthritis, lupus, and inflammatory bowel disease. It is not recommended for use in combination with other potent immunosuppressants, according to BMS.
The prescribing information and patient medication guide are available online.
The POETYK PSO-1 and POETYK PSO-2 studies were funded by Bristol Myers Squibb.
A version of this article first appeared on Medscape.com.
Psychiatrists’ views on psychoactive drugs clash with U.S. policy
“The consensus among experts, including psychiatrists, about specific drugs is not consistent or congruent with the schedule of these drugs” in the United States, lead author Adam Levin, MD, third-year psychiatry resident, Ohio State University, Columbus, and affiliate scholar at the Center for Psychedelic Drug Research and Education, Ohio State College of Social Work, told this news organization.
Dr. Levin stressed the importance of appropriate drug scheduling to improve access to treatments such as psilocybin (psychedelic mushrooms) and 4-methylenedioxy methamphetamine (MDMA), which are now being tested for psychiatric disorders.
“We are in the middle of a mental health crisis so having any new tools would be really important,” he said.
The survey findings were published online in the International Journal of Drug Policy.
Five drug schedules
The Controlled Substances Act of 1970 created five “schedules” that organized drugs from most to least dangerous (schedule I-V). However, Dr. Levin said that the schedules do not accurately reflect the harms or therapeutic benefits of the various drugs.
Some drugs in lower, less restrictive schedules have greater potential for harm than do those in higher schedules, he noted. For example, methamphetamine, which has been recalled in multiple formulations because of concerns about abuse and limited medical use, remains a schedule II drug.
In addition, several schedule I drugs, including psilocybin and MDMA that are deemed dangerous and of no medical value, have shown therapeutic potential and low rates of misuse, addiction, or physical harm, the investigators noted.
In fact, the Food and Drug Administration has granted breakthrough therapy status to psilocybin for treatment-resistant depression and major depressive disorder (MDD) and to MDMA for posttraumatic stress disorder. This has positioned these drugs for possible FDA approval within the next few years.
Access to schedule I drugs for research purposes is tightly controlled. “Once psilocybin was placed in schedule I, there was this massive drop-off in the research funding and amount of research; and we’re just now starting to understand the potential therapeutic value of this drug,” said Dr. Levin.
Even with a recent research resurgence, most studies are funded by charitable donations or for-profit companies because of continued hesitancy on the part of grant-making organizations, he added.
Apparent contradictions
Given the pending approval of several schedule I drugs and escalating abuse of drugs in lower schedules, there is a growing need to understand physician attitudes surrounding the apparent contradictions in the drug schedule, the investigators noted.
Their survey included a geographically diverse group of 181 mostly middle-aged psychiatrists (65.2% were men) with an average of 16.2 years of practice after residency.
Participants were randomly assigned to respond to a vignette depicting a clinical scenario where a patient wants one of four drugs to help treat severe depression: psilocybin, a schedule I drug; methamphetamine (Desoxyn), a schedule II drug; ketamine, a Schedule III drug; or alprazolam (Xanax), a schedule IV drug.
Each of these therapies has established antidepressant properties, but none are FDA approved for treatment of MDD. However, an intranasal formulation of the ketamine enantiomer Spravato (esketamine) was recently approved for treatment-resistant depression.
There were significant differences among the groups presented with different vignettes. Participants were more likely to warn against repeated use of and development of a new psychiatric problem with methamphetamine and alprazolam compared with psilocybin or ketamine.
Respondents were most concerned about increased suicide risk after the nonprescribed use of alprazolam compared with psilocybin and ketamine.
Compared with all other drugs, ketamine was more likely to be integrated into treatment plans.
Therapeutic value, abuse potential
Participants were asked to rate the safety, therapeutic value, and abuse potential of the four drugs as well as alcohol, a nonscheduled legal drug, if used properly or as directed.
Respondents viewed psilocybin and ketamine as similarly safe – and safer than methamphetamine and alprazolam. They considered ketamine as having the highest therapeutic potential, followed by psilocybin, and then alprazolam and methamphetamine. “Last was alcohol, which we expected because alcohol is not used therapeutically,” said Dr. Levin.
Survey completers viewed methamphetamine, alprazolam, and alcohol as having similarly high abuse potential, and ketamine as having mid-level abuse potential. Psilocybin was rated as having the lowest abuse potential, “which is exactly the opposite of what is implied by its schedule I status,” noted Dr. Levin.
The results provide evidence these drugs “are incorrectly scheduled,” he said.
“This suggests the schedule does not reflect current evidence, which I think is really important to understand because there are consequences to the drug schedule,” including criminal justice and research consequences, he added.
Dr. Levin pointed out that possession of drugs in more harmful schedules is linked to sometimes lengthy prison sentences.
The psychiatrists’ perceptions of the drugs “overlaps pretty significantly” with recent surveys of other mental health professionals, including psychologists and addiction experts, he noted.
The study was funded by the Drug Enforcement and Policy Center, Moritz College of Law, and The Ohio State University. Dr. Levin reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“The consensus among experts, including psychiatrists, about specific drugs is not consistent or congruent with the schedule of these drugs” in the United States, lead author Adam Levin, MD, third-year psychiatry resident, Ohio State University, Columbus, and affiliate scholar at the Center for Psychedelic Drug Research and Education, Ohio State College of Social Work, told this news organization.
Dr. Levin stressed the importance of appropriate drug scheduling to improve access to treatments such as psilocybin (psychedelic mushrooms) and 4-methylenedioxy methamphetamine (MDMA), which are now being tested for psychiatric disorders.
“We are in the middle of a mental health crisis so having any new tools would be really important,” he said.
The survey findings were published online in the International Journal of Drug Policy.
Five drug schedules
The Controlled Substances Act of 1970 created five “schedules” that organized drugs from most to least dangerous (schedule I-V). However, Dr. Levin said that the schedules do not accurately reflect the harms or therapeutic benefits of the various drugs.
Some drugs in lower, less restrictive schedules have greater potential for harm than do those in higher schedules, he noted. For example, methamphetamine, which has been recalled in multiple formulations because of concerns about abuse and limited medical use, remains a schedule II drug.
In addition, several schedule I drugs, including psilocybin and MDMA that are deemed dangerous and of no medical value, have shown therapeutic potential and low rates of misuse, addiction, or physical harm, the investigators noted.
In fact, the Food and Drug Administration has granted breakthrough therapy status to psilocybin for treatment-resistant depression and major depressive disorder (MDD) and to MDMA for posttraumatic stress disorder. This has positioned these drugs for possible FDA approval within the next few years.
Access to schedule I drugs for research purposes is tightly controlled. “Once psilocybin was placed in schedule I, there was this massive drop-off in the research funding and amount of research; and we’re just now starting to understand the potential therapeutic value of this drug,” said Dr. Levin.
Even with a recent research resurgence, most studies are funded by charitable donations or for-profit companies because of continued hesitancy on the part of grant-making organizations, he added.
Apparent contradictions
Given the pending approval of several schedule I drugs and escalating abuse of drugs in lower schedules, there is a growing need to understand physician attitudes surrounding the apparent contradictions in the drug schedule, the investigators noted.
Their survey included a geographically diverse group of 181 mostly middle-aged psychiatrists (65.2% were men) with an average of 16.2 years of practice after residency.
Participants were randomly assigned to respond to a vignette depicting a clinical scenario where a patient wants one of four drugs to help treat severe depression: psilocybin, a schedule I drug; methamphetamine (Desoxyn), a schedule II drug; ketamine, a Schedule III drug; or alprazolam (Xanax), a schedule IV drug.
Each of these therapies has established antidepressant properties, but none are FDA approved for treatment of MDD. However, an intranasal formulation of the ketamine enantiomer Spravato (esketamine) was recently approved for treatment-resistant depression.
There were significant differences among the groups presented with different vignettes. Participants were more likely to warn against repeated use of and development of a new psychiatric problem with methamphetamine and alprazolam compared with psilocybin or ketamine.
Respondents were most concerned about increased suicide risk after the nonprescribed use of alprazolam compared with psilocybin and ketamine.
Compared with all other drugs, ketamine was more likely to be integrated into treatment plans.
Therapeutic value, abuse potential
Participants were asked to rate the safety, therapeutic value, and abuse potential of the four drugs as well as alcohol, a nonscheduled legal drug, if used properly or as directed.
Respondents viewed psilocybin and ketamine as similarly safe – and safer than methamphetamine and alprazolam. They considered ketamine as having the highest therapeutic potential, followed by psilocybin, and then alprazolam and methamphetamine. “Last was alcohol, which we expected because alcohol is not used therapeutically,” said Dr. Levin.
Survey completers viewed methamphetamine, alprazolam, and alcohol as having similarly high abuse potential, and ketamine as having mid-level abuse potential. Psilocybin was rated as having the lowest abuse potential, “which is exactly the opposite of what is implied by its schedule I status,” noted Dr. Levin.
The results provide evidence these drugs “are incorrectly scheduled,” he said.
“This suggests the schedule does not reflect current evidence, which I think is really important to understand because there are consequences to the drug schedule,” including criminal justice and research consequences, he added.
Dr. Levin pointed out that possession of drugs in more harmful schedules is linked to sometimes lengthy prison sentences.
The psychiatrists’ perceptions of the drugs “overlaps pretty significantly” with recent surveys of other mental health professionals, including psychologists and addiction experts, he noted.
The study was funded by the Drug Enforcement and Policy Center, Moritz College of Law, and The Ohio State University. Dr. Levin reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
“The consensus among experts, including psychiatrists, about specific drugs is not consistent or congruent with the schedule of these drugs” in the United States, lead author Adam Levin, MD, third-year psychiatry resident, Ohio State University, Columbus, and affiliate scholar at the Center for Psychedelic Drug Research and Education, Ohio State College of Social Work, told this news organization.
Dr. Levin stressed the importance of appropriate drug scheduling to improve access to treatments such as psilocybin (psychedelic mushrooms) and 4-methylenedioxy methamphetamine (MDMA), which are now being tested for psychiatric disorders.
“We are in the middle of a mental health crisis so having any new tools would be really important,” he said.
The survey findings were published online in the International Journal of Drug Policy.
Five drug schedules
The Controlled Substances Act of 1970 created five “schedules” that organized drugs from most to least dangerous (schedule I-V). However, Dr. Levin said that the schedules do not accurately reflect the harms or therapeutic benefits of the various drugs.
Some drugs in lower, less restrictive schedules have greater potential for harm than do those in higher schedules, he noted. For example, methamphetamine, which has been recalled in multiple formulations because of concerns about abuse and limited medical use, remains a schedule II drug.
In addition, several schedule I drugs, including psilocybin and MDMA that are deemed dangerous and of no medical value, have shown therapeutic potential and low rates of misuse, addiction, or physical harm, the investigators noted.
In fact, the Food and Drug Administration has granted breakthrough therapy status to psilocybin for treatment-resistant depression and major depressive disorder (MDD) and to MDMA for posttraumatic stress disorder. This has positioned these drugs for possible FDA approval within the next few years.
Access to schedule I drugs for research purposes is tightly controlled. “Once psilocybin was placed in schedule I, there was this massive drop-off in the research funding and amount of research; and we’re just now starting to understand the potential therapeutic value of this drug,” said Dr. Levin.
Even with a recent research resurgence, most studies are funded by charitable donations or for-profit companies because of continued hesitancy on the part of grant-making organizations, he added.
Apparent contradictions
Given the pending approval of several schedule I drugs and escalating abuse of drugs in lower schedules, there is a growing need to understand physician attitudes surrounding the apparent contradictions in the drug schedule, the investigators noted.
Their survey included a geographically diverse group of 181 mostly middle-aged psychiatrists (65.2% were men) with an average of 16.2 years of practice after residency.
Participants were randomly assigned to respond to a vignette depicting a clinical scenario where a patient wants one of four drugs to help treat severe depression: psilocybin, a schedule I drug; methamphetamine (Desoxyn), a schedule II drug; ketamine, a Schedule III drug; or alprazolam (Xanax), a schedule IV drug.
Each of these therapies has established antidepressant properties, but none are FDA approved for treatment of MDD. However, an intranasal formulation of the ketamine enantiomer Spravato (esketamine) was recently approved for treatment-resistant depression.
There were significant differences among the groups presented with different vignettes. Participants were more likely to warn against repeated use of and development of a new psychiatric problem with methamphetamine and alprazolam compared with psilocybin or ketamine.
Respondents were most concerned about increased suicide risk after the nonprescribed use of alprazolam compared with psilocybin and ketamine.
Compared with all other drugs, ketamine was more likely to be integrated into treatment plans.
Therapeutic value, abuse potential
Participants were asked to rate the safety, therapeutic value, and abuse potential of the four drugs as well as alcohol, a nonscheduled legal drug, if used properly or as directed.
Respondents viewed psilocybin and ketamine as similarly safe – and safer than methamphetamine and alprazolam. They considered ketamine as having the highest therapeutic potential, followed by psilocybin, and then alprazolam and methamphetamine. “Last was alcohol, which we expected because alcohol is not used therapeutically,” said Dr. Levin.
Survey completers viewed methamphetamine, alprazolam, and alcohol as having similarly high abuse potential, and ketamine as having mid-level abuse potential. Psilocybin was rated as having the lowest abuse potential, “which is exactly the opposite of what is implied by its schedule I status,” noted Dr. Levin.
The results provide evidence these drugs “are incorrectly scheduled,” he said.
“This suggests the schedule does not reflect current evidence, which I think is really important to understand because there are consequences to the drug schedule,” including criminal justice and research consequences, he added.
Dr. Levin pointed out that possession of drugs in more harmful schedules is linked to sometimes lengthy prison sentences.
The psychiatrists’ perceptions of the drugs “overlaps pretty significantly” with recent surveys of other mental health professionals, including psychologists and addiction experts, he noted.
The study was funded by the Drug Enforcement and Policy Center, Moritz College of Law, and The Ohio State University. Dr. Levin reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
FROM THE INTERNATIONAL JOURNAL OF DRUG POLICY
DOJ: Indiana nurses allowed controlled substances during opioid recovery
, according to a statement released Sept. 1.
In March, the U.S. Department of Justice (DOJ) announced the findings of its investigation, stating that the board “violated the ADA by prohibiting nurses who take medication to treat OUD from participating in the Indiana State Nursing Assistance Program [ISNAP].”
ISNAP rehabilitates and monitors nurses with substance use disorders, and the nursing board contracts with vendors to administer the program. Nurses seeking recovery must typically enroll in ISNAP and complete the 1-year program to maintain an active nursing license or have a license reinstated.
Following the investigation, the nursing board was instructed to implement corrective measures, such as revising policies and handbooks and training nursing board staff and vendors on ADA guidelines and nondiscriminatory practices.
The state’s professional organization for nurses said the remediation efforts will help nurses who are struggling with opioid addiction.
Katherine Feley, DNP, RN, chief executive officer of the Indiana State Nurses Association, told this news organization, “Allowing nurses who take medication to treat OUD to remain on their medication when participating in [ISNAP] will avoid making nurses choose between their health and their profession. This improvement will increase access to treatment resources, enabling more nurses to complete treatment and progress toward a safe return to work.”
The DOJ opened an investigation after receiving a complaint from a nurse in which she alleged that she was denied participation in ISNAP because of her use of prescription medication for OUD. In 2013, while participating in a methadone maintenance program, the nurse was told she had to taper off the medication because ISNAP utilizes an “abstinence-based” model. Because of these restrictions, she could not complete the program, and her nursing license was suspended in late 2014.
In 2016, her physician prescribed a new medication, buprenorphine, and the nurse attempted to enroll in ISNAP again. The program vendor instructed her to taper off the drug within 3 months of enrollment, something her physician believed “would come with a significant risk of relapse [and possibly] death.” The nurse was unable to qualify for reinstatement of her license.
As part of the settlement, the nursing board has agreed to pay a total of $70,000 in damages to the complainant and report compliance with new guidelines to the DOJ every 6 months.
The DOJ says ISNAP’s OUD abstinence policy does not conform with the state’s statute, which mandates that substance abuse rehabilitation services be provided for nurses.
“Indiana may not deny individuals lifesaving medications, including medications that treat [OUD], based on stereotypes and misinformation,” Assistant Attorney General Kristen Clarke of the Justice Department’s Civil Rights Division said of the settlement. “Requiring nurses to stop taking prescribed medication as a condition of maintaining a nursing license violates the ADA and not only creates barriers to recovery but inappropriately limits employment opportunities based on disability.”
In April, the DOJ issued guidance for protecting the civil rights of people with OUD under the ADA to ensure that individuals seeking treatment or recovery can continue participating in society and the workplace.
“The opioid epidemic has greatly impacted professionals and families of all walks of life, and Indiana nurses have the right to seek medically approved treatment for [OUD] under federal law,” U.S. Attorney Zachary A. Myers, of the Southern District of Indiana, said of the settlement. “Following the Justice Department’s findings and the parties’ settlement agreement, Indiana must now enact policies to ensure that Hoosier nurses will not be forced to choose between their recovery and their livelihoods.”
Under the terms of the agreement, the nursing board must allow nurses who are taking OUD medication to participate in ISNAP when the medication is prescribed by a licensed practitioner as part of a medically necessary treatment plan and is incorporated into a recovery monitoring agreement.
A version of this article first appeared on Medscape.com.
, according to a statement released Sept. 1.
In March, the U.S. Department of Justice (DOJ) announced the findings of its investigation, stating that the board “violated the ADA by prohibiting nurses who take medication to treat OUD from participating in the Indiana State Nursing Assistance Program [ISNAP].”
ISNAP rehabilitates and monitors nurses with substance use disorders, and the nursing board contracts with vendors to administer the program. Nurses seeking recovery must typically enroll in ISNAP and complete the 1-year program to maintain an active nursing license or have a license reinstated.
Following the investigation, the nursing board was instructed to implement corrective measures, such as revising policies and handbooks and training nursing board staff and vendors on ADA guidelines and nondiscriminatory practices.
The state’s professional organization for nurses said the remediation efforts will help nurses who are struggling with opioid addiction.
Katherine Feley, DNP, RN, chief executive officer of the Indiana State Nurses Association, told this news organization, “Allowing nurses who take medication to treat OUD to remain on their medication when participating in [ISNAP] will avoid making nurses choose between their health and their profession. This improvement will increase access to treatment resources, enabling more nurses to complete treatment and progress toward a safe return to work.”
The DOJ opened an investigation after receiving a complaint from a nurse in which she alleged that she was denied participation in ISNAP because of her use of prescription medication for OUD. In 2013, while participating in a methadone maintenance program, the nurse was told she had to taper off the medication because ISNAP utilizes an “abstinence-based” model. Because of these restrictions, she could not complete the program, and her nursing license was suspended in late 2014.
In 2016, her physician prescribed a new medication, buprenorphine, and the nurse attempted to enroll in ISNAP again. The program vendor instructed her to taper off the drug within 3 months of enrollment, something her physician believed “would come with a significant risk of relapse [and possibly] death.” The nurse was unable to qualify for reinstatement of her license.
As part of the settlement, the nursing board has agreed to pay a total of $70,000 in damages to the complainant and report compliance with new guidelines to the DOJ every 6 months.
The DOJ says ISNAP’s OUD abstinence policy does not conform with the state’s statute, which mandates that substance abuse rehabilitation services be provided for nurses.
“Indiana may not deny individuals lifesaving medications, including medications that treat [OUD], based on stereotypes and misinformation,” Assistant Attorney General Kristen Clarke of the Justice Department’s Civil Rights Division said of the settlement. “Requiring nurses to stop taking prescribed medication as a condition of maintaining a nursing license violates the ADA and not only creates barriers to recovery but inappropriately limits employment opportunities based on disability.”
In April, the DOJ issued guidance for protecting the civil rights of people with OUD under the ADA to ensure that individuals seeking treatment or recovery can continue participating in society and the workplace.
“The opioid epidemic has greatly impacted professionals and families of all walks of life, and Indiana nurses have the right to seek medically approved treatment for [OUD] under federal law,” U.S. Attorney Zachary A. Myers, of the Southern District of Indiana, said of the settlement. “Following the Justice Department’s findings and the parties’ settlement agreement, Indiana must now enact policies to ensure that Hoosier nurses will not be forced to choose between their recovery and their livelihoods.”
Under the terms of the agreement, the nursing board must allow nurses who are taking OUD medication to participate in ISNAP when the medication is prescribed by a licensed practitioner as part of a medically necessary treatment plan and is incorporated into a recovery monitoring agreement.
A version of this article first appeared on Medscape.com.
, according to a statement released Sept. 1.
In March, the U.S. Department of Justice (DOJ) announced the findings of its investigation, stating that the board “violated the ADA by prohibiting nurses who take medication to treat OUD from participating in the Indiana State Nursing Assistance Program [ISNAP].”
ISNAP rehabilitates and monitors nurses with substance use disorders, and the nursing board contracts with vendors to administer the program. Nurses seeking recovery must typically enroll in ISNAP and complete the 1-year program to maintain an active nursing license or have a license reinstated.
Following the investigation, the nursing board was instructed to implement corrective measures, such as revising policies and handbooks and training nursing board staff and vendors on ADA guidelines and nondiscriminatory practices.
The state’s professional organization for nurses said the remediation efforts will help nurses who are struggling with opioid addiction.
Katherine Feley, DNP, RN, chief executive officer of the Indiana State Nurses Association, told this news organization, “Allowing nurses who take medication to treat OUD to remain on their medication when participating in [ISNAP] will avoid making nurses choose between their health and their profession. This improvement will increase access to treatment resources, enabling more nurses to complete treatment and progress toward a safe return to work.”
The DOJ opened an investigation after receiving a complaint from a nurse in which she alleged that she was denied participation in ISNAP because of her use of prescription medication for OUD. In 2013, while participating in a methadone maintenance program, the nurse was told she had to taper off the medication because ISNAP utilizes an “abstinence-based” model. Because of these restrictions, she could not complete the program, and her nursing license was suspended in late 2014.
In 2016, her physician prescribed a new medication, buprenorphine, and the nurse attempted to enroll in ISNAP again. The program vendor instructed her to taper off the drug within 3 months of enrollment, something her physician believed “would come with a significant risk of relapse [and possibly] death.” The nurse was unable to qualify for reinstatement of her license.
As part of the settlement, the nursing board has agreed to pay a total of $70,000 in damages to the complainant and report compliance with new guidelines to the DOJ every 6 months.
The DOJ says ISNAP’s OUD abstinence policy does not conform with the state’s statute, which mandates that substance abuse rehabilitation services be provided for nurses.
“Indiana may not deny individuals lifesaving medications, including medications that treat [OUD], based on stereotypes and misinformation,” Assistant Attorney General Kristen Clarke of the Justice Department’s Civil Rights Division said of the settlement. “Requiring nurses to stop taking prescribed medication as a condition of maintaining a nursing license violates the ADA and not only creates barriers to recovery but inappropriately limits employment opportunities based on disability.”
In April, the DOJ issued guidance for protecting the civil rights of people with OUD under the ADA to ensure that individuals seeking treatment or recovery can continue participating in society and the workplace.
“The opioid epidemic has greatly impacted professionals and families of all walks of life, and Indiana nurses have the right to seek medically approved treatment for [OUD] under federal law,” U.S. Attorney Zachary A. Myers, of the Southern District of Indiana, said of the settlement. “Following the Justice Department’s findings and the parties’ settlement agreement, Indiana must now enact policies to ensure that Hoosier nurses will not be forced to choose between their recovery and their livelihoods.”
Under the terms of the agreement, the nursing board must allow nurses who are taking OUD medication to participate in ISNAP when the medication is prescribed by a licensed practitioner as part of a medically necessary treatment plan and is incorporated into a recovery monitoring agreement.
A version of this article first appeared on Medscape.com.
Hepatitis C meds linked to improved PTSD symptoms
The combination of the two antiviral medications glecaprevir and pibrentasvir (Mavyret) is linked to improved symptoms in posttraumatic stress disorder, new research suggests.
A national cohort study of U.S. Veterans Affairs patients included more than 250 participants with PTSD and comorbid hepatitis C virus.
Results showed in the study, including ledipasvir/sofosbuvir.
“While there are great treatments available for PTSD, there’s a lot of desire in the field to find a new medication that will be helpful,” lead author Brian Shiner, MD, acting associate chief of staff for research, VA Medical Center, White River Junction, Vt., told this news organization.
“We had a great opportunity to use a novel data mining method to look in a wonderful database for a new treatment and we found something very promising,” said Dr. Shiner, who is also an associate professor of psychiatry at the Geisel School of Medicine at Dartmouth, Hanover, N.H.
The findings were published online in the American Journal of Epidemiology.
Common psychiatric disorder
PTSD is one of the most common psychiatric disorders, with an estimated lifetime prevalence of 6.4% in the United States. Yet only two drugs, the SSRIs sertraline (Zoloft) and paroxetine (Paxil), have been approved by the Food and Drug Administration to treat PTSD.
The VA recommends trauma-based psychotherapy, such as prolonged exposure and cognitive processing therapy, as first-line treatments for PTSD. However, not all patents respond to or have access to these approaches, said Dr. Shiner.
The investigators wanted to examine whether existing medications might reduce PTSD symptoms. Their previous exploratory study used “data mining” of national VA medical records.
Results from that study showed the three hepatitis C antivirals of GLE (an NS3/4A protease inhibitor), PIB (a NS5A protein inhibitor), and velpatasvir (another NS5A protein inhibitor) were associated with more than double the expected number of patients experiencing a clinically meaningful improvement in PTSD symptoms.
Sertraline was associated with only a slightly higher than expected improvement.
“SSRIs are effective, better than placebo, but the effects are not as good as we would hope,” Dr. Shiner said.
He noted that GLE and PIB are always prescribed together (Mavyret), whereas velpatasvir is commonly prescribed with the NS5B polymerase inhibitor sofosbuvir under the brand name Epclusa. Sofosbuvir is also commonly prescribed with the NS5A protein inhibitor ledipasvir under the brand name Harvoni.
Strong association
The new study included 253 VA users with a diagnosis of PTSD and hepatitis C. Of these, 54 were receiving GLE/PIB, 145 were receiving ledipasvir/sofosbuvir, and 54 were receiving sofosbuvir/velpatasvir.
Researchers compared the groups with respect to change over 8-12 weeks on the PTSD Checklist (PCL), a 20-item self-report scale.
In adjusted analyses, the largest mean improvement on the PCL was 14.9 points for the GLE/PIB group and the smallest adjusted mean improvement on the PCL was 7.5 points for the ledipasvir/sofosbuvir group (mean difference, 7.34 points; 95% confidence interval, 1.05-13.63).
The adjusted proportion of patients improving by 15 points or more on the PCL was highest for the GLE/PIB group at 43.6% and lowest for the ledipasvir/sofosbuvir group at 26.3%.
Even when accounting for patients receiving trauma-based therapy or SSRIs, “it still looks like there’s a strong association of the hepatitis C antivirals with PTSD symptom improvement,” said Dr. Shiner.
Researchers also carried out a sensitivity analysis among only patients who were cured of HCV (over 90% of the total sample), defined as having an undetectable HCV viral load up to a year after completion of therapy. The analysis showed PTSD outcomes were still superior for participants receiving GLE/PIB.
“The sensitivity analysis was not that robust because almost everyone was cured, so it included almost everybody, but it didn’t point us away from the possibility of an off-target effect,” Dr. Shiner said.
Why antivirals may improve PTSD symptoms is not clear, but they may affect the immune response in patients with hepatitis C – and there may also be an immune response in PTSD, he noted. “Some of those factors may be shared, and that could explain some of the off-target effect.”
However, he noted the GLE/PIB drug combination is costly and patients with PTSD can probably access it only through enrolling in a study.
“We are not recommending that people go out and purchase this very expensive drug to treat their PTSD at this point,” Dr. Shiner said.
He added that the research team has now received funding from the Department of Defense to conduct a randomized, placebo-controlled trial of GLE/PIB as a potential treatment for PTSD.
Promising potential treatment
PTSD expert Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, D.C., said the results suggest GLE/PIB is a promising potential treatment for PTSD.
“I definitely think this should be looked at further,” said Dr. Ritchie, who was not involved with the research.
She noted that current PTSD therapies have drawbacks. SSRIs have side effects, the most “troubling” being sexual dysfunction. And although cognitive-behavioral therapy is effective, “people have to stick with it” and studies show about two thirds of patients drop out, she said.
Potentially effective PTSD treatment approaches include “self-soothing” or “self-regulating” techniques such as exercise, meditation, yoga, and working with animals, she added.
Dr. Ritchie pointed out the numbers of participants in the study were relatively small, including two groups that had only 54 patients each.
And while the GLE/PIB combination should be explored further, cost, availability, and side effects of this medication need to be taken into consideration, she said.
Dr. Ritchie added she is not overly concerned that the mechanism of action for the combination on PTSD may not be well understood. She noted several psychiatric medications fall into that category, including electroconvulsive therapy and lithium.
“When lithium was first found to be effective against bipolar disorder, we had no clue why,” she said. “So I would not discount the antiviral based on us not knowing how it works.”
However, “we’re a long way off” from starting a patient with PTSD on an antiviral, said Dr. Ritchie, adding there are “a lot of steps to go through” to get FDA approval.
The study was funded by the National Institute of Mental Health. The cohort used for this study was developed through support from the Department of Defense. Dr. Shiner is a coinventor on a provisional patent application covering the use of glecaprevir, pibrentasvir, and velpatasvir for PTSD and other psychiatric indications. Dr. Ritchie reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The combination of the two antiviral medications glecaprevir and pibrentasvir (Mavyret) is linked to improved symptoms in posttraumatic stress disorder, new research suggests.
A national cohort study of U.S. Veterans Affairs patients included more than 250 participants with PTSD and comorbid hepatitis C virus.
Results showed in the study, including ledipasvir/sofosbuvir.
“While there are great treatments available for PTSD, there’s a lot of desire in the field to find a new medication that will be helpful,” lead author Brian Shiner, MD, acting associate chief of staff for research, VA Medical Center, White River Junction, Vt., told this news organization.
“We had a great opportunity to use a novel data mining method to look in a wonderful database for a new treatment and we found something very promising,” said Dr. Shiner, who is also an associate professor of psychiatry at the Geisel School of Medicine at Dartmouth, Hanover, N.H.
The findings were published online in the American Journal of Epidemiology.
Common psychiatric disorder
PTSD is one of the most common psychiatric disorders, with an estimated lifetime prevalence of 6.4% in the United States. Yet only two drugs, the SSRIs sertraline (Zoloft) and paroxetine (Paxil), have been approved by the Food and Drug Administration to treat PTSD.
The VA recommends trauma-based psychotherapy, such as prolonged exposure and cognitive processing therapy, as first-line treatments for PTSD. However, not all patents respond to or have access to these approaches, said Dr. Shiner.
The investigators wanted to examine whether existing medications might reduce PTSD symptoms. Their previous exploratory study used “data mining” of national VA medical records.
Results from that study showed the three hepatitis C antivirals of GLE (an NS3/4A protease inhibitor), PIB (a NS5A protein inhibitor), and velpatasvir (another NS5A protein inhibitor) were associated with more than double the expected number of patients experiencing a clinically meaningful improvement in PTSD symptoms.
Sertraline was associated with only a slightly higher than expected improvement.
“SSRIs are effective, better than placebo, but the effects are not as good as we would hope,” Dr. Shiner said.
He noted that GLE and PIB are always prescribed together (Mavyret), whereas velpatasvir is commonly prescribed with the NS5B polymerase inhibitor sofosbuvir under the brand name Epclusa. Sofosbuvir is also commonly prescribed with the NS5A protein inhibitor ledipasvir under the brand name Harvoni.
Strong association
The new study included 253 VA users with a diagnosis of PTSD and hepatitis C. Of these, 54 were receiving GLE/PIB, 145 were receiving ledipasvir/sofosbuvir, and 54 were receiving sofosbuvir/velpatasvir.
Researchers compared the groups with respect to change over 8-12 weeks on the PTSD Checklist (PCL), a 20-item self-report scale.
In adjusted analyses, the largest mean improvement on the PCL was 14.9 points for the GLE/PIB group and the smallest adjusted mean improvement on the PCL was 7.5 points for the ledipasvir/sofosbuvir group (mean difference, 7.34 points; 95% confidence interval, 1.05-13.63).
The adjusted proportion of patients improving by 15 points or more on the PCL was highest for the GLE/PIB group at 43.6% and lowest for the ledipasvir/sofosbuvir group at 26.3%.
Even when accounting for patients receiving trauma-based therapy or SSRIs, “it still looks like there’s a strong association of the hepatitis C antivirals with PTSD symptom improvement,” said Dr. Shiner.
Researchers also carried out a sensitivity analysis among only patients who were cured of HCV (over 90% of the total sample), defined as having an undetectable HCV viral load up to a year after completion of therapy. The analysis showed PTSD outcomes were still superior for participants receiving GLE/PIB.
“The sensitivity analysis was not that robust because almost everyone was cured, so it included almost everybody, but it didn’t point us away from the possibility of an off-target effect,” Dr. Shiner said.
Why antivirals may improve PTSD symptoms is not clear, but they may affect the immune response in patients with hepatitis C – and there may also be an immune response in PTSD, he noted. “Some of those factors may be shared, and that could explain some of the off-target effect.”
However, he noted the GLE/PIB drug combination is costly and patients with PTSD can probably access it only through enrolling in a study.
“We are not recommending that people go out and purchase this very expensive drug to treat their PTSD at this point,” Dr. Shiner said.
He added that the research team has now received funding from the Department of Defense to conduct a randomized, placebo-controlled trial of GLE/PIB as a potential treatment for PTSD.
Promising potential treatment
PTSD expert Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, D.C., said the results suggest GLE/PIB is a promising potential treatment for PTSD.
“I definitely think this should be looked at further,” said Dr. Ritchie, who was not involved with the research.
She noted that current PTSD therapies have drawbacks. SSRIs have side effects, the most “troubling” being sexual dysfunction. And although cognitive-behavioral therapy is effective, “people have to stick with it” and studies show about two thirds of patients drop out, she said.
Potentially effective PTSD treatment approaches include “self-soothing” or “self-regulating” techniques such as exercise, meditation, yoga, and working with animals, she added.
Dr. Ritchie pointed out the numbers of participants in the study were relatively small, including two groups that had only 54 patients each.
And while the GLE/PIB combination should be explored further, cost, availability, and side effects of this medication need to be taken into consideration, she said.
Dr. Ritchie added she is not overly concerned that the mechanism of action for the combination on PTSD may not be well understood. She noted several psychiatric medications fall into that category, including electroconvulsive therapy and lithium.
“When lithium was first found to be effective against bipolar disorder, we had no clue why,” she said. “So I would not discount the antiviral based on us not knowing how it works.”
However, “we’re a long way off” from starting a patient with PTSD on an antiviral, said Dr. Ritchie, adding there are “a lot of steps to go through” to get FDA approval.
The study was funded by the National Institute of Mental Health. The cohort used for this study was developed through support from the Department of Defense. Dr. Shiner is a coinventor on a provisional patent application covering the use of glecaprevir, pibrentasvir, and velpatasvir for PTSD and other psychiatric indications. Dr. Ritchie reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.
The combination of the two antiviral medications glecaprevir and pibrentasvir (Mavyret) is linked to improved symptoms in posttraumatic stress disorder, new research suggests.
A national cohort study of U.S. Veterans Affairs patients included more than 250 participants with PTSD and comorbid hepatitis C virus.
Results showed in the study, including ledipasvir/sofosbuvir.
“While there are great treatments available for PTSD, there’s a lot of desire in the field to find a new medication that will be helpful,” lead author Brian Shiner, MD, acting associate chief of staff for research, VA Medical Center, White River Junction, Vt., told this news organization.
“We had a great opportunity to use a novel data mining method to look in a wonderful database for a new treatment and we found something very promising,” said Dr. Shiner, who is also an associate professor of psychiatry at the Geisel School of Medicine at Dartmouth, Hanover, N.H.
The findings were published online in the American Journal of Epidemiology.
Common psychiatric disorder
PTSD is one of the most common psychiatric disorders, with an estimated lifetime prevalence of 6.4% in the United States. Yet only two drugs, the SSRIs sertraline (Zoloft) and paroxetine (Paxil), have been approved by the Food and Drug Administration to treat PTSD.
The VA recommends trauma-based psychotherapy, such as prolonged exposure and cognitive processing therapy, as first-line treatments for PTSD. However, not all patents respond to or have access to these approaches, said Dr. Shiner.
The investigators wanted to examine whether existing medications might reduce PTSD symptoms. Their previous exploratory study used “data mining” of national VA medical records.
Results from that study showed the three hepatitis C antivirals of GLE (an NS3/4A protease inhibitor), PIB (a NS5A protein inhibitor), and velpatasvir (another NS5A protein inhibitor) were associated with more than double the expected number of patients experiencing a clinically meaningful improvement in PTSD symptoms.
Sertraline was associated with only a slightly higher than expected improvement.
“SSRIs are effective, better than placebo, but the effects are not as good as we would hope,” Dr. Shiner said.
He noted that GLE and PIB are always prescribed together (Mavyret), whereas velpatasvir is commonly prescribed with the NS5B polymerase inhibitor sofosbuvir under the brand name Epclusa. Sofosbuvir is also commonly prescribed with the NS5A protein inhibitor ledipasvir under the brand name Harvoni.
Strong association
The new study included 253 VA users with a diagnosis of PTSD and hepatitis C. Of these, 54 were receiving GLE/PIB, 145 were receiving ledipasvir/sofosbuvir, and 54 were receiving sofosbuvir/velpatasvir.
Researchers compared the groups with respect to change over 8-12 weeks on the PTSD Checklist (PCL), a 20-item self-report scale.
In adjusted analyses, the largest mean improvement on the PCL was 14.9 points for the GLE/PIB group and the smallest adjusted mean improvement on the PCL was 7.5 points for the ledipasvir/sofosbuvir group (mean difference, 7.34 points; 95% confidence interval, 1.05-13.63).
The adjusted proportion of patients improving by 15 points or more on the PCL was highest for the GLE/PIB group at 43.6% and lowest for the ledipasvir/sofosbuvir group at 26.3%.
Even when accounting for patients receiving trauma-based therapy or SSRIs, “it still looks like there’s a strong association of the hepatitis C antivirals with PTSD symptom improvement,” said Dr. Shiner.
Researchers also carried out a sensitivity analysis among only patients who were cured of HCV (over 90% of the total sample), defined as having an undetectable HCV viral load up to a year after completion of therapy. The analysis showed PTSD outcomes were still superior for participants receiving GLE/PIB.
“The sensitivity analysis was not that robust because almost everyone was cured, so it included almost everybody, but it didn’t point us away from the possibility of an off-target effect,” Dr. Shiner said.
Why antivirals may improve PTSD symptoms is not clear, but they may affect the immune response in patients with hepatitis C – and there may also be an immune response in PTSD, he noted. “Some of those factors may be shared, and that could explain some of the off-target effect.”
However, he noted the GLE/PIB drug combination is costly and patients with PTSD can probably access it only through enrolling in a study.
“We are not recommending that people go out and purchase this very expensive drug to treat their PTSD at this point,” Dr. Shiner said.
He added that the research team has now received funding from the Department of Defense to conduct a randomized, placebo-controlled trial of GLE/PIB as a potential treatment for PTSD.
Promising potential treatment
PTSD expert Elspeth Cameron Ritchie, MD, chief of psychiatry at Medstar Washington Hospital Center, Washington, D.C., said the results suggest GLE/PIB is a promising potential treatment for PTSD.
“I definitely think this should be looked at further,” said Dr. Ritchie, who was not involved with the research.
She noted that current PTSD therapies have drawbacks. SSRIs have side effects, the most “troubling” being sexual dysfunction. And although cognitive-behavioral therapy is effective, “people have to stick with it” and studies show about two thirds of patients drop out, she said.
Potentially effective PTSD treatment approaches include “self-soothing” or “self-regulating” techniques such as exercise, meditation, yoga, and working with animals, she added.
Dr. Ritchie pointed out the numbers of participants in the study were relatively small, including two groups that had only 54 patients each.
And while the GLE/PIB combination should be explored further, cost, availability, and side effects of this medication need to be taken into consideration, she said.
Dr. Ritchie added she is not overly concerned that the mechanism of action for the combination on PTSD may not be well understood. She noted several psychiatric medications fall into that category, including electroconvulsive therapy and lithium.
“When lithium was first found to be effective against bipolar disorder, we had no clue why,” she said. “So I would not discount the antiviral based on us not knowing how it works.”
However, “we’re a long way off” from starting a patient with PTSD on an antiviral, said Dr. Ritchie, adding there are “a lot of steps to go through” to get FDA approval.
The study was funded by the National Institute of Mental Health. The cohort used for this study was developed through support from the Department of Defense. Dr. Shiner is a coinventor on a provisional patent application covering the use of glecaprevir, pibrentasvir, and velpatasvir for PTSD and other psychiatric indications. Dr. Ritchie reported no relevant financial relationships.
A version of this article first appeared on Medscape.com.