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Adjuvant capecitabine shown a less punishing option after NPC chemoradiation
Adjuvant capecitabine is an effective and better tolerated alternative to chemotherapy following chemoradiation for locoregionally advanced nasopharyngeal carcinoma, according to two phase 3 trials from China.
Despite using different dosing strategies, 3-year failure-free survival approached 90% in both trials, comparable to the standard approach with adjuvant platinum doublets, but with better compliance.
The study teams were looking for “a way to make adjuvant therapy more tolerable,” said oncologist Herbert Loong, MBBS, clinical associate professor at the Chinese University of Hong Kong, who discussed both trials after they were presented at the American Society for Clinical Oncology annual meeting.
Compliance is low with platinum doublets because of the toxicity. About 60%-70% of patients can tolerate 2-3 cycles after chemoradiation, and about a third can’t even start because of the toll chemoradiation took on their bodies, he said.
Induction chemotherapy is an alternative, but patients seem to derive more benefit form adjuvant therapy after chemoradiation. Indeed, “given the fact that we may now have a well established, well tolerated adjuvant therapy for our patients” – capecitabine – “the role of induction therapy” is in question, Dr. Loong said.
Metronomic dosing
One trial randomized 204 patients to metronomic dosing of capecitabine, 650 mg/m2 twice daily for 1 year within 12 to 16 weeks after the last radiation, and 202 others to observation.
The idea of metronomic dosing was to give a lower dose of the agent over a longer period to reduce side effects and perhaps improve efficacy.
Subjects had high-risk stage III to IVA disease with no locoregional disease or distant metastasis after chemoradiotherapy. Almost 80% in both arms also had induction chemotherapy, most commonly docetaxel and cisplatin.
Almost three-quarters of people in the treatment arm complied with capecitabine for an entire year.
At a median follow-up of 38 months, 3-year failure-free survival was 85.3% with metronomic capecitabine vs. 75.7% with observation (hazard ratio, .50, P = .002). Three-year overall survival was 93.3% with capecitabine and 88.6% with observation (HR .44, P = .018).
The incidence of grade 3/4 adverse events was 17.4% with metronomic capecitabine vs. 5.5% with observation. Hand-foot syndrome was the most common complication, occurring in 9% of capecitabine subjects. There were no treatment-related deaths, and there was no clinically meaningful deterioration in quality of life associated with treatment.
The approach “significantly improved” outcomes, “with a manageable safety profile and no compromise to quality of life ... Metronomic adjuvant capecitabine can be an option for first-line treatment in this high-risk” group, concluded investigators led by Jun Ma, MD, professor of radiation oncology and deputy president of Sun Yat-sen University Cancer Center in Guangzhou, China.
Standard dosing
The second trial used standard dosing. The researchers randomized 90 subjects to capecitabine 1,000 mg/m2 twice daily for 14 days in eight 21-day cycles after chemoradiation; 90 subjects were randomized to observation. None of the subjects received induction chemotherapy.
Patients had stage III-IVb disease plus at least one high-risk feature, such as high Epstein Barr virus DNA titers. The majority of patients in both arms had three or more high risk features.
Over 80% of capecitabine subjects completed all eight cycles of treatment.
At a median follow-up of 44.8 months, 3-year failure-free survival was 87.7% with capecitabine vs. 73.3% in the control arm (HR .52, P = .037). Three-year overall survival was 92.6% with capecitabine vs. 88.9% with observation, which wasn’t statistically significant.
The incidence of acute grade 3/4 adverse events was 57.8% with standard dose capecitabine. Rates of hand foot syndrome, mucositis, anemia, and other problems were substantially higher than with observation.
For high-risk patients unable to tolerate chemotherapy, adjuvant capecitabine is a “suitable alternative treatment option,” said lead investigator Jingjing Miao, MD, of the department of nasopharyngeal carcinoma at Sun Yat-sen University Cancer Center, Guangzhou, China.
The trials were funded by Sun Yat-sen University and others. The investigators had no disclosures. Dr. Loong is an adviser, speaker, and/or researcher for a number of companies, including Novartis, Pfizer, and Lilly.
Adjuvant capecitabine is an effective and better tolerated alternative to chemotherapy following chemoradiation for locoregionally advanced nasopharyngeal carcinoma, according to two phase 3 trials from China.
Despite using different dosing strategies, 3-year failure-free survival approached 90% in both trials, comparable to the standard approach with adjuvant platinum doublets, but with better compliance.
The study teams were looking for “a way to make adjuvant therapy more tolerable,” said oncologist Herbert Loong, MBBS, clinical associate professor at the Chinese University of Hong Kong, who discussed both trials after they were presented at the American Society for Clinical Oncology annual meeting.
Compliance is low with platinum doublets because of the toxicity. About 60%-70% of patients can tolerate 2-3 cycles after chemoradiation, and about a third can’t even start because of the toll chemoradiation took on their bodies, he said.
Induction chemotherapy is an alternative, but patients seem to derive more benefit form adjuvant therapy after chemoradiation. Indeed, “given the fact that we may now have a well established, well tolerated adjuvant therapy for our patients” – capecitabine – “the role of induction therapy” is in question, Dr. Loong said.
Metronomic dosing
One trial randomized 204 patients to metronomic dosing of capecitabine, 650 mg/m2 twice daily for 1 year within 12 to 16 weeks after the last radiation, and 202 others to observation.
The idea of metronomic dosing was to give a lower dose of the agent over a longer period to reduce side effects and perhaps improve efficacy.
Subjects had high-risk stage III to IVA disease with no locoregional disease or distant metastasis after chemoradiotherapy. Almost 80% in both arms also had induction chemotherapy, most commonly docetaxel and cisplatin.
Almost three-quarters of people in the treatment arm complied with capecitabine for an entire year.
At a median follow-up of 38 months, 3-year failure-free survival was 85.3% with metronomic capecitabine vs. 75.7% with observation (hazard ratio, .50, P = .002). Three-year overall survival was 93.3% with capecitabine and 88.6% with observation (HR .44, P = .018).
The incidence of grade 3/4 adverse events was 17.4% with metronomic capecitabine vs. 5.5% with observation. Hand-foot syndrome was the most common complication, occurring in 9% of capecitabine subjects. There were no treatment-related deaths, and there was no clinically meaningful deterioration in quality of life associated with treatment.
The approach “significantly improved” outcomes, “with a manageable safety profile and no compromise to quality of life ... Metronomic adjuvant capecitabine can be an option for first-line treatment in this high-risk” group, concluded investigators led by Jun Ma, MD, professor of radiation oncology and deputy president of Sun Yat-sen University Cancer Center in Guangzhou, China.
Standard dosing
The second trial used standard dosing. The researchers randomized 90 subjects to capecitabine 1,000 mg/m2 twice daily for 14 days in eight 21-day cycles after chemoradiation; 90 subjects were randomized to observation. None of the subjects received induction chemotherapy.
Patients had stage III-IVb disease plus at least one high-risk feature, such as high Epstein Barr virus DNA titers. The majority of patients in both arms had three or more high risk features.
Over 80% of capecitabine subjects completed all eight cycles of treatment.
At a median follow-up of 44.8 months, 3-year failure-free survival was 87.7% with capecitabine vs. 73.3% in the control arm (HR .52, P = .037). Three-year overall survival was 92.6% with capecitabine vs. 88.9% with observation, which wasn’t statistically significant.
The incidence of acute grade 3/4 adverse events was 57.8% with standard dose capecitabine. Rates of hand foot syndrome, mucositis, anemia, and other problems were substantially higher than with observation.
For high-risk patients unable to tolerate chemotherapy, adjuvant capecitabine is a “suitable alternative treatment option,” said lead investigator Jingjing Miao, MD, of the department of nasopharyngeal carcinoma at Sun Yat-sen University Cancer Center, Guangzhou, China.
The trials were funded by Sun Yat-sen University and others. The investigators had no disclosures. Dr. Loong is an adviser, speaker, and/or researcher for a number of companies, including Novartis, Pfizer, and Lilly.
Adjuvant capecitabine is an effective and better tolerated alternative to chemotherapy following chemoradiation for locoregionally advanced nasopharyngeal carcinoma, according to two phase 3 trials from China.
Despite using different dosing strategies, 3-year failure-free survival approached 90% in both trials, comparable to the standard approach with adjuvant platinum doublets, but with better compliance.
The study teams were looking for “a way to make adjuvant therapy more tolerable,” said oncologist Herbert Loong, MBBS, clinical associate professor at the Chinese University of Hong Kong, who discussed both trials after they were presented at the American Society for Clinical Oncology annual meeting.
Compliance is low with platinum doublets because of the toxicity. About 60%-70% of patients can tolerate 2-3 cycles after chemoradiation, and about a third can’t even start because of the toll chemoradiation took on their bodies, he said.
Induction chemotherapy is an alternative, but patients seem to derive more benefit form adjuvant therapy after chemoradiation. Indeed, “given the fact that we may now have a well established, well tolerated adjuvant therapy for our patients” – capecitabine – “the role of induction therapy” is in question, Dr. Loong said.
Metronomic dosing
One trial randomized 204 patients to metronomic dosing of capecitabine, 650 mg/m2 twice daily for 1 year within 12 to 16 weeks after the last radiation, and 202 others to observation.
The idea of metronomic dosing was to give a lower dose of the agent over a longer period to reduce side effects and perhaps improve efficacy.
Subjects had high-risk stage III to IVA disease with no locoregional disease or distant metastasis after chemoradiotherapy. Almost 80% in both arms also had induction chemotherapy, most commonly docetaxel and cisplatin.
Almost three-quarters of people in the treatment arm complied with capecitabine for an entire year.
At a median follow-up of 38 months, 3-year failure-free survival was 85.3% with metronomic capecitabine vs. 75.7% with observation (hazard ratio, .50, P = .002). Three-year overall survival was 93.3% with capecitabine and 88.6% with observation (HR .44, P = .018).
The incidence of grade 3/4 adverse events was 17.4% with metronomic capecitabine vs. 5.5% with observation. Hand-foot syndrome was the most common complication, occurring in 9% of capecitabine subjects. There were no treatment-related deaths, and there was no clinically meaningful deterioration in quality of life associated with treatment.
The approach “significantly improved” outcomes, “with a manageable safety profile and no compromise to quality of life ... Metronomic adjuvant capecitabine can be an option for first-line treatment in this high-risk” group, concluded investigators led by Jun Ma, MD, professor of radiation oncology and deputy president of Sun Yat-sen University Cancer Center in Guangzhou, China.
Standard dosing
The second trial used standard dosing. The researchers randomized 90 subjects to capecitabine 1,000 mg/m2 twice daily for 14 days in eight 21-day cycles after chemoradiation; 90 subjects were randomized to observation. None of the subjects received induction chemotherapy.
Patients had stage III-IVb disease plus at least one high-risk feature, such as high Epstein Barr virus DNA titers. The majority of patients in both arms had three or more high risk features.
Over 80% of capecitabine subjects completed all eight cycles of treatment.
At a median follow-up of 44.8 months, 3-year failure-free survival was 87.7% with capecitabine vs. 73.3% in the control arm (HR .52, P = .037). Three-year overall survival was 92.6% with capecitabine vs. 88.9% with observation, which wasn’t statistically significant.
The incidence of acute grade 3/4 adverse events was 57.8% with standard dose capecitabine. Rates of hand foot syndrome, mucositis, anemia, and other problems were substantially higher than with observation.
For high-risk patients unable to tolerate chemotherapy, adjuvant capecitabine is a “suitable alternative treatment option,” said lead investigator Jingjing Miao, MD, of the department of nasopharyngeal carcinoma at Sun Yat-sen University Cancer Center, Guangzhou, China.
The trials were funded by Sun Yat-sen University and others. The investigators had no disclosures. Dr. Loong is an adviser, speaker, and/or researcher for a number of companies, including Novartis, Pfizer, and Lilly.
FROM ASCO 2021
Cabozantinib gains ground for salvage in differentiated thyroid cancer
The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.
The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.
The vascular endothelial growth factor receptor 2 blocker cabozantinib prolonged progression-free survival in radioiodine-refractory differentiated thyroid cancer following progression on first-line VEGFR inhibitors in a phase 3 trial from cabozantinib maker, Exelixis.
After a median follow up of 6.2 months, the 125 subjects on cabozantinib 60 mg every day had not reached median progression-free survival, but among the 62 randomized to placebo, mPFS was only 1.9 months.
The results led the Food and Drug Administration to grant cabozantinib breakthrough therapy status for salvage after progression on lenvatinib or sorafenib, the two VEGFR inhibitors approved for first-line treatment in radioiodine refractory differentiated thyroid cancer. Cabozantinib already carries a first-line indication for progressive, metastatic medullary thyroid cancer.
“We were all so excited to have sorafenib and lenvatinib,” but patients need another option after they develop resistance. “Cabozantinib is positioned to be the next in line,” said lead investigator Marcia Brose, MD, PhD, a thyroid specialist and professor at the University of Pennsylvania, Philadelphia, who presented the findings at the American Society of Clinical Oncology Annual Meeting.
The trial discussant, medical oncologist Nicole Chau, MD, clinical associate professor at the University of British Columbia, Vancouver, said the results “support cabozantinib as a potential second- or third-line” option, but its impact on quality of life and financial toxicity “should be evaluated.”
Subjects in the trial – dubbed COSMIC-311 – had locally advanced or metastatic disease that had progressed during or after first-line VEGFR treatment, including about 40% with lenvatinib, almost 40% with sorafenib, and over 20% with both.
The median age in the study was 66 years, and 55% of the subjects were women. Bone and liver metastases were more common in the cabozantinib arm.
Promising results
The robust of mPFS benefit (hazard ratio, 0.22; P < .0001) held across subgroups. The mPFS in the placebo arm of 1.9 months demonstrates that “these patients [progress rapidly], so you have to be ready with the next thing in line” to start it quickly, Dr. Brose said.
Overall survival favored cabozantinib (HR, 0.54) but didn’t reach statistical significance perhaps because placebo patients were allowed to cross over to cabozantinib after progression.
The overall response rate was 15% with cabozantinib versus no responders with placebo, which also didn’t meet the study’s criteria for clinical significance. Even so, the disease control rate of 60% with cabozantinib versus 27% with placebo, “is clinically meaningful in this heavily pretreated population,” Dr. Chau said.
Adverse events
Safety was consistent with previous reports and included diarrhea in 51% of cabozantinib subjects, hand-foot skin reaction in 46%, hypertension in 28%, fatigue in 27%, and nausea in 24%, all substantially higher than with placebo. Over half of cabozantinib subjects had grade 3-4 adverse events versus 26% on placebo. There were no treatment related deaths.
Adverse events led to dose reductions or holds in the majority of cabozantinib subjects, but only 5% discontinued the drug; the number might have been higher with longer follow-up, Dr. Chau said.
Genotype-targeted therapy is an option for patients with fusion alterations, but whether it should come before or after VEGFR inhibition is unclear, Dr. Brose noted.
Biomarkers to help with such treatment decisions will become “increasingly important as we move beyond the era of single-agent” VEGFR inhibitors, Dr. Chau said.
The study was funded by cabozantinib maker Exelixis, and three investigators were employees. Dr. Brose disclosed research funding and honoraria from the company, and is an adviser. Dr. Chau has no involvement with Exelixis.
FROM ASCO 2021
GLOW: Ibrutinib+venetoclax shines in first line for CLL/SLL
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
For older, unfit patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), first-line treatment with the all-oral combination of ibrutinib (Imbruvica) and venetoclax (Venclexta) was associated with superior progression-free survival, compared with chlorambucil and obinutuzumab (Gazyva), results of the phase 3 GLOW trial showed.
Among 211 patients with CLL/SLL who were 65 or older, or younger patients with a high comorbidity burden, the median progression-free survival (PFS) after 27.7 months of follow-up was not reached for patients treated with a fixed duration combination of ibrutinib plus venetoclax (I+V), compared with 21 months for patients who received chlorambucil plus obinutuzumab (Clb+O), reported Arnon P. Kater, MD, PhD, from Amsterdam University Medical Centers.
The oral combination was also associated with a higher rate of undetectable minimal residual disease (MRD) 3 months after the end of treatment, at 51.9% vs. 17.1% with Clb+O, he said in a late-breaking abstract presented during the European Hematology Association annual meeting (Abstract LB1902).
“Overall, the results from GLOW support a positive clinical profile of I+V as an all-oral, once-daily, fixed-duration regimen in older patients with newly diagnosed CLL,” he said.
A low bar
But the bar for success in the GLOW trial may have been set low, with the older combination of chlorambucil plus obinutuzumab used as the comparator, rather than a more contemporary regimen, said Clive S. Zent , MD, from the Wilmot Cancer Institute at the University of Rochester (New York) Medical Center, who was not involved in the study.
“Really, nobody in this country that I’m aware of, certainly not in academic medicine, would be using chlorambucil and obinutuzumab or rituximab for standard of care,” Dr. Zent said in an interview.
“This is like comparing a mule cart to a Tesla,” he said.
Apart from possibly providing a rationale for using ibrutinib and venetoclax in this population, the GLOW results do not add much beyond that already in the CAPTIVE MRD trial, he added.
“What we’re really interested in, is ibrutinib and venetoclax better than ibrutinib alone or venetoclax alone? And that has not been asked or answered yet,” he said.
Dr. Zent acknowledged that the combination works very well and is well tolerated, and the idea of fixed duration therapy is attractive, as are the long-term outcomes for many patients following cessation of therapy.
“But remember, if you take ibrutinib, you’ve got a 90% chance of going into remission, and an over 80% chance of being in remission 5 years later, so that’s pretty good as well,” he said.
Paolo P. Ghia, MD, from Univerista Vita-Salute San Raffaele in Milan, who has studied fixed-duration I+V in younger patients with CLL in the CAPTIVATE trial agreed that “in general, there is very little role for chemoimmunotherapy in CLL.”
But Dr. Ghia, who was not involved in the GLOW study, said in an interview that the results add to the growing body of evidence of the efficacy and safety of ibrutinib -venetoclax in a wide range of patients.
“Overall between the two studies [CAPTIVATE and GLOW] we have now over 400 patients who have been treated with the combination, and the message is rather similar in the two studies: you have a high frequency of undetectable MRD in peripheral blood and in the bone marrow, with a high concordance between the two tissues, and in particular we have a durability of the response,” he said.
GLOW details
Dr. Kater noted that ibrutinib and venetoclax have distinct and complementary modes of action, with ibrutinib mobilizing CLL cells out of their “protective lymphoid niches” and inhibiting their proliferation, as well as accelerating apoptosis by sensitizing cells to inhibition by the anti–B-cell lymphoma 2 (BCL-2) agent venetoclax. The combination leads to high levels of MRD negative by eliminating subpopulations of resting and dividing CLL cells.
The GLOW investigators enrolled 211 patients who were 65 or older, or were younger than 65 with a cumulative illness rating scale (CIRS) score of greater than 6, or creatinine clearance rate of less than 70 mL/min, and no known deletion 17p (del17p) or TP53 mutation.
The patients all had Eastern Cooperative Oncology Group performance status scores of 0-2.
After stratification by immunoglobulin heavy chain variable (IGHV) region genes and presence of deletion 11q (del11q), the patients were randomly assigned to either a three cycle run-in with ibrutinib 420 mg daily followed by ibrutinib plus venetoclax ramped up from 20 to 400 mg, or to chlorambucil 0.5 mg/kg on days and 15 for six cycles, and obinutuzumab 1,000 mg on days 1,2, 8, and 15 of cycle 1, and day 1 of cycles 2-6.
About one-third of patients in each study arm were 75 or older. Baseline characteristics were generally similar between the arms, except for a higher frequency of CIRS scores above 6 in the I+V arm, and a higher frequency of elevated lactate dehydrogenase in the Clb+O arm.
Superior PFS
As noted, the primary endpoint of PFS as assessed by independent review committee (IRC) after 27.7 months of follow-up had not been reached in I+V arm, compared with 21 months in the Clb+O arm, translating into a hazard ratio or progression with I+V of 0.21 (P < .0001). Investigator-assessed PFS was similar, with an HR of 2.07 (P < .0001).
PFS was superior with I+V across all subgroups, including age, baseline performance status. CIRS total score, Rai stage, bulky disease, elevated LDH at baseline, IGHV mutated or unmutated, and presence or absence of del(11q).
IRC-assessed combined complete response (CR) or CR with incomplete recovery of blood counts (CRi) rates were 38.7% with I+V vs. 11.4% with Clb+O (P < .0001).
Responses were also more durable with the oral combination, with 90% of patients having a sustained IRC-assessed response at 24 months, compared with 41% in the chemoimmunotherapy arm.
Rates of undetectable MRD by next-generation sequencing 3 months after the end of treatment were also significantly higher with I+V in both bone marrow (51.9% vs. 17.1%, respectively, P < .0001) and peripheral blood (54.7% vs. 39%, P = .0259).
One year post treatment 49% of patients assigned to I+V had undetectable MRD in peripheral blood, compared with 12% of patients assigned to Clb+O).
Safety
In all, 11 patients assigned to I+V discontinued treatment because of adverse events, compared with 2 in the Clb+O arm. Two patients in the I+V arm (1.9%) discontinued ibrutinib because of atrial fibrillation (AF). Serious adverse events in 5% or more of patients that were more frequent with I+V include infections (12.3% vs. 8.6% and AF (6.6% vs. o%). The tumor lysis syndrome (TLS) was not seen in the I+V arm, but occurred in 5.7% of patients in the Clb+O arm.
There were a total of 11 deaths in the I+V arm and 12 in the Clb+O arm during treatment or follow-up.
Causes of death were generally similar between the arms, with infections and cardiac events being the most common causes, Dr. Kater said.
Of the four deaths that occurred during ibrutinib lead-in, one was due to infection, one to metastatic carcinoma, and two due to cardiac disorders. Of the three that occurred in the I+V arm during treatment, two were from sudden death, and one from a nervous system disorder. Four patients in this arm died during follow-up, two from infections, one from sudden death, and one from progressive disease with Richter transformation.
In the Clb+O arm, one patient died during treatment from an infection and one died from hepatobiliary disease. Of the 10 that died during follow-up, 6 died from infections/infestations, 2 from cardiac disorders, and 1 each from nervous system and respiratory/thoracic/mediastinal disorder.
The study was supported by Janssen Research & Development. Dr. Kater disclosed advisory board activity, research committee, and steering committee participation for Janssen, and similar relationships with others. Dr. Zent disclosed research funding to the University of Rochester from AstraZenca/Acerta and TG Therpeutics. Dr. Ghia disclosed consultancy, honoraria, travel expenses, and research funding from Janssen and others.
FROM EHA 2021
Moving more, sitting less vital for migraine patients
according to a presentation at the American Headache Society’s 2021 annual meeting.
Though reliable research is sparse overall on how much physical activity people with migraine get, enough exists to reveal the need for clinicians to help patients identify ways to increase their levels of physical activity and make it a habit, said Dale S. Bond, PhD, a professor of psychiatry and human behavior at the Miriam Hospital and Brown University, both in Providence, R.I.
He emphasized the need not only to replace sedentary time with physical activity but also to reduce sedentary time overall.
“It’s important to note that because active and sedentary represent different behavioral domains, people can still be active – that is, achieving recommended levels of moderate to vigorous physical activity [MVPA] – but still be highly sedentary because they sit for long hours throughout the day,” Dr. Bond said. “This is important because MVPA will not necessarily eliminate the health risks of long hours of sitting.”
Dr. Bond reviewed the existing literature on physical activity and sedentary behavior among patients with migraine. His presentation, “Move More, Sit Less,” aimed at finding ways to incorporate more physical activity into the daily lives of those with migraine. Dr. Bond began by briefly reviewing the well-established benefits of physical activity, including healthy sleep; cardiovascular, respiratory, musculoskeletal, mental, and cognitive health; and metabolic functioning.
“Physical activity and exercise in particular enhances the functioning of bodily systems, including those that have direct relevance to migraine in its comorbidities,” Dr. Bond said. “The positive systemic effects of exercise on bodily systems carries potential to reduce migraine severity and related disability and morbidity.”
He also explained the ways in which excessive sedentary time can exacerbate migraine triggers. “Long periods of interrupted sitting elevated levels of glucose and fat in the bloodstream, which in turn triggers the immune system to attack the body via inflammation,” Dr. Bond said. “Low grade chronic inflammation has long been hypothesized to play a role in migraine pathogenesis.”
Recommended levels of exercise
The World Health Organization and the U.S. Department of Health & Human Services recommends at least 150-300 minutes of moderate-intensity aerobic physical activity or 75-150 minutes of vigorous activity each week. An additional recommendation is at least 2 days per week of muscle strengthening activities that involve all major muscle groups.
While neither of those organizations has specific guidelines on how much reduction of sedentary time is recommended, the Canadian Society for Exercise Physiology recommends limiting sedentary time to 8 or fewer hours per day.
Exercise and migraine
“Unfortunately, at present, we have very few studies from which to draw conclusions about the extent to which individuals with migraine adhere to physical activity and sedentary guidelines,” Dr. Bond said. Existing studies vary widely in sample types, study design, physical activity measure and MVPA outcome, including the type or definition of MVPA. “This wide variability in measures and outcomes makes it challenging to draw any conclusions about adherence to guidelines among individuals with migraine,” he said.
Existing evidence suggests anywhere from 32% to 66% of migraine patients are at least moderately active, though it’s not clear what constitutes “moderately active” behavior. It appears that activity levels of patients with migraine are low overall, but it’s less clear the extent to which these levels are lower than in controls given the paucity of evidence.
In one of the few studies using objective measures to assess physical activity in migraine patients, the daily level of MVPA was significantly lower in 25 women with migraine than in 25 age- and body mass index–matched women without migraine (P <. 003). Both groups had obesity. The same study found that virtually no women with migraine adhered to the guidelines recommending less than 8 hours a day of sedentary time, compared with 30% of women without migraine.
“Also, low physical activity and high sedentary levels appear to be consistent across headache and nonheadache days,” Dr. Bond said. “This finding in particular raises an interesting question: If migraine severity is not related to physical activity and sedentary time, what is it about migraine that contributes to an inactive and sedentary lifestyle?”
Dr. Bond noted that future research needs to include reports of frequency, duration, and intensity of activities performed as well as the percentage of participants who meet guidelines for physical activity and sedentary time. Ideally, these studies should include not only self-report but also objective measures of activity as well as assess sleep and identify barriers and facilitators to physical activity in patients.
Exercise avoidance
Dr. Bond described findings from survey of 100 women he conducted to better understand potential barriers and reported that 78% of patients report intentionally avoiding physical activity. These patients typically avoided it an average of 4 days per week, regardless of intensity, and additional survey findings found “that participants who reported any avoidance had stronger beliefs that physical activity would both trigger and worsen a migraine attack, compared with participants who reported no avoidance,” he said.
That finding matches the clinical experience of Jennifer Robblee, MD, MSc, assistant professor of neurology at Barrow Neurological Institute in Phoenix, who viewed the presentation but was not involved with it.
“They often feel that it is a trigger for worsening an attack or, for some people, can actually trigger an attack, and that they feel worse in the midst of an attack when they’re exercising,” Dr. Robblee said in an interview regarding her patients who exercise less frequently. “Since so many of the patients I see have a daily and constant headache, it’s about how they can get themselves to start to exercise when something makes them feel worse, even if it makes them feel better in the long run.”
Yet, experimental research suggests that physical activity is not necessarily a reliable trigger of migraine attacks and only worsens migraine in a minority of attacks, Dr. Bond said, revealing an interesting paradox: “While engaging in regular physical activity is an important migraine management strategy, most individuals in the study reported doing the exact opposite – that is, avoiding physical activity as a management strategy – and this strategy was associated with higher frequency and duration of attacks. Research from our group and others also suggested individuals with migraine could be overestimating the role that physical activity hasn’t triggering or worsening of attacks.”
Encouraging patients to exercise
Since the benefits of physical activity and limiting sedentary time outweigh the potential harms, “some physical activity is better than none,” Dr. Bond said. To help patients begin increasing their physical activity, he recommended advising them to start with small amounts and then gradually increase frequency, intensity, and duration over time.
Dr. Robblee follows a similar approach, taking into account each patient’s particular circumstances and any medications they’re taking, including the side effects of those medications.
“It’s about starting where they are,” Dr. Robblee said. “Some patients, despite having severe migraine, have built themselves up so they’re doing exercise three or four times per week, or every day, and I have other people who never exercise,” she said. “For those patients who are very sedentary, if I can get them to start with 5 minutes per week so they have that sense of accomplishment, then that’s where I start. Then slowly build it up over time. Like most things in the migraine world, I individualize it for the person.”
Dr. Bond offered the following specific tips to clinicians in educating and encouraging patients to increase physical activity:
- Educate patients regarding the short-and long-term benefits of moving more and sitting less, both for their migraines and for overall health.
- Correct misconceptions about the negative effects of physical activity as it relates to migraines.
- Personalize the rationale for physical activity to that patient’s specific values and personal goals.
- Encourage patients to use an activity tracker, both for tracking physical activity and sedentary time, and to monitor migraine attacks, stress, energy levels, and fatigue on days they do and do not exercise.
- Help patients set goals for eventually meeting MVPA recommendations and interrupting prolonged periods of sitting with brief movement breaks.
- Help patients identify rewards for meeting goals that are tied to the activity, such as new exercise clothing.
- Encourage patients to identify a consistent time for physical activity each day to establish a habit, “ideally in the morning before barriers and life get in the way,” he said.
Eventually, physical activity itself should become intrinsically rewarding, Dr. Bond said.
“To limit sitting and encourage more movement throughout the day, we want to make the choice to engage in physical activity easier by adding environmental cues that encourage physical activity,” he said. “Conversely, we want to make the choice to engage in sedentary behavior more difficult by increasing the amount of effort that is required to engage in these behaviors.”
Dr. Robblee found Dr. Bond’s emphasis on sitting less – distinct from moving more – a helpful frame to consider with her patients. “I really like the approach of looking at it from that approach: in addition to how do we get you up and moving, how much time are you sitting, and how often can you break that up into smaller increments so that you’re up more often?” Dr. Robblee said. “That sometimes sounds less scary than ‘let’s get you exercising.’ So ‘let’s get you sitting a little bit less.’ I think that is something I might start to adopt.”
No external funding was noted. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem. Dr. Bond reported no disclosures.
according to a presentation at the American Headache Society’s 2021 annual meeting.
Though reliable research is sparse overall on how much physical activity people with migraine get, enough exists to reveal the need for clinicians to help patients identify ways to increase their levels of physical activity and make it a habit, said Dale S. Bond, PhD, a professor of psychiatry and human behavior at the Miriam Hospital and Brown University, both in Providence, R.I.
He emphasized the need not only to replace sedentary time with physical activity but also to reduce sedentary time overall.
“It’s important to note that because active and sedentary represent different behavioral domains, people can still be active – that is, achieving recommended levels of moderate to vigorous physical activity [MVPA] – but still be highly sedentary because they sit for long hours throughout the day,” Dr. Bond said. “This is important because MVPA will not necessarily eliminate the health risks of long hours of sitting.”
Dr. Bond reviewed the existing literature on physical activity and sedentary behavior among patients with migraine. His presentation, “Move More, Sit Less,” aimed at finding ways to incorporate more physical activity into the daily lives of those with migraine. Dr. Bond began by briefly reviewing the well-established benefits of physical activity, including healthy sleep; cardiovascular, respiratory, musculoskeletal, mental, and cognitive health; and metabolic functioning.
“Physical activity and exercise in particular enhances the functioning of bodily systems, including those that have direct relevance to migraine in its comorbidities,” Dr. Bond said. “The positive systemic effects of exercise on bodily systems carries potential to reduce migraine severity and related disability and morbidity.”
He also explained the ways in which excessive sedentary time can exacerbate migraine triggers. “Long periods of interrupted sitting elevated levels of glucose and fat in the bloodstream, which in turn triggers the immune system to attack the body via inflammation,” Dr. Bond said. “Low grade chronic inflammation has long been hypothesized to play a role in migraine pathogenesis.”
Recommended levels of exercise
The World Health Organization and the U.S. Department of Health & Human Services recommends at least 150-300 minutes of moderate-intensity aerobic physical activity or 75-150 minutes of vigorous activity each week. An additional recommendation is at least 2 days per week of muscle strengthening activities that involve all major muscle groups.
While neither of those organizations has specific guidelines on how much reduction of sedentary time is recommended, the Canadian Society for Exercise Physiology recommends limiting sedentary time to 8 or fewer hours per day.
Exercise and migraine
“Unfortunately, at present, we have very few studies from which to draw conclusions about the extent to which individuals with migraine adhere to physical activity and sedentary guidelines,” Dr. Bond said. Existing studies vary widely in sample types, study design, physical activity measure and MVPA outcome, including the type or definition of MVPA. “This wide variability in measures and outcomes makes it challenging to draw any conclusions about adherence to guidelines among individuals with migraine,” he said.
Existing evidence suggests anywhere from 32% to 66% of migraine patients are at least moderately active, though it’s not clear what constitutes “moderately active” behavior. It appears that activity levels of patients with migraine are low overall, but it’s less clear the extent to which these levels are lower than in controls given the paucity of evidence.
In one of the few studies using objective measures to assess physical activity in migraine patients, the daily level of MVPA was significantly lower in 25 women with migraine than in 25 age- and body mass index–matched women without migraine (P <. 003). Both groups had obesity. The same study found that virtually no women with migraine adhered to the guidelines recommending less than 8 hours a day of sedentary time, compared with 30% of women without migraine.
“Also, low physical activity and high sedentary levels appear to be consistent across headache and nonheadache days,” Dr. Bond said. “This finding in particular raises an interesting question: If migraine severity is not related to physical activity and sedentary time, what is it about migraine that contributes to an inactive and sedentary lifestyle?”
Dr. Bond noted that future research needs to include reports of frequency, duration, and intensity of activities performed as well as the percentage of participants who meet guidelines for physical activity and sedentary time. Ideally, these studies should include not only self-report but also objective measures of activity as well as assess sleep and identify barriers and facilitators to physical activity in patients.
Exercise avoidance
Dr. Bond described findings from survey of 100 women he conducted to better understand potential barriers and reported that 78% of patients report intentionally avoiding physical activity. These patients typically avoided it an average of 4 days per week, regardless of intensity, and additional survey findings found “that participants who reported any avoidance had stronger beliefs that physical activity would both trigger and worsen a migraine attack, compared with participants who reported no avoidance,” he said.
That finding matches the clinical experience of Jennifer Robblee, MD, MSc, assistant professor of neurology at Barrow Neurological Institute in Phoenix, who viewed the presentation but was not involved with it.
“They often feel that it is a trigger for worsening an attack or, for some people, can actually trigger an attack, and that they feel worse in the midst of an attack when they’re exercising,” Dr. Robblee said in an interview regarding her patients who exercise less frequently. “Since so many of the patients I see have a daily and constant headache, it’s about how they can get themselves to start to exercise when something makes them feel worse, even if it makes them feel better in the long run.”
Yet, experimental research suggests that physical activity is not necessarily a reliable trigger of migraine attacks and only worsens migraine in a minority of attacks, Dr. Bond said, revealing an interesting paradox: “While engaging in regular physical activity is an important migraine management strategy, most individuals in the study reported doing the exact opposite – that is, avoiding physical activity as a management strategy – and this strategy was associated with higher frequency and duration of attacks. Research from our group and others also suggested individuals with migraine could be overestimating the role that physical activity hasn’t triggering or worsening of attacks.”
Encouraging patients to exercise
Since the benefits of physical activity and limiting sedentary time outweigh the potential harms, “some physical activity is better than none,” Dr. Bond said. To help patients begin increasing their physical activity, he recommended advising them to start with small amounts and then gradually increase frequency, intensity, and duration over time.
Dr. Robblee follows a similar approach, taking into account each patient’s particular circumstances and any medications they’re taking, including the side effects of those medications.
“It’s about starting where they are,” Dr. Robblee said. “Some patients, despite having severe migraine, have built themselves up so they’re doing exercise three or four times per week, or every day, and I have other people who never exercise,” she said. “For those patients who are very sedentary, if I can get them to start with 5 minutes per week so they have that sense of accomplishment, then that’s where I start. Then slowly build it up over time. Like most things in the migraine world, I individualize it for the person.”
Dr. Bond offered the following specific tips to clinicians in educating and encouraging patients to increase physical activity:
- Educate patients regarding the short-and long-term benefits of moving more and sitting less, both for their migraines and for overall health.
- Correct misconceptions about the negative effects of physical activity as it relates to migraines.
- Personalize the rationale for physical activity to that patient’s specific values and personal goals.
- Encourage patients to use an activity tracker, both for tracking physical activity and sedentary time, and to monitor migraine attacks, stress, energy levels, and fatigue on days they do and do not exercise.
- Help patients set goals for eventually meeting MVPA recommendations and interrupting prolonged periods of sitting with brief movement breaks.
- Help patients identify rewards for meeting goals that are tied to the activity, such as new exercise clothing.
- Encourage patients to identify a consistent time for physical activity each day to establish a habit, “ideally in the morning before barriers and life get in the way,” he said.
Eventually, physical activity itself should become intrinsically rewarding, Dr. Bond said.
“To limit sitting and encourage more movement throughout the day, we want to make the choice to engage in physical activity easier by adding environmental cues that encourage physical activity,” he said. “Conversely, we want to make the choice to engage in sedentary behavior more difficult by increasing the amount of effort that is required to engage in these behaviors.”
Dr. Robblee found Dr. Bond’s emphasis on sitting less – distinct from moving more – a helpful frame to consider with her patients. “I really like the approach of looking at it from that approach: in addition to how do we get you up and moving, how much time are you sitting, and how often can you break that up into smaller increments so that you’re up more often?” Dr. Robblee said. “That sometimes sounds less scary than ‘let’s get you exercising.’ So ‘let’s get you sitting a little bit less.’ I think that is something I might start to adopt.”
No external funding was noted. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem. Dr. Bond reported no disclosures.
according to a presentation at the American Headache Society’s 2021 annual meeting.
Though reliable research is sparse overall on how much physical activity people with migraine get, enough exists to reveal the need for clinicians to help patients identify ways to increase their levels of physical activity and make it a habit, said Dale S. Bond, PhD, a professor of psychiatry and human behavior at the Miriam Hospital and Brown University, both in Providence, R.I.
He emphasized the need not only to replace sedentary time with physical activity but also to reduce sedentary time overall.
“It’s important to note that because active and sedentary represent different behavioral domains, people can still be active – that is, achieving recommended levels of moderate to vigorous physical activity [MVPA] – but still be highly sedentary because they sit for long hours throughout the day,” Dr. Bond said. “This is important because MVPA will not necessarily eliminate the health risks of long hours of sitting.”
Dr. Bond reviewed the existing literature on physical activity and sedentary behavior among patients with migraine. His presentation, “Move More, Sit Less,” aimed at finding ways to incorporate more physical activity into the daily lives of those with migraine. Dr. Bond began by briefly reviewing the well-established benefits of physical activity, including healthy sleep; cardiovascular, respiratory, musculoskeletal, mental, and cognitive health; and metabolic functioning.
“Physical activity and exercise in particular enhances the functioning of bodily systems, including those that have direct relevance to migraine in its comorbidities,” Dr. Bond said. “The positive systemic effects of exercise on bodily systems carries potential to reduce migraine severity and related disability and morbidity.”
He also explained the ways in which excessive sedentary time can exacerbate migraine triggers. “Long periods of interrupted sitting elevated levels of glucose and fat in the bloodstream, which in turn triggers the immune system to attack the body via inflammation,” Dr. Bond said. “Low grade chronic inflammation has long been hypothesized to play a role in migraine pathogenesis.”
Recommended levels of exercise
The World Health Organization and the U.S. Department of Health & Human Services recommends at least 150-300 minutes of moderate-intensity aerobic physical activity or 75-150 minutes of vigorous activity each week. An additional recommendation is at least 2 days per week of muscle strengthening activities that involve all major muscle groups.
While neither of those organizations has specific guidelines on how much reduction of sedentary time is recommended, the Canadian Society for Exercise Physiology recommends limiting sedentary time to 8 or fewer hours per day.
Exercise and migraine
“Unfortunately, at present, we have very few studies from which to draw conclusions about the extent to which individuals with migraine adhere to physical activity and sedentary guidelines,” Dr. Bond said. Existing studies vary widely in sample types, study design, physical activity measure and MVPA outcome, including the type or definition of MVPA. “This wide variability in measures and outcomes makes it challenging to draw any conclusions about adherence to guidelines among individuals with migraine,” he said.
Existing evidence suggests anywhere from 32% to 66% of migraine patients are at least moderately active, though it’s not clear what constitutes “moderately active” behavior. It appears that activity levels of patients with migraine are low overall, but it’s less clear the extent to which these levels are lower than in controls given the paucity of evidence.
In one of the few studies using objective measures to assess physical activity in migraine patients, the daily level of MVPA was significantly lower in 25 women with migraine than in 25 age- and body mass index–matched women without migraine (P <. 003). Both groups had obesity. The same study found that virtually no women with migraine adhered to the guidelines recommending less than 8 hours a day of sedentary time, compared with 30% of women without migraine.
“Also, low physical activity and high sedentary levels appear to be consistent across headache and nonheadache days,” Dr. Bond said. “This finding in particular raises an interesting question: If migraine severity is not related to physical activity and sedentary time, what is it about migraine that contributes to an inactive and sedentary lifestyle?”
Dr. Bond noted that future research needs to include reports of frequency, duration, and intensity of activities performed as well as the percentage of participants who meet guidelines for physical activity and sedentary time. Ideally, these studies should include not only self-report but also objective measures of activity as well as assess sleep and identify barriers and facilitators to physical activity in patients.
Exercise avoidance
Dr. Bond described findings from survey of 100 women he conducted to better understand potential barriers and reported that 78% of patients report intentionally avoiding physical activity. These patients typically avoided it an average of 4 days per week, regardless of intensity, and additional survey findings found “that participants who reported any avoidance had stronger beliefs that physical activity would both trigger and worsen a migraine attack, compared with participants who reported no avoidance,” he said.
That finding matches the clinical experience of Jennifer Robblee, MD, MSc, assistant professor of neurology at Barrow Neurological Institute in Phoenix, who viewed the presentation but was not involved with it.
“They often feel that it is a trigger for worsening an attack or, for some people, can actually trigger an attack, and that they feel worse in the midst of an attack when they’re exercising,” Dr. Robblee said in an interview regarding her patients who exercise less frequently. “Since so many of the patients I see have a daily and constant headache, it’s about how they can get themselves to start to exercise when something makes them feel worse, even if it makes them feel better in the long run.”
Yet, experimental research suggests that physical activity is not necessarily a reliable trigger of migraine attacks and only worsens migraine in a minority of attacks, Dr. Bond said, revealing an interesting paradox: “While engaging in regular physical activity is an important migraine management strategy, most individuals in the study reported doing the exact opposite – that is, avoiding physical activity as a management strategy – and this strategy was associated with higher frequency and duration of attacks. Research from our group and others also suggested individuals with migraine could be overestimating the role that physical activity hasn’t triggering or worsening of attacks.”
Encouraging patients to exercise
Since the benefits of physical activity and limiting sedentary time outweigh the potential harms, “some physical activity is better than none,” Dr. Bond said. To help patients begin increasing their physical activity, he recommended advising them to start with small amounts and then gradually increase frequency, intensity, and duration over time.
Dr. Robblee follows a similar approach, taking into account each patient’s particular circumstances and any medications they’re taking, including the side effects of those medications.
“It’s about starting where they are,” Dr. Robblee said. “Some patients, despite having severe migraine, have built themselves up so they’re doing exercise three or four times per week, or every day, and I have other people who never exercise,” she said. “For those patients who are very sedentary, if I can get them to start with 5 minutes per week so they have that sense of accomplishment, then that’s where I start. Then slowly build it up over time. Like most things in the migraine world, I individualize it for the person.”
Dr. Bond offered the following specific tips to clinicians in educating and encouraging patients to increase physical activity:
- Educate patients regarding the short-and long-term benefits of moving more and sitting less, both for their migraines and for overall health.
- Correct misconceptions about the negative effects of physical activity as it relates to migraines.
- Personalize the rationale for physical activity to that patient’s specific values and personal goals.
- Encourage patients to use an activity tracker, both for tracking physical activity and sedentary time, and to monitor migraine attacks, stress, energy levels, and fatigue on days they do and do not exercise.
- Help patients set goals for eventually meeting MVPA recommendations and interrupting prolonged periods of sitting with brief movement breaks.
- Help patients identify rewards for meeting goals that are tied to the activity, such as new exercise clothing.
- Encourage patients to identify a consistent time for physical activity each day to establish a habit, “ideally in the morning before barriers and life get in the way,” he said.
Eventually, physical activity itself should become intrinsically rewarding, Dr. Bond said.
“To limit sitting and encourage more movement throughout the day, we want to make the choice to engage in physical activity easier by adding environmental cues that encourage physical activity,” he said. “Conversely, we want to make the choice to engage in sedentary behavior more difficult by increasing the amount of effort that is required to engage in these behaviors.”
Dr. Robblee found Dr. Bond’s emphasis on sitting less – distinct from moving more – a helpful frame to consider with her patients. “I really like the approach of looking at it from that approach: in addition to how do we get you up and moving, how much time are you sitting, and how often can you break that up into smaller increments so that you’re up more often?” Dr. Robblee said. “That sometimes sounds less scary than ‘let’s get you exercising.’ So ‘let’s get you sitting a little bit less.’ I think that is something I might start to adopt.”
No external funding was noted. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem. Dr. Bond reported no disclosures.
FROM AHS 2021
Topical histone deacetylase inhibitor reduced BCC size in phase 2 study
according to research presented at the annual meeting of the Society for Investigative Dermatology.
“Our results demonstrate a clinically significant decrease in tumor size in response to 6 weeks of topical 1% remetinostat therapy in 70% of per-protocol tumors, with 55% reaching complete pathological resolution,” James M. Kilgour, MD, a postdoctoral research fellow at the Sarin Lab at Stanford (Calif.) University, said at the meeting.
Surgical excision is the preferred treatment for BCC, but there is still a need for noninvasive treatment options, Dr. Kilgour said. “Given the potential morbidity associated with excision, particularly for patients experiencing multiple or recurrent tumors, such as the immunosuppressed or patients with Gorlin syndrome, an effective and tolerable topical therapy would be a significant benefit,” he noted.
Previously, in an in silico screen experiment, Dr. Kilgour and colleagues identified HDAC inhibitors as a “top predicted therapeutic” for BCC treatment, and found that in mice studies, HDAC inhibitors were able to suppress the growth of BCC cell lines and BCC allografts.
Remetinostat, a pan-HDAC inhibitor, is being investigated as a treatment for cutaneous T-cell lymphoma.
HDAC inhibitors are thought to “alter expression of key oncogenes and tumor suppressors through epigenetic modification of histone and nonhistone proteins,” he noted.
To evaluate the efficacy of topical remetinostat for BCC, the investigators enrolled 30 patients with 49 BCC tumors in a phase 2, open-label, single-arm trial. Participants had tumors that were greater than 5 mm in diameter and had been referred to surgery at Stanford before enrollment. Patients were a mean of 59 years old, 63% were men, and 90% were White; 59.2% of participants had tumors with a diameter greater than 10 mm, the rest had tumors with a diameter of 10 mm or less.
After the tumors were photographed and measured, participants received 6 weeks of topical remetinostat therapy, followed by final measurement and photography of the tumors at 8 weeks and surgical excision. Topical remetinostat 1% gel was applied three times per day under bandage occlusion.
Overall, 25 participants with 33 tumors were included in the per-protocol analysis. At 8 weeks, there was at least a 30% decrease in diameter from baseline for 69.7% of tumors in these patients, with 17 of 33 tumors showing a complete response by week 8.
Regarding tumor subtypes, there was a 100% overall response rate for the 6 superficial BCC tumors (1 partial response, 5 complete responses), a 68.2% ORR for the 22 nodular tumors (5 partial responses, 10 complete responses), and a 66.7% ORR for the 3 infiltrative tumors (no partial responses, 2 complete responses). There were no partial or complete responses for the two micronodular tumors.
Most adverse events in the study were localized drug reactions, with no serious or systemic adverse events, Dr. Kilgour noted, with 10 tumors demonstrating either no reaction or a grade 1 reaction, and 23 tumors having a grade 2 or grade 3 response.
The investigators also used imaging (ImageJ) software to evaluate the average decrease in cross-sectional tumor area. The results of the analysis showed an average decrease at 8 weeks from baseline of 71.5%. In addition, histological assessment at 8 weeks demonstrated that 54.8% of tumors had complete pathological resolution.
“In the future, we advocate for a follow-up blinded, randomized, controlled trial of remetinostat with greater participant diversity,” Dr. Kilgour said. “Specifically, greater power is needed to understand which histological subtypes of BCC will respond best to the treatment and we need to understand the long-term durability of tumor resolution.”
Remetinostat promising as topical BCC therapy
In an interview, Beth G. Goldstein, MD, a dermatologist and Mohs surgeon in Chapel Hill, N.C., noted that the preliminary study was “an exciting report of a safe, well-tolerated nonsurgical option for patients with superficial BCCs on the trunk and extremities,” which has potential to be used in the future for nonsuperficial BCCs. The study shows that superficial BCCs can respond at a rate of 100% on nonfacial areas, said Dr. Goldstein, who was not involved in the research. “These lesions can be quite large with higher chances of recurrence and difficulty with wound care.
“This type of directed therapy hopefully continues to be perfected for treatment of BCC that avoids scarring and is well tolerated,” she added.
Dr. Goldstein commented that complete pathological resolution of 54.8% “was still unacceptably low for the remaining tumor types.” For those cases, she said remetinostat could possibly “provide a topical option as an adjunctive treatment for potentially reducing the size of the BCC prior to surgical removal,” as an alternative to a systemic therapy like vismodegib (Erivedge).
Dr. Goldstein said the strengths of the study were in the variety of tumors, close follow-up with histologic evaluation and safety signals. In terms of limitations, she said whether there were any cases of Gorlin syndrome was not clear. In addition, at least 30% of BCCs have a mixed tumor type on Mohs surgery that differs from the original biopsy, and “there was no mention if the residual tumor remained with the same histology,” she said.
In the future, a large, randomized trial is warranted to stratify for Gorlin syndrome, patients who are immunosuppressed, and additional tumor types that were underrepresented in this study, such as micronodular tumors, Dr. Goldstein said. Future studies also should examine how remetinostat impacts BCC in facial areas, the effect of multiple applications, and how the therapy performs as an adjunctive treatment before surgery.
This study was funded by Medivir, the Damon Runyon Foundation, National Cancer Institute, an American Skin Association Hambrick Medical Student grant, and Stanford Medical Scholars. Dr. Kilgour and Dr. Goldstein reported no relevant financial disclosures.
according to research presented at the annual meeting of the Society for Investigative Dermatology.
“Our results demonstrate a clinically significant decrease in tumor size in response to 6 weeks of topical 1% remetinostat therapy in 70% of per-protocol tumors, with 55% reaching complete pathological resolution,” James M. Kilgour, MD, a postdoctoral research fellow at the Sarin Lab at Stanford (Calif.) University, said at the meeting.
Surgical excision is the preferred treatment for BCC, but there is still a need for noninvasive treatment options, Dr. Kilgour said. “Given the potential morbidity associated with excision, particularly for patients experiencing multiple or recurrent tumors, such as the immunosuppressed or patients with Gorlin syndrome, an effective and tolerable topical therapy would be a significant benefit,” he noted.
Previously, in an in silico screen experiment, Dr. Kilgour and colleagues identified HDAC inhibitors as a “top predicted therapeutic” for BCC treatment, and found that in mice studies, HDAC inhibitors were able to suppress the growth of BCC cell lines and BCC allografts.
Remetinostat, a pan-HDAC inhibitor, is being investigated as a treatment for cutaneous T-cell lymphoma.
HDAC inhibitors are thought to “alter expression of key oncogenes and tumor suppressors through epigenetic modification of histone and nonhistone proteins,” he noted.
To evaluate the efficacy of topical remetinostat for BCC, the investigators enrolled 30 patients with 49 BCC tumors in a phase 2, open-label, single-arm trial. Participants had tumors that were greater than 5 mm in diameter and had been referred to surgery at Stanford before enrollment. Patients were a mean of 59 years old, 63% were men, and 90% were White; 59.2% of participants had tumors with a diameter greater than 10 mm, the rest had tumors with a diameter of 10 mm or less.
After the tumors were photographed and measured, participants received 6 weeks of topical remetinostat therapy, followed by final measurement and photography of the tumors at 8 weeks and surgical excision. Topical remetinostat 1% gel was applied three times per day under bandage occlusion.
Overall, 25 participants with 33 tumors were included in the per-protocol analysis. At 8 weeks, there was at least a 30% decrease in diameter from baseline for 69.7% of tumors in these patients, with 17 of 33 tumors showing a complete response by week 8.
Regarding tumor subtypes, there was a 100% overall response rate for the 6 superficial BCC tumors (1 partial response, 5 complete responses), a 68.2% ORR for the 22 nodular tumors (5 partial responses, 10 complete responses), and a 66.7% ORR for the 3 infiltrative tumors (no partial responses, 2 complete responses). There were no partial or complete responses for the two micronodular tumors.
Most adverse events in the study were localized drug reactions, with no serious or systemic adverse events, Dr. Kilgour noted, with 10 tumors demonstrating either no reaction or a grade 1 reaction, and 23 tumors having a grade 2 or grade 3 response.
The investigators also used imaging (ImageJ) software to evaluate the average decrease in cross-sectional tumor area. The results of the analysis showed an average decrease at 8 weeks from baseline of 71.5%. In addition, histological assessment at 8 weeks demonstrated that 54.8% of tumors had complete pathological resolution.
“In the future, we advocate for a follow-up blinded, randomized, controlled trial of remetinostat with greater participant diversity,” Dr. Kilgour said. “Specifically, greater power is needed to understand which histological subtypes of BCC will respond best to the treatment and we need to understand the long-term durability of tumor resolution.”
Remetinostat promising as topical BCC therapy
In an interview, Beth G. Goldstein, MD, a dermatologist and Mohs surgeon in Chapel Hill, N.C., noted that the preliminary study was “an exciting report of a safe, well-tolerated nonsurgical option for patients with superficial BCCs on the trunk and extremities,” which has potential to be used in the future for nonsuperficial BCCs. The study shows that superficial BCCs can respond at a rate of 100% on nonfacial areas, said Dr. Goldstein, who was not involved in the research. “These lesions can be quite large with higher chances of recurrence and difficulty with wound care.
“This type of directed therapy hopefully continues to be perfected for treatment of BCC that avoids scarring and is well tolerated,” she added.
Dr. Goldstein commented that complete pathological resolution of 54.8% “was still unacceptably low for the remaining tumor types.” For those cases, she said remetinostat could possibly “provide a topical option as an adjunctive treatment for potentially reducing the size of the BCC prior to surgical removal,” as an alternative to a systemic therapy like vismodegib (Erivedge).
Dr. Goldstein said the strengths of the study were in the variety of tumors, close follow-up with histologic evaluation and safety signals. In terms of limitations, she said whether there were any cases of Gorlin syndrome was not clear. In addition, at least 30% of BCCs have a mixed tumor type on Mohs surgery that differs from the original biopsy, and “there was no mention if the residual tumor remained with the same histology,” she said.
In the future, a large, randomized trial is warranted to stratify for Gorlin syndrome, patients who are immunosuppressed, and additional tumor types that were underrepresented in this study, such as micronodular tumors, Dr. Goldstein said. Future studies also should examine how remetinostat impacts BCC in facial areas, the effect of multiple applications, and how the therapy performs as an adjunctive treatment before surgery.
This study was funded by Medivir, the Damon Runyon Foundation, National Cancer Institute, an American Skin Association Hambrick Medical Student grant, and Stanford Medical Scholars. Dr. Kilgour and Dr. Goldstein reported no relevant financial disclosures.
according to research presented at the annual meeting of the Society for Investigative Dermatology.
“Our results demonstrate a clinically significant decrease in tumor size in response to 6 weeks of topical 1% remetinostat therapy in 70% of per-protocol tumors, with 55% reaching complete pathological resolution,” James M. Kilgour, MD, a postdoctoral research fellow at the Sarin Lab at Stanford (Calif.) University, said at the meeting.
Surgical excision is the preferred treatment for BCC, but there is still a need for noninvasive treatment options, Dr. Kilgour said. “Given the potential morbidity associated with excision, particularly for patients experiencing multiple or recurrent tumors, such as the immunosuppressed or patients with Gorlin syndrome, an effective and tolerable topical therapy would be a significant benefit,” he noted.
Previously, in an in silico screen experiment, Dr. Kilgour and colleagues identified HDAC inhibitors as a “top predicted therapeutic” for BCC treatment, and found that in mice studies, HDAC inhibitors were able to suppress the growth of BCC cell lines and BCC allografts.
Remetinostat, a pan-HDAC inhibitor, is being investigated as a treatment for cutaneous T-cell lymphoma.
HDAC inhibitors are thought to “alter expression of key oncogenes and tumor suppressors through epigenetic modification of histone and nonhistone proteins,” he noted.
To evaluate the efficacy of topical remetinostat for BCC, the investigators enrolled 30 patients with 49 BCC tumors in a phase 2, open-label, single-arm trial. Participants had tumors that were greater than 5 mm in diameter and had been referred to surgery at Stanford before enrollment. Patients were a mean of 59 years old, 63% were men, and 90% were White; 59.2% of participants had tumors with a diameter greater than 10 mm, the rest had tumors with a diameter of 10 mm or less.
After the tumors were photographed and measured, participants received 6 weeks of topical remetinostat therapy, followed by final measurement and photography of the tumors at 8 weeks and surgical excision. Topical remetinostat 1% gel was applied three times per day under bandage occlusion.
Overall, 25 participants with 33 tumors were included in the per-protocol analysis. At 8 weeks, there was at least a 30% decrease in diameter from baseline for 69.7% of tumors in these patients, with 17 of 33 tumors showing a complete response by week 8.
Regarding tumor subtypes, there was a 100% overall response rate for the 6 superficial BCC tumors (1 partial response, 5 complete responses), a 68.2% ORR for the 22 nodular tumors (5 partial responses, 10 complete responses), and a 66.7% ORR for the 3 infiltrative tumors (no partial responses, 2 complete responses). There were no partial or complete responses for the two micronodular tumors.
Most adverse events in the study were localized drug reactions, with no serious or systemic adverse events, Dr. Kilgour noted, with 10 tumors demonstrating either no reaction or a grade 1 reaction, and 23 tumors having a grade 2 or grade 3 response.
The investigators also used imaging (ImageJ) software to evaluate the average decrease in cross-sectional tumor area. The results of the analysis showed an average decrease at 8 weeks from baseline of 71.5%. In addition, histological assessment at 8 weeks demonstrated that 54.8% of tumors had complete pathological resolution.
“In the future, we advocate for a follow-up blinded, randomized, controlled trial of remetinostat with greater participant diversity,” Dr. Kilgour said. “Specifically, greater power is needed to understand which histological subtypes of BCC will respond best to the treatment and we need to understand the long-term durability of tumor resolution.”
Remetinostat promising as topical BCC therapy
In an interview, Beth G. Goldstein, MD, a dermatologist and Mohs surgeon in Chapel Hill, N.C., noted that the preliminary study was “an exciting report of a safe, well-tolerated nonsurgical option for patients with superficial BCCs on the trunk and extremities,” which has potential to be used in the future for nonsuperficial BCCs. The study shows that superficial BCCs can respond at a rate of 100% on nonfacial areas, said Dr. Goldstein, who was not involved in the research. “These lesions can be quite large with higher chances of recurrence and difficulty with wound care.
“This type of directed therapy hopefully continues to be perfected for treatment of BCC that avoids scarring and is well tolerated,” she added.
Dr. Goldstein commented that complete pathological resolution of 54.8% “was still unacceptably low for the remaining tumor types.” For those cases, she said remetinostat could possibly “provide a topical option as an adjunctive treatment for potentially reducing the size of the BCC prior to surgical removal,” as an alternative to a systemic therapy like vismodegib (Erivedge).
Dr. Goldstein said the strengths of the study were in the variety of tumors, close follow-up with histologic evaluation and safety signals. In terms of limitations, she said whether there were any cases of Gorlin syndrome was not clear. In addition, at least 30% of BCCs have a mixed tumor type on Mohs surgery that differs from the original biopsy, and “there was no mention if the residual tumor remained with the same histology,” she said.
In the future, a large, randomized trial is warranted to stratify for Gorlin syndrome, patients who are immunosuppressed, and additional tumor types that were underrepresented in this study, such as micronodular tumors, Dr. Goldstein said. Future studies also should examine how remetinostat impacts BCC in facial areas, the effect of multiple applications, and how the therapy performs as an adjunctive treatment before surgery.
This study was funded by Medivir, the Damon Runyon Foundation, National Cancer Institute, an American Skin Association Hambrick Medical Student grant, and Stanford Medical Scholars. Dr. Kilgour and Dr. Goldstein reported no relevant financial disclosures.
FROM SID 2021
Ubrogepant effective for acute migraine even with preventive monoclonal antibody therapy
according to preliminary findings presented at the American Headache Society’s 2021 annual meeting.
“Because prevention [with mAbs] is rarely 100% effective, virtually everyone on preventive treatment needs to also take acute treatment,” presenter Richard B. Lipton, MD, a professor of neurology and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said in an interview after his presentation. He explained that ubrogepant, a small-molecule CGRP receptor blocker, is approved for acute treatment of migraine, while mAbs, which block the CGRP receptor or CGRP itself, are approved for prevention. “Many people predicted that gepants would not work in people on CGRP-targeted mAbs because of overlapping mechanisms.”
Dr. Lipton himself was not surprised by the findings, however. “For me, the surprise was that ubrogepant worked so well,” he said.
Novel data collection
Uniquely, his study used an entirely remote design with mobile applications to safely evaluate the drug’s real-world effectiveness in the midst of the COVID-19 pandemic. The prospective, observational study used the mobile app Migraine Buddy to collect data and assess outcomes from the use of 50 mg or 100 mg of ubrogepant along with a mAb, onabotA, or both.
In most migraine trials, researchers ask patients to track their symptoms in electronic diaries they learn how to use in the clinic.
“One disadvantage of this approach is that people usually need to carry two devices, the study device and their smartphone,” Dr. Lipton said in an interview. “In this study, people download an app at home to their smartphone and only need to carry one device. Though remote studies are particularly valuable in the time of pandemic, I believe that apps like Migraine Buddy are and will remain a valuable tool for addressing many research questions.”
Jennifer Robblee, MD, MSc, an assistant professor of neurology at Barrow Neurological Institute in Phoenix, viewed the presentation and was also impressed with the novel use of a smartphone app to conduct the study. “I think that was a unique and cool demonstration of what can be done with the apps out there now,” Dr. Robblee said in an interview. “If you want to have really good tracking and more through tracking, apps like this are fabulous and are very patient forward and patient friendly.”
Combination therapy
The researchers invited 4,541 adults to participate in the study if they had previously reported at least three migraine attacks in the past 30 days and if they had treated at least three prior attacks with ubrogepant. The 483 participants who enrolled after consent and screening included 272 taking ubrogepant with mAb, 132 participants taking ubrogepant with onabotA, and 79 taking ubrogepant with both onabotA and mAb.
For 30 days, participants reported in the app’s diary their pain relief and the time elapsed since taking ubrogepant until they returned to normal functioning. Endpoints included meaningful pain relief – defined as “a level of pain relief that is meaningful to you” – and return to normal function at 2 and 4 hours.
During the study, 352 participants reported treating a migraine attack with a single dose of ubrogepant, and 78 participants treated migraine with two doses. The former group included 193 patients in the ubrogepant plus mAb group, 102 patients in the ubrogepant plus onabotA group, and 57 patients in the ubrogepant plus both group. Because of the limited enrollment in the second two arms, the data Dr. Lipton presented data only on the ubrogepant with mAb arm.
Most of this group (89.1%) was female, with an average age of 40 years and an average Migraine Disability Assessment score of 72.2. Most of the patients were taking erenumab (44.6%) or galcanezumab (34.2%) with the remaining patients taking fremanezumab (17.6%), eptinezumab (3.1%) or multiple mAbs (0.5%). Most participants (59.6%) were prescribed 100-mg ubrogepant dose while the remaining participants took 50 mg.
The analysis of the ubrogepant plus mAb group revealed that 64.2% of patients reported meaningful pain relief at 2 hours, and 84.5% had meaningful pain relief 4 hours after taking ubrogepant. The odds of achieving meaningful pain relief were statistically significant at both time points and remained significant after adjustment for participants’ age, Migraine Disability Assessment score and self-reported prescribed ubrogepant dose (P < .001).
“This study shows that in patients with migraine on CGRP-targeted monoclonal antibodies, ubrogepant is an acute treatment to consider for breakthrough headaches,” Dr. Lipton said. He added that they have now completed the study with more participants and begun analyzing all three groups.
“Full analyses will include data from multiple attacks, attacks treated with a second dose of ubrogepant, additional daily and 30-day effectiveness measures for use of ubrogepant with onabotA and use of ubrogepant with both onabotA and CGRP mAbs,” Dr. Lipton said.
While the findings did not surprise Dr. Robblee, she was happy to see a study that explicitly testing the combination of these treatments, especially given access challenges. “Right now, because treatments are new, we get a lot of insurance denials,” Dr. Robblee said in an interview. “It’s great to have a study out there that we can turn to and say, ‘hey, look, they had all these patients safely using these together.’ It’s going to help us improve access for patients.”
Though Dr. Robblee typically uses old-school pen-and-calendar diaries with her patients, she also sees potential for the use of apps going forward, just as she sees for virtual health care.
“I’ve found telemedicine in general to be a really great addition to the migraine world, and this plays into our ability to use telemedicine paired with tracking,” Dr. Robblee said. “In so many studies, we’re doing a diary anyway, so if there are standard diaries and programs we’re all using, that would be a nice way to do these.”
She notes that most symptom tracking for pain is subjective already, and these apps often include the options to print out the data or to export or transfer it electronically to physicians. “It’s giving us meaningful data,” she said.
The research was funded by AbbVie. Dr. Lipton has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector and Vedanta Research. He holds stock options in Biohaven and Ctrl M. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem.
according to preliminary findings presented at the American Headache Society’s 2021 annual meeting.
“Because prevention [with mAbs] is rarely 100% effective, virtually everyone on preventive treatment needs to also take acute treatment,” presenter Richard B. Lipton, MD, a professor of neurology and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said in an interview after his presentation. He explained that ubrogepant, a small-molecule CGRP receptor blocker, is approved for acute treatment of migraine, while mAbs, which block the CGRP receptor or CGRP itself, are approved for prevention. “Many people predicted that gepants would not work in people on CGRP-targeted mAbs because of overlapping mechanisms.”
Dr. Lipton himself was not surprised by the findings, however. “For me, the surprise was that ubrogepant worked so well,” he said.
Novel data collection
Uniquely, his study used an entirely remote design with mobile applications to safely evaluate the drug’s real-world effectiveness in the midst of the COVID-19 pandemic. The prospective, observational study used the mobile app Migraine Buddy to collect data and assess outcomes from the use of 50 mg or 100 mg of ubrogepant along with a mAb, onabotA, or both.
In most migraine trials, researchers ask patients to track their symptoms in electronic diaries they learn how to use in the clinic.
“One disadvantage of this approach is that people usually need to carry two devices, the study device and their smartphone,” Dr. Lipton said in an interview. “In this study, people download an app at home to their smartphone and only need to carry one device. Though remote studies are particularly valuable in the time of pandemic, I believe that apps like Migraine Buddy are and will remain a valuable tool for addressing many research questions.”
Jennifer Robblee, MD, MSc, an assistant professor of neurology at Barrow Neurological Institute in Phoenix, viewed the presentation and was also impressed with the novel use of a smartphone app to conduct the study. “I think that was a unique and cool demonstration of what can be done with the apps out there now,” Dr. Robblee said in an interview. “If you want to have really good tracking and more through tracking, apps like this are fabulous and are very patient forward and patient friendly.”
Combination therapy
The researchers invited 4,541 adults to participate in the study if they had previously reported at least three migraine attacks in the past 30 days and if they had treated at least three prior attacks with ubrogepant. The 483 participants who enrolled after consent and screening included 272 taking ubrogepant with mAb, 132 participants taking ubrogepant with onabotA, and 79 taking ubrogepant with both onabotA and mAb.
For 30 days, participants reported in the app’s diary their pain relief and the time elapsed since taking ubrogepant until they returned to normal functioning. Endpoints included meaningful pain relief – defined as “a level of pain relief that is meaningful to you” – and return to normal function at 2 and 4 hours.
During the study, 352 participants reported treating a migraine attack with a single dose of ubrogepant, and 78 participants treated migraine with two doses. The former group included 193 patients in the ubrogepant plus mAb group, 102 patients in the ubrogepant plus onabotA group, and 57 patients in the ubrogepant plus both group. Because of the limited enrollment in the second two arms, the data Dr. Lipton presented data only on the ubrogepant with mAb arm.
Most of this group (89.1%) was female, with an average age of 40 years and an average Migraine Disability Assessment score of 72.2. Most of the patients were taking erenumab (44.6%) or galcanezumab (34.2%) with the remaining patients taking fremanezumab (17.6%), eptinezumab (3.1%) or multiple mAbs (0.5%). Most participants (59.6%) were prescribed 100-mg ubrogepant dose while the remaining participants took 50 mg.
The analysis of the ubrogepant plus mAb group revealed that 64.2% of patients reported meaningful pain relief at 2 hours, and 84.5% had meaningful pain relief 4 hours after taking ubrogepant. The odds of achieving meaningful pain relief were statistically significant at both time points and remained significant after adjustment for participants’ age, Migraine Disability Assessment score and self-reported prescribed ubrogepant dose (P < .001).
“This study shows that in patients with migraine on CGRP-targeted monoclonal antibodies, ubrogepant is an acute treatment to consider for breakthrough headaches,” Dr. Lipton said. He added that they have now completed the study with more participants and begun analyzing all three groups.
“Full analyses will include data from multiple attacks, attacks treated with a second dose of ubrogepant, additional daily and 30-day effectiveness measures for use of ubrogepant with onabotA and use of ubrogepant with both onabotA and CGRP mAbs,” Dr. Lipton said.
While the findings did not surprise Dr. Robblee, she was happy to see a study that explicitly testing the combination of these treatments, especially given access challenges. “Right now, because treatments are new, we get a lot of insurance denials,” Dr. Robblee said in an interview. “It’s great to have a study out there that we can turn to and say, ‘hey, look, they had all these patients safely using these together.’ It’s going to help us improve access for patients.”
Though Dr. Robblee typically uses old-school pen-and-calendar diaries with her patients, she also sees potential for the use of apps going forward, just as she sees for virtual health care.
“I’ve found telemedicine in general to be a really great addition to the migraine world, and this plays into our ability to use telemedicine paired with tracking,” Dr. Robblee said. “In so many studies, we’re doing a diary anyway, so if there are standard diaries and programs we’re all using, that would be a nice way to do these.”
She notes that most symptom tracking for pain is subjective already, and these apps often include the options to print out the data or to export or transfer it electronically to physicians. “It’s giving us meaningful data,” she said.
The research was funded by AbbVie. Dr. Lipton has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector and Vedanta Research. He holds stock options in Biohaven and Ctrl M. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem.
according to preliminary findings presented at the American Headache Society’s 2021 annual meeting.
“Because prevention [with mAbs] is rarely 100% effective, virtually everyone on preventive treatment needs to also take acute treatment,” presenter Richard B. Lipton, MD, a professor of neurology and director of the Montefiore Headache Center at Albert Einstein College of Medicine, New York, said in an interview after his presentation. He explained that ubrogepant, a small-molecule CGRP receptor blocker, is approved for acute treatment of migraine, while mAbs, which block the CGRP receptor or CGRP itself, are approved for prevention. “Many people predicted that gepants would not work in people on CGRP-targeted mAbs because of overlapping mechanisms.”
Dr. Lipton himself was not surprised by the findings, however. “For me, the surprise was that ubrogepant worked so well,” he said.
Novel data collection
Uniquely, his study used an entirely remote design with mobile applications to safely evaluate the drug’s real-world effectiveness in the midst of the COVID-19 pandemic. The prospective, observational study used the mobile app Migraine Buddy to collect data and assess outcomes from the use of 50 mg or 100 mg of ubrogepant along with a mAb, onabotA, or both.
In most migraine trials, researchers ask patients to track their symptoms in electronic diaries they learn how to use in the clinic.
“One disadvantage of this approach is that people usually need to carry two devices, the study device and their smartphone,” Dr. Lipton said in an interview. “In this study, people download an app at home to their smartphone and only need to carry one device. Though remote studies are particularly valuable in the time of pandemic, I believe that apps like Migraine Buddy are and will remain a valuable tool for addressing many research questions.”
Jennifer Robblee, MD, MSc, an assistant professor of neurology at Barrow Neurological Institute in Phoenix, viewed the presentation and was also impressed with the novel use of a smartphone app to conduct the study. “I think that was a unique and cool demonstration of what can be done with the apps out there now,” Dr. Robblee said in an interview. “If you want to have really good tracking and more through tracking, apps like this are fabulous and are very patient forward and patient friendly.”
Combination therapy
The researchers invited 4,541 adults to participate in the study if they had previously reported at least three migraine attacks in the past 30 days and if they had treated at least three prior attacks with ubrogepant. The 483 participants who enrolled after consent and screening included 272 taking ubrogepant with mAb, 132 participants taking ubrogepant with onabotA, and 79 taking ubrogepant with both onabotA and mAb.
For 30 days, participants reported in the app’s diary their pain relief and the time elapsed since taking ubrogepant until they returned to normal functioning. Endpoints included meaningful pain relief – defined as “a level of pain relief that is meaningful to you” – and return to normal function at 2 and 4 hours.
During the study, 352 participants reported treating a migraine attack with a single dose of ubrogepant, and 78 participants treated migraine with two doses. The former group included 193 patients in the ubrogepant plus mAb group, 102 patients in the ubrogepant plus onabotA group, and 57 patients in the ubrogepant plus both group. Because of the limited enrollment in the second two arms, the data Dr. Lipton presented data only on the ubrogepant with mAb arm.
Most of this group (89.1%) was female, with an average age of 40 years and an average Migraine Disability Assessment score of 72.2. Most of the patients were taking erenumab (44.6%) or galcanezumab (34.2%) with the remaining patients taking fremanezumab (17.6%), eptinezumab (3.1%) or multiple mAbs (0.5%). Most participants (59.6%) were prescribed 100-mg ubrogepant dose while the remaining participants took 50 mg.
The analysis of the ubrogepant plus mAb group revealed that 64.2% of patients reported meaningful pain relief at 2 hours, and 84.5% had meaningful pain relief 4 hours after taking ubrogepant. The odds of achieving meaningful pain relief were statistically significant at both time points and remained significant after adjustment for participants’ age, Migraine Disability Assessment score and self-reported prescribed ubrogepant dose (P < .001).
“This study shows that in patients with migraine on CGRP-targeted monoclonal antibodies, ubrogepant is an acute treatment to consider for breakthrough headaches,” Dr. Lipton said. He added that they have now completed the study with more participants and begun analyzing all three groups.
“Full analyses will include data from multiple attacks, attacks treated with a second dose of ubrogepant, additional daily and 30-day effectiveness measures for use of ubrogepant with onabotA and use of ubrogepant with both onabotA and CGRP mAbs,” Dr. Lipton said.
While the findings did not surprise Dr. Robblee, she was happy to see a study that explicitly testing the combination of these treatments, especially given access challenges. “Right now, because treatments are new, we get a lot of insurance denials,” Dr. Robblee said in an interview. “It’s great to have a study out there that we can turn to and say, ‘hey, look, they had all these patients safely using these together.’ It’s going to help us improve access for patients.”
Though Dr. Robblee typically uses old-school pen-and-calendar diaries with her patients, she also sees potential for the use of apps going forward, just as she sees for virtual health care.
“I’ve found telemedicine in general to be a really great addition to the migraine world, and this plays into our ability to use telemedicine paired with tracking,” Dr. Robblee said. “In so many studies, we’re doing a diary anyway, so if there are standard diaries and programs we’re all using, that would be a nice way to do these.”
She notes that most symptom tracking for pain is subjective already, and these apps often include the options to print out the data or to export or transfer it electronically to physicians. “It’s giving us meaningful data,” she said.
The research was funded by AbbVie. Dr. Lipton has received honoraria or research support from AbbVie, Amgen, Biohaven, Dr. Reddy’s Laboratories, electroCore, Eli Lilly, eNeura Therapeutics, GlaxoSmithKline, Merck, Novartis, Teva, Vector and Vedanta Research. He holds stock options in Biohaven and Ctrl M. Dr. Robblee is a principal investigator for a study sponsored by Eli Lilly and receives stipends for MedLink Neurology and Neurodiem.
FROM AHS 2021
Cross-sectional study finds chronic skin conditions have highest opioid prescribing rates
at dermatology visits.
“Overall, opioid prescribing rates among dermatologists were low. However, dermatologists should remain aware of risk factors for long-term opioid use and consider using nonnarcotic or nonpharmacologic interventions when possible,” Sarah P. Pourali, a medical student at Vanderbilt University, Nashville, said at the annual meeting of the Society for Investigative Dermatology, where she presented the results.
Ms. Pourali said that although Mohs surgery and dermatologic procedures are the focus of “much of the literature” concerning opioid use in dermatology, there are limited data on medication prescribing patterns for other skin conditions treated by dermatologists.
She and her colleagues performed a cross-sectional study using data from the National Ambulatory Medical Care Survey (NAMCS) from 2009 to 2016 on 288,462,610 weighted dermatology visits. The researchers used International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes to identify dermatologic diseases. They also identified and grouped oral pain medication into the following categories: opiate analgesics, nonsteroidal anti-inflammatory drugs, acetaminophen, and gabapentin. A linear regression analysis was used to evaluate pain medicine prescribing each year, and the researchers used a logistic regression analysis to explore how opiate prescriptions were connected to patient clinical characteristics. The analysis was adjusted for age, gender, race, ethnicity, and region.
Overall, most dermatology visits were for patients older than 65 years (36.2%) and 45-64 years old (32.1%). Over half of the dermatologist visits were for women (56.4%) and most (92.2%) visits were for patients who were White (5.1 % were for patients who were Black); most were non-Hispanic or Latino (93.5%). Most dermatology visits were in the South (35.4%) and West (25.2%), followed by the Northeast (21.9%) and Midwest (17.5%).
Opioids were prescribed in 1.3% of the visits, Ms. Pourali said. In addition, 4.7% of visits included an NSAID prescription, 0.7% an acetaminophen prescription, and 0.6% a gabapentin prescription.
Dermatologic procedure visits accounted for 43.1% of opioid prescriptions, she noted. The most common skin conditions for which opioids were prescribed included vitiligo (10.3%), hemangioma (3.8%), pemphigus (3.6%), atopic dermatitis (3.4%), and psoriasis (2.5%).
Although patients older than 65 years accounted for 36.2% of visits to dermatologists, 58.5% of opioids prescribed by dermatologists were for patients in this age group. “We hypothesize that this may be due to a higher proportion of older patients requiring skin cancer surgeries where a lot of opioids are prescribed within dermatology,” Ms. Pourali said.
The highest population-adjusted prescription rates for opiates were in the Northeast and Western regions of the United States, which “partially corroborates” previous studies that have found “higher rates of opioid prescribing in the southern and western U.S.,” she noted.
When evaluating risk-factors for long-term opiate use, Ms. Pourali and colleagues found opioids were also prescribed in 13.2% of visits where a benzodiazepine was prescribed (adjusted odds ratio, 8.17; 95% confidence interval, 5.3-12.7), 8.4% of visits where the patient had a substance abuse disorder (adjusted OR, 9.40; 95% CI, 2.0-44.4), 5.2% of visits with a patient who had depression (adjusted OR, 3.28; 95% CI, 2.0-5.4), and 2.4% of visits with a patient who used tobacco (adjusted OR, 1.09; 95% CI, 1.0-1.1).
Consider nonopioid postoperative pain management options
In an interview, Sailesh Konda, MD, associate clinical professor of dermatology and director of Mohs surgery and surgical dermatology at the University of Florida, Gainesville, who was not involved with the research, noted the finding in the study that vitiligo, hemangioma, pemphigus, AD, and psoriasis were diagnoses with the highest rates of opioid prescription was surprising. “In general, these are conditions that are not routinely managed with opioids,” he said.
NAMCS contains a primary diagnosis field and space for four additional diagnoses such as chronic conditions, as well as thirty fields for medications. “If an opioid was prescribed at a visit, it could have been prescribed for any of the diagnoses related to the visit,” Dr. Konda said. “Additionally, for those opioid prescriptions associated with dermatologic procedures, it would have been helpful to have a breakdown of the specific procedures.”
Dr. Konda compared these results to a recent study of opioid prescribing patterns in the dermatology Medicare population, which found that 93.9% of the top 1% of opioid prescribers were dermatologists working in a surgical practice.
He said that recommendations for opioid prescribing should be developed for general dermatology as they have been for Mohs surgery and dermatologic surgery. For dermatologists currently prescribing opioids, he recommended monitoring prescribing patterns and to “consider nonopioid interventions, such as acetaminophen plus ibuprofen, which has been found to effectively control postoperative pain with fewer complications.”
Ms. Pourali reports no relevant financial disclosures. Her coauthors included the principal investigator, April Armstrong, MD, MPH, professor of dermatology, University of Southern California, Los Angeles. Dr. Konda reports no relevant financial disclosures.
at dermatology visits.
“Overall, opioid prescribing rates among dermatologists were low. However, dermatologists should remain aware of risk factors for long-term opioid use and consider using nonnarcotic or nonpharmacologic interventions when possible,” Sarah P. Pourali, a medical student at Vanderbilt University, Nashville, said at the annual meeting of the Society for Investigative Dermatology, where she presented the results.
Ms. Pourali said that although Mohs surgery and dermatologic procedures are the focus of “much of the literature” concerning opioid use in dermatology, there are limited data on medication prescribing patterns for other skin conditions treated by dermatologists.
She and her colleagues performed a cross-sectional study using data from the National Ambulatory Medical Care Survey (NAMCS) from 2009 to 2016 on 288,462,610 weighted dermatology visits. The researchers used International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes to identify dermatologic diseases. They also identified and grouped oral pain medication into the following categories: opiate analgesics, nonsteroidal anti-inflammatory drugs, acetaminophen, and gabapentin. A linear regression analysis was used to evaluate pain medicine prescribing each year, and the researchers used a logistic regression analysis to explore how opiate prescriptions were connected to patient clinical characteristics. The analysis was adjusted for age, gender, race, ethnicity, and region.
Overall, most dermatology visits were for patients older than 65 years (36.2%) and 45-64 years old (32.1%). Over half of the dermatologist visits were for women (56.4%) and most (92.2%) visits were for patients who were White (5.1 % were for patients who were Black); most were non-Hispanic or Latino (93.5%). Most dermatology visits were in the South (35.4%) and West (25.2%), followed by the Northeast (21.9%) and Midwest (17.5%).
Opioids were prescribed in 1.3% of the visits, Ms. Pourali said. In addition, 4.7% of visits included an NSAID prescription, 0.7% an acetaminophen prescription, and 0.6% a gabapentin prescription.
Dermatologic procedure visits accounted for 43.1% of opioid prescriptions, she noted. The most common skin conditions for which opioids were prescribed included vitiligo (10.3%), hemangioma (3.8%), pemphigus (3.6%), atopic dermatitis (3.4%), and psoriasis (2.5%).
Although patients older than 65 years accounted for 36.2% of visits to dermatologists, 58.5% of opioids prescribed by dermatologists were for patients in this age group. “We hypothesize that this may be due to a higher proportion of older patients requiring skin cancer surgeries where a lot of opioids are prescribed within dermatology,” Ms. Pourali said.
The highest population-adjusted prescription rates for opiates were in the Northeast and Western regions of the United States, which “partially corroborates” previous studies that have found “higher rates of opioid prescribing in the southern and western U.S.,” she noted.
When evaluating risk-factors for long-term opiate use, Ms. Pourali and colleagues found opioids were also prescribed in 13.2% of visits where a benzodiazepine was prescribed (adjusted odds ratio, 8.17; 95% confidence interval, 5.3-12.7), 8.4% of visits where the patient had a substance abuse disorder (adjusted OR, 9.40; 95% CI, 2.0-44.4), 5.2% of visits with a patient who had depression (adjusted OR, 3.28; 95% CI, 2.0-5.4), and 2.4% of visits with a patient who used tobacco (adjusted OR, 1.09; 95% CI, 1.0-1.1).
Consider nonopioid postoperative pain management options
In an interview, Sailesh Konda, MD, associate clinical professor of dermatology and director of Mohs surgery and surgical dermatology at the University of Florida, Gainesville, who was not involved with the research, noted the finding in the study that vitiligo, hemangioma, pemphigus, AD, and psoriasis were diagnoses with the highest rates of opioid prescription was surprising. “In general, these are conditions that are not routinely managed with opioids,” he said.
NAMCS contains a primary diagnosis field and space for four additional diagnoses such as chronic conditions, as well as thirty fields for medications. “If an opioid was prescribed at a visit, it could have been prescribed for any of the diagnoses related to the visit,” Dr. Konda said. “Additionally, for those opioid prescriptions associated with dermatologic procedures, it would have been helpful to have a breakdown of the specific procedures.”
Dr. Konda compared these results to a recent study of opioid prescribing patterns in the dermatology Medicare population, which found that 93.9% of the top 1% of opioid prescribers were dermatologists working in a surgical practice.
He said that recommendations for opioid prescribing should be developed for general dermatology as they have been for Mohs surgery and dermatologic surgery. For dermatologists currently prescribing opioids, he recommended monitoring prescribing patterns and to “consider nonopioid interventions, such as acetaminophen plus ibuprofen, which has been found to effectively control postoperative pain with fewer complications.”
Ms. Pourali reports no relevant financial disclosures. Her coauthors included the principal investigator, April Armstrong, MD, MPH, professor of dermatology, University of Southern California, Los Angeles. Dr. Konda reports no relevant financial disclosures.
at dermatology visits.
“Overall, opioid prescribing rates among dermatologists were low. However, dermatologists should remain aware of risk factors for long-term opioid use and consider using nonnarcotic or nonpharmacologic interventions when possible,” Sarah P. Pourali, a medical student at Vanderbilt University, Nashville, said at the annual meeting of the Society for Investigative Dermatology, where she presented the results.
Ms. Pourali said that although Mohs surgery and dermatologic procedures are the focus of “much of the literature” concerning opioid use in dermatology, there are limited data on medication prescribing patterns for other skin conditions treated by dermatologists.
She and her colleagues performed a cross-sectional study using data from the National Ambulatory Medical Care Survey (NAMCS) from 2009 to 2016 on 288,462,610 weighted dermatology visits. The researchers used International Classification of Diseases, Ninth Revision (ICD-9) and ICD-10 codes to identify dermatologic diseases. They also identified and grouped oral pain medication into the following categories: opiate analgesics, nonsteroidal anti-inflammatory drugs, acetaminophen, and gabapentin. A linear regression analysis was used to evaluate pain medicine prescribing each year, and the researchers used a logistic regression analysis to explore how opiate prescriptions were connected to patient clinical characteristics. The analysis was adjusted for age, gender, race, ethnicity, and region.
Overall, most dermatology visits were for patients older than 65 years (36.2%) and 45-64 years old (32.1%). Over half of the dermatologist visits were for women (56.4%) and most (92.2%) visits were for patients who were White (5.1 % were for patients who were Black); most were non-Hispanic or Latino (93.5%). Most dermatology visits were in the South (35.4%) and West (25.2%), followed by the Northeast (21.9%) and Midwest (17.5%).
Opioids were prescribed in 1.3% of the visits, Ms. Pourali said. In addition, 4.7% of visits included an NSAID prescription, 0.7% an acetaminophen prescription, and 0.6% a gabapentin prescription.
Dermatologic procedure visits accounted for 43.1% of opioid prescriptions, she noted. The most common skin conditions for which opioids were prescribed included vitiligo (10.3%), hemangioma (3.8%), pemphigus (3.6%), atopic dermatitis (3.4%), and psoriasis (2.5%).
Although patients older than 65 years accounted for 36.2% of visits to dermatologists, 58.5% of opioids prescribed by dermatologists were for patients in this age group. “We hypothesize that this may be due to a higher proportion of older patients requiring skin cancer surgeries where a lot of opioids are prescribed within dermatology,” Ms. Pourali said.
The highest population-adjusted prescription rates for opiates were in the Northeast and Western regions of the United States, which “partially corroborates” previous studies that have found “higher rates of opioid prescribing in the southern and western U.S.,” she noted.
When evaluating risk-factors for long-term opiate use, Ms. Pourali and colleagues found opioids were also prescribed in 13.2% of visits where a benzodiazepine was prescribed (adjusted odds ratio, 8.17; 95% confidence interval, 5.3-12.7), 8.4% of visits where the patient had a substance abuse disorder (adjusted OR, 9.40; 95% CI, 2.0-44.4), 5.2% of visits with a patient who had depression (adjusted OR, 3.28; 95% CI, 2.0-5.4), and 2.4% of visits with a patient who used tobacco (adjusted OR, 1.09; 95% CI, 1.0-1.1).
Consider nonopioid postoperative pain management options
In an interview, Sailesh Konda, MD, associate clinical professor of dermatology and director of Mohs surgery and surgical dermatology at the University of Florida, Gainesville, who was not involved with the research, noted the finding in the study that vitiligo, hemangioma, pemphigus, AD, and psoriasis were diagnoses with the highest rates of opioid prescription was surprising. “In general, these are conditions that are not routinely managed with opioids,” he said.
NAMCS contains a primary diagnosis field and space for four additional diagnoses such as chronic conditions, as well as thirty fields for medications. “If an opioid was prescribed at a visit, it could have been prescribed for any of the diagnoses related to the visit,” Dr. Konda said. “Additionally, for those opioid prescriptions associated with dermatologic procedures, it would have been helpful to have a breakdown of the specific procedures.”
Dr. Konda compared these results to a recent study of opioid prescribing patterns in the dermatology Medicare population, which found that 93.9% of the top 1% of opioid prescribers were dermatologists working in a surgical practice.
He said that recommendations for opioid prescribing should be developed for general dermatology as they have been for Mohs surgery and dermatologic surgery. For dermatologists currently prescribing opioids, he recommended monitoring prescribing patterns and to “consider nonopioid interventions, such as acetaminophen plus ibuprofen, which has been found to effectively control postoperative pain with fewer complications.”
Ms. Pourali reports no relevant financial disclosures. Her coauthors included the principal investigator, April Armstrong, MD, MPH, professor of dermatology, University of Southern California, Los Angeles. Dr. Konda reports no relevant financial disclosures.
FROM SID 2021
TNF inhibitors have delayed effect on spondyloarthritis radiographic progression
Tumor necrosis factor inhibitors reduce both spinal and sacroiliac radiographic progression in early axial spondyloarthritis (axSpA), but the effects take time.
According to data from the German Spondyloarthritis Inception Cohort (GESPIC), it could take 2-4 years after the initiation of TNF inhibitor treatment before x-rays will show any sign of a benefit in either the spine or sacroiliac joints (SIJ).
“The association between anti-TNF treatment and the retardation of radiographic spinal progression in spondyloarthritis appears to be time-shifted,” GESPIC study investigator Denis Poddubnyy, MD, said at the annual European Congress of Rheumatology.
Reporting the spinal findings, Dr. Poddubnyy, who is head of the rheumatology department at Campus Benjamin Franklin of the Charité University Hospital in Berlin noted that “at least 4 years of observation is required” to see an effect of TNF inhibitors on new bone formation. “This might be related to the intermediate and long-lasting process of bone repair that follows the resolution of inflammation and precedes the development of new bone,” he suggested.
The effect on the SIJ may precede the spinal damage, so it’s important to look at how anti-inflammatory treatment might affect the SIJ, Dr. Poddubnyy said in an interview. Results from the SIJ analysis, which were presented by Murat Torgutalp, MD, suggested that there might be a 2-year time lag between TNFi treatment and being able to see something on x-rays.
“Everybody in the past focused on the spine, considering that spinal changes are functionally more relevant than changes in the SIJ,” Dr. Poddubnyy observed.
Structural damage in the spine and SIJ in radiographic axSpA probably occur by different processes, he explained. While it’s more to do with new bone formation in the spine, it’s more to do with erosive damage followed by repair in the SIJ. “It is very likely that in the majority of patients we see that those two processes are somehow disconnected in time,” he suggested.
The GESPIC cohort provides a good base from which to examine the effects of TNF inhibitors on radiographic progression in patients with axSpA for several reasons, observed Dr. Poddubnyy. For one it was established in 2000, so “well before the introduction of TNF-alpha inhibitors.” That means that almost all patients would have been put on TNF inhibitors while enrolled in the cohort, he said, “so we could really follow up them prospectively for a few years.” In fact, just nine patients had been treated with TNF inhibitors at baseline.
Spinal findings
Although TNF inhibitors are widely accepted to be effective anti-inflammatory drugs that can relieve patients’ spinal symptoms, there were inconclusive data on whether they can also have an impact on radiographic progression.
To look at the possible immediate or later effect of TNF inhibitors on spinal radiographic progression, the GESPIC investigators looked at sets of radiographs, taken at least 2 years apart over a 10-year period, from 266 patients, 77 of whom who had been treated with a TNF inhibitor for at least 12 months or more. Overall, there were 103 2-year intervals covered by TNF inhibitor treatment of any duration, and 78 intervals in which treatment had lasted for at least 12 months.
“This cohort included patients with quite early disease, including both nonradiographic and radiographic forms,” Dr. Poddubnyy said, adding that some patients had been treated with a TNF inhibitor for up to 10 years.
While there were no significant changes in radiographic progression as measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) between patients who had and who had not received at least 12 months’ TNF inhibitor therapy in the first 2 years, there was a substantial difference after 4 years.
The mSASSS change in scores over 2 years in patients who were and were not treated with a TNF inhibitor for 12 months or more were a respective 0.35 and 0.81 (P = .047) considering treatment in the previous 2-year treatment period, and 0.33 and 0.77 (also P = .047) considering treatment in the prior 2-year treatment period and the current 2-year period.
“Our interpretation is that within the first 2 years we see a resolution of inflammation, a process of repair, maybe even a process of bone formation, but then if you continue this inflammation control for longer than 2 years, then we see the effect on structural damage,” Dr. Poddubnyy said.
SIJ findings
The SIJ analysis included 301 patients who had at least two sets of radiographs taken every 2 years over a 10-year follow-up period, 87 (28.9%) of whom had been treated with at least one TNF inhibitor during follow-up.
Radiographic SIJ progression was defined as the change in the sacroiliitis sum score over 2 years. Calculations considered both the current 2-year period and the previous 2-year period, as well as any use of TNF inhibitors or more than 12 months’ use.
There were no significant differences in sacroiliitis sum scores comparing people who were and were not treated with TNF inhibitors for at least 12 months in the current 2-year period. However, when the previous 2-year period was looked at there was a significant difference in the score between those who had and had not been treated for 12 or more months (0.15 vs. 0.27, respectively; P = .024).
“These data indicate that TNF inhibitors have a late effect,” Dr. Torgutalp said. “You cannot observe the effect of the TNF inhibitor on radiographic progression in the same interval, you have to wait to see this effect in the next interval,” he explained. That means that when a patient uses a TNF inhibitor, you must wait to see the effect on SIJ progression in the subsequent 2 years, he qualified.
Lessons for practice
“If we control inflammation, we might control structural damage progression,” Dr. Poddubnyy said.
If this is the case, then it is likely that other drugs that control inflammation in axSpA will have a similar effect, such as those that target interleukin-17 or Janus kinases. This is something in the future to look at in the GESPIC cohort once enough patient-years of data are available.
Early treatment is probably important, Dr. Poddubnyy suggested, “because in patients with early disease we can expect not that much structural damage at baseline.” Starting treatment early, at the inflammatory stage rather than at the stage where there was a lot of damage already there, could yield better results, he proposed.
“As a clinician, as a researcher, I would be really interested in demonstrating in a prospective, clinical trial that treating patients to target, achieving a remission, would be associated with retardation of structural damage progression. This has only been shown in observational studies so far, so this is an open question.”
Questions on adjustments made for confounding factors
Questions on the spinal presentation included whether there were any differences in NSAID use, to which Dr. Poddubnyy responded, “Patients on TNF inhibitors normally reduce NSAIDs. We adjusted, therefore, for NSAID use.”
The SIJ presentation garnered more questioning. Dr. Torgutalp qualified that both radiographic and nonradiographic patients had been included in the analysis, and “we observe the same effect.”
Asked how clinically relevant the findings were, he noted that, “to the best of our knowledge, this is the first data for sacroiliac joint progression.” The data for spinal progression seem to “reconcile the results from previous investigators,” where there had been some conflicting data on whether 2 or 4 years’ TNF-inhibitor therapy had any effect on radiographic progression.
“I don’t think you’ve adjusted for the baseline level of damage of the SIJ?” queried Pedro Machado, MD, of University College London Hospital. “As you know, in the spine, but also at the SIJ level, the baseline level of damage is usually one of the strongest predictors of further damage.”
This is not something that was adjusted for, Dr. Torgutalp conceded. “We will do it for further analysis,” he said.
Since 2010, GESPIC has been supported by grants from AbbVie. Dr. Poddubnyy reported financial relationships with AbbVie and numerous other pharmaceutical companies. Dr. Torgutalp had no relevant disclosures.
Tumor necrosis factor inhibitors reduce both spinal and sacroiliac radiographic progression in early axial spondyloarthritis (axSpA), but the effects take time.
According to data from the German Spondyloarthritis Inception Cohort (GESPIC), it could take 2-4 years after the initiation of TNF inhibitor treatment before x-rays will show any sign of a benefit in either the spine or sacroiliac joints (SIJ).
“The association between anti-TNF treatment and the retardation of radiographic spinal progression in spondyloarthritis appears to be time-shifted,” GESPIC study investigator Denis Poddubnyy, MD, said at the annual European Congress of Rheumatology.
Reporting the spinal findings, Dr. Poddubnyy, who is head of the rheumatology department at Campus Benjamin Franklin of the Charité University Hospital in Berlin noted that “at least 4 years of observation is required” to see an effect of TNF inhibitors on new bone formation. “This might be related to the intermediate and long-lasting process of bone repair that follows the resolution of inflammation and precedes the development of new bone,” he suggested.
The effect on the SIJ may precede the spinal damage, so it’s important to look at how anti-inflammatory treatment might affect the SIJ, Dr. Poddubnyy said in an interview. Results from the SIJ analysis, which were presented by Murat Torgutalp, MD, suggested that there might be a 2-year time lag between TNFi treatment and being able to see something on x-rays.
“Everybody in the past focused on the spine, considering that spinal changes are functionally more relevant than changes in the SIJ,” Dr. Poddubnyy observed.
Structural damage in the spine and SIJ in radiographic axSpA probably occur by different processes, he explained. While it’s more to do with new bone formation in the spine, it’s more to do with erosive damage followed by repair in the SIJ. “It is very likely that in the majority of patients we see that those two processes are somehow disconnected in time,” he suggested.
The GESPIC cohort provides a good base from which to examine the effects of TNF inhibitors on radiographic progression in patients with axSpA for several reasons, observed Dr. Poddubnyy. For one it was established in 2000, so “well before the introduction of TNF-alpha inhibitors.” That means that almost all patients would have been put on TNF inhibitors while enrolled in the cohort, he said, “so we could really follow up them prospectively for a few years.” In fact, just nine patients had been treated with TNF inhibitors at baseline.
Spinal findings
Although TNF inhibitors are widely accepted to be effective anti-inflammatory drugs that can relieve patients’ spinal symptoms, there were inconclusive data on whether they can also have an impact on radiographic progression.
To look at the possible immediate or later effect of TNF inhibitors on spinal radiographic progression, the GESPIC investigators looked at sets of radiographs, taken at least 2 years apart over a 10-year period, from 266 patients, 77 of whom who had been treated with a TNF inhibitor for at least 12 months or more. Overall, there were 103 2-year intervals covered by TNF inhibitor treatment of any duration, and 78 intervals in which treatment had lasted for at least 12 months.
“This cohort included patients with quite early disease, including both nonradiographic and radiographic forms,” Dr. Poddubnyy said, adding that some patients had been treated with a TNF inhibitor for up to 10 years.
While there were no significant changes in radiographic progression as measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) between patients who had and who had not received at least 12 months’ TNF inhibitor therapy in the first 2 years, there was a substantial difference after 4 years.
The mSASSS change in scores over 2 years in patients who were and were not treated with a TNF inhibitor for 12 months or more were a respective 0.35 and 0.81 (P = .047) considering treatment in the previous 2-year treatment period, and 0.33 and 0.77 (also P = .047) considering treatment in the prior 2-year treatment period and the current 2-year period.
“Our interpretation is that within the first 2 years we see a resolution of inflammation, a process of repair, maybe even a process of bone formation, but then if you continue this inflammation control for longer than 2 years, then we see the effect on structural damage,” Dr. Poddubnyy said.
SIJ findings
The SIJ analysis included 301 patients who had at least two sets of radiographs taken every 2 years over a 10-year follow-up period, 87 (28.9%) of whom had been treated with at least one TNF inhibitor during follow-up.
Radiographic SIJ progression was defined as the change in the sacroiliitis sum score over 2 years. Calculations considered both the current 2-year period and the previous 2-year period, as well as any use of TNF inhibitors or more than 12 months’ use.
There were no significant differences in sacroiliitis sum scores comparing people who were and were not treated with TNF inhibitors for at least 12 months in the current 2-year period. However, when the previous 2-year period was looked at there was a significant difference in the score between those who had and had not been treated for 12 or more months (0.15 vs. 0.27, respectively; P = .024).
“These data indicate that TNF inhibitors have a late effect,” Dr. Torgutalp said. “You cannot observe the effect of the TNF inhibitor on radiographic progression in the same interval, you have to wait to see this effect in the next interval,” he explained. That means that when a patient uses a TNF inhibitor, you must wait to see the effect on SIJ progression in the subsequent 2 years, he qualified.
Lessons for practice
“If we control inflammation, we might control structural damage progression,” Dr. Poddubnyy said.
If this is the case, then it is likely that other drugs that control inflammation in axSpA will have a similar effect, such as those that target interleukin-17 or Janus kinases. This is something in the future to look at in the GESPIC cohort once enough patient-years of data are available.
Early treatment is probably important, Dr. Poddubnyy suggested, “because in patients with early disease we can expect not that much structural damage at baseline.” Starting treatment early, at the inflammatory stage rather than at the stage where there was a lot of damage already there, could yield better results, he proposed.
“As a clinician, as a researcher, I would be really interested in demonstrating in a prospective, clinical trial that treating patients to target, achieving a remission, would be associated with retardation of structural damage progression. This has only been shown in observational studies so far, so this is an open question.”
Questions on adjustments made for confounding factors
Questions on the spinal presentation included whether there were any differences in NSAID use, to which Dr. Poddubnyy responded, “Patients on TNF inhibitors normally reduce NSAIDs. We adjusted, therefore, for NSAID use.”
The SIJ presentation garnered more questioning. Dr. Torgutalp qualified that both radiographic and nonradiographic patients had been included in the analysis, and “we observe the same effect.”
Asked how clinically relevant the findings were, he noted that, “to the best of our knowledge, this is the first data for sacroiliac joint progression.” The data for spinal progression seem to “reconcile the results from previous investigators,” where there had been some conflicting data on whether 2 or 4 years’ TNF-inhibitor therapy had any effect on radiographic progression.
“I don’t think you’ve adjusted for the baseline level of damage of the SIJ?” queried Pedro Machado, MD, of University College London Hospital. “As you know, in the spine, but also at the SIJ level, the baseline level of damage is usually one of the strongest predictors of further damage.”
This is not something that was adjusted for, Dr. Torgutalp conceded. “We will do it for further analysis,” he said.
Since 2010, GESPIC has been supported by grants from AbbVie. Dr. Poddubnyy reported financial relationships with AbbVie and numerous other pharmaceutical companies. Dr. Torgutalp had no relevant disclosures.
Tumor necrosis factor inhibitors reduce both spinal and sacroiliac radiographic progression in early axial spondyloarthritis (axSpA), but the effects take time.
According to data from the German Spondyloarthritis Inception Cohort (GESPIC), it could take 2-4 years after the initiation of TNF inhibitor treatment before x-rays will show any sign of a benefit in either the spine or sacroiliac joints (SIJ).
“The association between anti-TNF treatment and the retardation of radiographic spinal progression in spondyloarthritis appears to be time-shifted,” GESPIC study investigator Denis Poddubnyy, MD, said at the annual European Congress of Rheumatology.
Reporting the spinal findings, Dr. Poddubnyy, who is head of the rheumatology department at Campus Benjamin Franklin of the Charité University Hospital in Berlin noted that “at least 4 years of observation is required” to see an effect of TNF inhibitors on new bone formation. “This might be related to the intermediate and long-lasting process of bone repair that follows the resolution of inflammation and precedes the development of new bone,” he suggested.
The effect on the SIJ may precede the spinal damage, so it’s important to look at how anti-inflammatory treatment might affect the SIJ, Dr. Poddubnyy said in an interview. Results from the SIJ analysis, which were presented by Murat Torgutalp, MD, suggested that there might be a 2-year time lag between TNFi treatment and being able to see something on x-rays.
“Everybody in the past focused on the spine, considering that spinal changes are functionally more relevant than changes in the SIJ,” Dr. Poddubnyy observed.
Structural damage in the spine and SIJ in radiographic axSpA probably occur by different processes, he explained. While it’s more to do with new bone formation in the spine, it’s more to do with erosive damage followed by repair in the SIJ. “It is very likely that in the majority of patients we see that those two processes are somehow disconnected in time,” he suggested.
The GESPIC cohort provides a good base from which to examine the effects of TNF inhibitors on radiographic progression in patients with axSpA for several reasons, observed Dr. Poddubnyy. For one it was established in 2000, so “well before the introduction of TNF-alpha inhibitors.” That means that almost all patients would have been put on TNF inhibitors while enrolled in the cohort, he said, “so we could really follow up them prospectively for a few years.” In fact, just nine patients had been treated with TNF inhibitors at baseline.
Spinal findings
Although TNF inhibitors are widely accepted to be effective anti-inflammatory drugs that can relieve patients’ spinal symptoms, there were inconclusive data on whether they can also have an impact on radiographic progression.
To look at the possible immediate or later effect of TNF inhibitors on spinal radiographic progression, the GESPIC investigators looked at sets of radiographs, taken at least 2 years apart over a 10-year period, from 266 patients, 77 of whom who had been treated with a TNF inhibitor for at least 12 months or more. Overall, there were 103 2-year intervals covered by TNF inhibitor treatment of any duration, and 78 intervals in which treatment had lasted for at least 12 months.
“This cohort included patients with quite early disease, including both nonradiographic and radiographic forms,” Dr. Poddubnyy said, adding that some patients had been treated with a TNF inhibitor for up to 10 years.
While there were no significant changes in radiographic progression as measured using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS) between patients who had and who had not received at least 12 months’ TNF inhibitor therapy in the first 2 years, there was a substantial difference after 4 years.
The mSASSS change in scores over 2 years in patients who were and were not treated with a TNF inhibitor for 12 months or more were a respective 0.35 and 0.81 (P = .047) considering treatment in the previous 2-year treatment period, and 0.33 and 0.77 (also P = .047) considering treatment in the prior 2-year treatment period and the current 2-year period.
“Our interpretation is that within the first 2 years we see a resolution of inflammation, a process of repair, maybe even a process of bone formation, but then if you continue this inflammation control for longer than 2 years, then we see the effect on structural damage,” Dr. Poddubnyy said.
SIJ findings
The SIJ analysis included 301 patients who had at least two sets of radiographs taken every 2 years over a 10-year follow-up period, 87 (28.9%) of whom had been treated with at least one TNF inhibitor during follow-up.
Radiographic SIJ progression was defined as the change in the sacroiliitis sum score over 2 years. Calculations considered both the current 2-year period and the previous 2-year period, as well as any use of TNF inhibitors or more than 12 months’ use.
There were no significant differences in sacroiliitis sum scores comparing people who were and were not treated with TNF inhibitors for at least 12 months in the current 2-year period. However, when the previous 2-year period was looked at there was a significant difference in the score between those who had and had not been treated for 12 or more months (0.15 vs. 0.27, respectively; P = .024).
“These data indicate that TNF inhibitors have a late effect,” Dr. Torgutalp said. “You cannot observe the effect of the TNF inhibitor on radiographic progression in the same interval, you have to wait to see this effect in the next interval,” he explained. That means that when a patient uses a TNF inhibitor, you must wait to see the effect on SIJ progression in the subsequent 2 years, he qualified.
Lessons for practice
“If we control inflammation, we might control structural damage progression,” Dr. Poddubnyy said.
If this is the case, then it is likely that other drugs that control inflammation in axSpA will have a similar effect, such as those that target interleukin-17 or Janus kinases. This is something in the future to look at in the GESPIC cohort once enough patient-years of data are available.
Early treatment is probably important, Dr. Poddubnyy suggested, “because in patients with early disease we can expect not that much structural damage at baseline.” Starting treatment early, at the inflammatory stage rather than at the stage where there was a lot of damage already there, could yield better results, he proposed.
“As a clinician, as a researcher, I would be really interested in demonstrating in a prospective, clinical trial that treating patients to target, achieving a remission, would be associated with retardation of structural damage progression. This has only been shown in observational studies so far, so this is an open question.”
Questions on adjustments made for confounding factors
Questions on the spinal presentation included whether there were any differences in NSAID use, to which Dr. Poddubnyy responded, “Patients on TNF inhibitors normally reduce NSAIDs. We adjusted, therefore, for NSAID use.”
The SIJ presentation garnered more questioning. Dr. Torgutalp qualified that both radiographic and nonradiographic patients had been included in the analysis, and “we observe the same effect.”
Asked how clinically relevant the findings were, he noted that, “to the best of our knowledge, this is the first data for sacroiliac joint progression.” The data for spinal progression seem to “reconcile the results from previous investigators,” where there had been some conflicting data on whether 2 or 4 years’ TNF-inhibitor therapy had any effect on radiographic progression.
“I don’t think you’ve adjusted for the baseline level of damage of the SIJ?” queried Pedro Machado, MD, of University College London Hospital. “As you know, in the spine, but also at the SIJ level, the baseline level of damage is usually one of the strongest predictors of further damage.”
This is not something that was adjusted for, Dr. Torgutalp conceded. “We will do it for further analysis,” he said.
Since 2010, GESPIC has been supported by grants from AbbVie. Dr. Poddubnyy reported financial relationships with AbbVie and numerous other pharmaceutical companies. Dr. Torgutalp had no relevant disclosures.
FROM THE EULAR 2021 CONGRESS
Lenabasum missed mark for systemic sclerosis but may show promise for adjunctive therapy
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Although a phase 3 trial of lenabasum did not meet its primary endpoint for treatment of diffuse cutaneous systemic sclerosis (dcSSc), the drug led to more improvement in participants who were not receiving background immunosuppressant therapy during the trial than that seen in participants who received the placebo. Lenabasum also had a favorable safety profile, according to findings presented at the annual European Congress of Rheumatology.
The double-blind, randomized, placebo-controlled trial involved 363 adults who had had dcSSc for up to 6 years. One third of the participants received 5 mg of oral lenabasum, one third received 20 mg, and one third received a placebo. Patients already receiving immunosuppressant therapy could continue to receive it during the trial if the dose had been stable for at least 8 weeks before screening and corticosteroid therapy did not exceed 10 mg prednisone per day or the equivalent.
“The decision to allow background immunosuppressant therapies was made to reflect real-world clinical practice,” coprincipal investigator Robert Dr. Spiera, MD, director of the Vasculitis and Scleroderma Program at the Hospital for Special Surgery, New York, told attendees.
“It is surprising that we do not see any added efficacy of lenabasum in this trial, given the fact that the previous phase 2 trial in 42 patients did show a clear benefit of lenabasum over placebo in the same population,” Jeska K. de Vries-Bouwstra, MD, PhD, a rheumatologist at Leiden (the Netherlands) University Medical Center told this news organization. “Even more, the clinical response in the phase 2 study was supported by a greater change in gene expression in skin tissue of pathways involved in inflammation and fibrosis with lenabasum as compared to placebo.”
Background immunosuppressants contribute to unprecedented placebo responses
The researchers compared the ACR CRISS (Combined Response Index in Diffuse Cutaneous Systemic Sclerosis) score and several secondary endpoints at 52 weeks between the 123 participants who received the placebo and the 120 participants who received 20 mg of lenabasum. A total of 60% of the lenabasum group and 66% of the placebo group had a disease duration of 3 or fewer years, and the modified Rodnan skin score (mRSS) was 22 in the lenabasum group and 23.3 in the placebo group at baseline.
A large majority of participants in both groups – 89% in the lenabasum group and 84% in the placebo group – were receiving background immunosuppressant therapy during the trial. Specifically, 53% of each group was taking mycophenolate, and 23% of the lenabasum group and 32% of the placebo group were taking corticosteroids. In addition, 22% of the lenabasum group and 12% of the placebo group were on methotrexate, and 27% of the lenabasum group and 22% of the placebo group were on another immunosuppressant therapy.
Half of the placebo group and 58% of the lenabasum group were taking only one immunosuppressive therapy. About one-third of the lenabasum (32%) and placebo (34%) groups were taking two or more immunosuppressive therapies.
The primary endpoint at 52 weeks was not significantly different between the two groups: a CRISS score of 0.888 in the lenabasum group and 0.887 in the placebo group. A CRISS score of 0.6 or higher indicates likelihood that a patient improved on treatment. Patients with significant worsening of renal or cardiopulmonary involvement are classified as not improved (score of 0), regardless of improvements in other core items.
“We had very high CRISS scores in all three groups, and they were comparable in all three groups,” Dr. Spiera reported. Because improvement in placebo group far exceeded expectations, the researchers were unable to discern the treatment effect of lenabasum on top of the placebo effect.
The placebo group had better outcomes than expected because of the background immunosuppressant therapy, particularly the use of mycophenolate. When the researchers looked only at placebo participants, the CRISS score was 0.936 in the 97 patients receiving background immunosuppressant therapy of any kind and 0.935 in the 29 patients taking only mycophenolate with no other immunosuppressant therapy, compared with 0.417 in the 16 patients not receiving any background therapy.
In a prespecified analysis, the researchers investigated background immunosuppressive therapy as a mediator. The CRISS score for the 10 lenabasum participants not receiving background therapy was 0.811, compared with 0.417 seen in the placebo group patients not on background therapy.
Among the 173 participants taking mycophenolate in particular, the mycophenolate “had a statistically significant improvement on CRISS score that increased with each visit,” Dr. Spiera reported. The duration of mycophenolate therapy also affected efficacy results.
Patients who had been taking mycophenolate longer saw less improvement in their CRISS score over time. Those taking it more than 2 years at baseline had a CRISS score of 0.86, compared with 0.96 for those taking it for 1-2 years at baseline and 0.98 for those taking it from 6 months to 1 year at baseline. Those who had only been taking mycophenolate for up to 6 months at baseline had a CRISS score of 0.99. Meanwhile, patients not taking any background immunosuppressant therapies only had a CRISS score of about 0.35.
Changes in secondary endpoints followed same pattern as CRISS
The secondary endpoints similarly showed no statistically significant difference when comparing the lenabasum and placebo groups overall. These endpoints included change in mRSS score, change in forced vital capacity (FVC) percentage and volume, and change in the Health Assessment Questionnaire Disability Index (HAQ-DI) score.
However, the researchers again found that duration of background therapy affected FVC.
“You were more likely to have declined [in FVC] if you were on placebo and more likely to have improved or stayed stable if you were on lenabasum if you were a patient on more than 2 years of immunomodulatory therapy at baseline,” Dr. Spiera reported. “There was evidence for an effect of lenabasum on FVC suggested by post-hoc analyses that considered the effect of background immunosuppressive therapies on outcomes, but those results would require confirmation in additional studies to determine the potential of lenabasum for treating patients with diffuse cutaneous systemic sclerosis,” Dr. Spiera noted in his conclusions.
Serious adverse events occurred in 9.2% of the lenabasum group and 5.8% of the placebo group. Rates of severe adverse events were similar between the lenabasum (14.6%) and placebo (13%) groups.
Is there a subgroup for whom lenabasum would be efficacious?
Although De Vries-Bouwstra of Leiden University Medical Center acknowledged the role of mycophenolate in the trial, she does not think background therapy can totally explain the observation and speculated on other possibilities.
“For example, there were fewer males in the placebo group as compared to the phase 2 study. From previous cohort studies we know that males have higher risk of worsening of skin disease,” she said. “In addition, it could be worthwhile to evaluate antibody profiles of the population under study; some subpopulations defined by autoantibody have higher risk for skin progression, while others can show spontaneous improvement.”
Dr. De Vries-Bouwstra said that, although it’s not currently appropriate to advocate for lenabasum to treat dcSSc, it may eventually become an additional treatment in those who still show active skin or lung disease after 2 years of mycophenolate treatment if future research identifies a benefit from that application. She would also like to see an evaluation of lenabasum’s possible benefits in patients with very early and active inflammatory disease. “Ideally, one could stratify patients based on biomarkers reflecting activation in relevant pathways, for example by using gene expression analysis from skin tissue to stratify,” she said.
Jacob M. van Laar, MD, PhD, professor of rheumatology at University Medical Center Utrecht (the Netherlands), also commented on the potential differences in using the drug in early versus later disease.
“Based on ex vivo analyses of skin samples from systemic sclerosis patients, one would expect such a mechanism of action to be particularly relevant in very early disease, so the observation that it might also be effective at a later disease stage is interesting,” Dr. van Laar told this news organization. “We still have a lot to learn about this complex disease.”
Given that safety does not appear to be a major concern and that there may be a benefit in a subgroup of patients, Dr. van Laar also said he hoped “the company is not deterred by the seemingly negative result of the primary endpoint.”
Dr. Spiera expressed optimism about what this trial’s findings have revealed about management of dcSSc.
“Independent of what lenabasum did or didn’t do in this trial, I think there’s going to be a lot that we’re going to learn from this trial and that we’re already learning and analyzing right now about treating scleroderma,” he said in an interview.
He reiterated the value of allowing background therapy in the trial to ensure it better replicated real-world clinical practice.
“You’re not withholding therapies that we think are probably active from patients with active disease that, once you incur organ damage, is probably not going to be reversible,” Dr. Spiera said. “The downside is that it makes it harder to see an effect of a drug on top of the background therapy if that background therapy is effective. So what we saw in terms of this absence of benefit from lenabasum really may have been a ceiling effect.”
Nevertheless, Dr. Spiera said the findings still strongly suggest that lenabasum is an active compound.
“It’s not an enormously powerful effect, but it probably has a role as an adjunctive therapy in people on stable background therapy who have either plateaued or are getting worse,” he said. “The thing we have to keep in mind also is this was an incredibly safe therapy. It’s not immunosuppressive.”
The trial was funded by Corbus. Dr. Spiera has received grant support or consulting fees from Roche-Genentech, GlaxoSmithKline, Boehringer Ingelheim, Chemocentryx, Corbus, Formation Biologics, Inflarx, Kadmon, AstraZeneca, AbbVie, CSL Behring, Sanofi, and Janssen. Dr. De Vries-Bouwstra has received consulting fees from AbbVie and Boehringer Ingelheim and research grants from Galapagos and Janssen. Dr. Van Laar has received grant funding or personal fees from Arthrogen, Arxx Therapeutics, AstraZeneca, Bristol-Myers Squibb, Eli Lilly, Gesynta, Leadiant, Merck Sharp & Dohme, Roche, Sanofi, and Thermofisher.
A version of this article first appeared on Medscape.com.
Trial yields evidence that laser resurfacing may prevent NMSC in aged skin
A on treated areas, according to the results of a small, randomized trial.
“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”
Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.
To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.
Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m2 with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.
At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001, Dr. Wargo reported. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”
Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.
“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.
He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.
Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.
The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.
A on treated areas, according to the results of a small, randomized trial.
“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”
Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.
To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.
Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m2 with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.
At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001, Dr. Wargo reported. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”
Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.
“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.
He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.
Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.
The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.
A on treated areas, according to the results of a small, randomized trial.
“Previous research suggests a new model to explain why older patients obtain nonmelanoma skin cancer in areas of ongoing sun exposure,” presenting author Jeffrey Wargo, MD, said during the annual conference of the American Society for Laser Medicine and Surgery. “Insulinlike growth factor-1 produced by dermal fibroblasts dictates how overlying skin keratinocytes respond to UVB radiation. The skin of a patient aged in their 20s produces normal levels of healthy fibroblasts, normal levels of insulinlike growth factor 1, and appropriate UVB response via activation of nucleotide excision, repair, and DNA damage checkpoint-signaling systems.”
Older patients, meanwhile, have an increase in senescent fibroblasts, decreased insulinlike growth factor-1 (IGF-1), and an inappropriate UVB response to DNA damage, continued Dr. Wargo, a dermatologist at the Ohio State University Wexner Medical Center in Columbus. Previous studies conducted by his mentor, Jeffrey B. Travers, MD, PhD, a dermatologist and pharmacologist at Wright State University, Dayton, showed that fractionated laser resurfacing (FLR) restores UVB response in older patients’ skin by resulting in new fibroblasts and increased levels of IGF 2 years post wounding.
To determine if FLR of aged skin can prevent the development of actinic keratosis (AK) and nonmelanoma skin cancer, Dr. Travers and Dr. Wargo recruited 48 patients at the Dayton VA Medical Center who were 60 years or older and had at least five AKs on each arm that were 3 mm or smaller, with nothing concerning for skin cancer at the screening visit.
Randomization of which arm was treated was based on an odd or even Social Security Number. That arm was treated with the 2,790 nm Erbium:YSSG ablative laser at 120 J/m2 with one pass at 24% coverage from the elbow to hand dorsally. Previously published data reported outcomes for 30 of these patients at 3 and 6 months following treatment. Subsequent to that report, 18 additional subjects have been recruited to the study and follow-up has been extended. Of the 48 patients, 47 were male and their average age was 74, with a range between 61 and 87 years.
At 3 months following FLR, the ratio of AKs on the treated vs. untreated arms was reduced by fourfold, with a P value less than .00001, Dr. Wargo reported. “Throughout the current 30-month follow-up period, this ratio has been maintained,” he said. “In fact, none of the ratios determined at 3, 6, 12, 18, 24, or 30 months post FLR are significantly different. Hence, as described in our first report on this work, these data indicate FLR is an effective treatment for existing AKs. However, our model predicts that FLR treatment will also prevent the occurrence of new AK lesions.”
Among 19 of the study participants who have been followed out to 30 months, untreated arms continued to accumulate increasing number of AKs. In contrast, AKs on treated arms are decreasing with time, indicating the lack of newly initiated lesions.
“A second analysis of the data posits that, if FLR were only removing existing lesions, one would predict the number of AKs that were present at 3 months on both the untreated and FLR-treated [arms] would accumulate at the same rate subsequent to 3 months point in time,” Dr. Wargo said.
He pointed out that 12 patients were removed from the study: two at 12 months, one at 18 months, eight at 24 months, and one at 30 months, as they were found to have 20 or more AKs on their untreated arm and required treatment.
Over the entire study period, “consistent with the notion that FLR was preventing new actinic neoplasia, we noted a dramatic difference in numbers of nonmelanoma skin cancer diagnosed in the untreated areas (22) versus FLR treated areas (2),” Dr. Wargo said. The majority of nonmelanoma skin cancers diagnosed were SCC (17) and 5 basal cell carcinomas on the untreated arms, whereas the 2 diagnosed on the treated arm were SCC. “These studies indicate that a dermal-wounding strategy involving FLR, which upregulates dermal IGF-1 levels, not only treats AKs but prevents nonmelanoma skin cancer,” he said.
The study was funded by the National Institutes of Health. Dr. Travers is the principal investigator. Dr. Wargo reported having no financial disclosures.
FROM ASLMS 2021