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Pembrolizumab before surgery improves survival in early triple negative breast cancer
for improving survival in patients with early triple negative breast cancer (TNBC).
The findings were presented in Chicago June 4 and 5 at the annual meeting of the American Society of Clinical Oncology by study author Lajos Pusztai, MD, D.Phil, director of Breast Cancer Translational Research at Yale University, New Haven, Conn.
KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant setting.
The study included 1,174 patients (median age 49 years) with previously untreated stage II or III triple-negative breast cancer. Patients were randomly assigned to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After surgery, patients received pembrolizumab or placebeo for 9 cycles or until recurrence or unacceptable toxicity. The primary end points were pathological complete response and event-free survival.
A total of 784 patients were treated with pembrolizumab and chemotherapy, and the second group of 390 patients received a placebo and chemotherapy. After surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo and chemotherapy for every 3 weeks for up to nine cycles.
The estimated event-free survival at 36 months was 84.5% in the pembrolizumab-chemotherapy group, compared with 76.8% in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% confidence interval, 0.48 to 0.82; P <0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy.
At the first interim analysis, 64.8% achieved pathological complete response in the pembrolizumab group versus 51.2% in the placebo group. At the fourth interim analysis at 36 months, event-free survival was 76.8% in the placebo arm and 84.5% in the pembrolizumab arm. RCB-0 status was achieved by 63.4% and 56.2% of patients in the pembrolizumab and placebo arms, respectively.
Pembrolizumab did contribute immune-related adverse events, mostly grades 1-2, in about 17% of patients with thyroid function abnormalities most common with most occurring 20 weeks prior to surgical treatment.
Treatment with pembrolizumab added to chemotherapy, compared with chemotherapy alone, shifted residual cancer burden to lower categories across the entire spectrum of patients in the trial.
The hazard ratio for event-free survival with RCB-0, which Dr. Pusztai said is equivalent to a pathologic complete response (pCR), was 0.70 (0.38-1.31). For RCB-1 (minimal residual disease) it was 0.92 (0.39-2.20); for RCB-2 (moderate residual disease) it was 0.52 (0.32-0.82); and for RCB-3 (extensive residual disease) it was 1.24 (0.69-2.23).
“The most important finding is that patients in RCB-2, a group with a moderate amount of residual disease, experienced significant improvement with pembrolizumab. This clearly indicates not only that pembrolizumab leads to higher pCR rates but also that the pembrolizumCR/RCB-0 ... extends to patients who do not achieve pCR,” Dr. Pusztai said.
The benefit, he suggested, could be a result of the adjuvant pembrolizumab maintenance phase.
Patients in the RCB-3 category do poorly regardless of treatment (EFS of 34.6 % and 26.2% in the pembrolizumab and placebo arms, respectively).
“The RCB-3 population represents an unmet medical need, and they will need better drugs, and additional postoperative adjuvant therapy,” Dr. Pusztai said. The current standard of care is capecitabine for 6-8 cycles. Emerging new therapies, such as antibody drug conjugates, will be tested, he said.
In terms of limitations, adjuvant capecitabine was not allowed. “It remains uncertain how much better the RCB-2 and -3 patient outcomes would have been if capecitabine were administered,” he said.
The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Dr. Pusztai has received consulting fees and honoraria from Merck.
for improving survival in patients with early triple negative breast cancer (TNBC).
The findings were presented in Chicago June 4 and 5 at the annual meeting of the American Society of Clinical Oncology by study author Lajos Pusztai, MD, D.Phil, director of Breast Cancer Translational Research at Yale University, New Haven, Conn.
KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant setting.
The study included 1,174 patients (median age 49 years) with previously untreated stage II or III triple-negative breast cancer. Patients were randomly assigned to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After surgery, patients received pembrolizumab or placebeo for 9 cycles or until recurrence or unacceptable toxicity. The primary end points were pathological complete response and event-free survival.
A total of 784 patients were treated with pembrolizumab and chemotherapy, and the second group of 390 patients received a placebo and chemotherapy. After surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo and chemotherapy for every 3 weeks for up to nine cycles.
The estimated event-free survival at 36 months was 84.5% in the pembrolizumab-chemotherapy group, compared with 76.8% in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% confidence interval, 0.48 to 0.82; P <0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy.
At the first interim analysis, 64.8% achieved pathological complete response in the pembrolizumab group versus 51.2% in the placebo group. At the fourth interim analysis at 36 months, event-free survival was 76.8% in the placebo arm and 84.5% in the pembrolizumab arm. RCB-0 status was achieved by 63.4% and 56.2% of patients in the pembrolizumab and placebo arms, respectively.
Pembrolizumab did contribute immune-related adverse events, mostly grades 1-2, in about 17% of patients with thyroid function abnormalities most common with most occurring 20 weeks prior to surgical treatment.
Treatment with pembrolizumab added to chemotherapy, compared with chemotherapy alone, shifted residual cancer burden to lower categories across the entire spectrum of patients in the trial.
The hazard ratio for event-free survival with RCB-0, which Dr. Pusztai said is equivalent to a pathologic complete response (pCR), was 0.70 (0.38-1.31). For RCB-1 (minimal residual disease) it was 0.92 (0.39-2.20); for RCB-2 (moderate residual disease) it was 0.52 (0.32-0.82); and for RCB-3 (extensive residual disease) it was 1.24 (0.69-2.23).
“The most important finding is that patients in RCB-2, a group with a moderate amount of residual disease, experienced significant improvement with pembrolizumab. This clearly indicates not only that pembrolizumab leads to higher pCR rates but also that the pembrolizumCR/RCB-0 ... extends to patients who do not achieve pCR,” Dr. Pusztai said.
The benefit, he suggested, could be a result of the adjuvant pembrolizumab maintenance phase.
Patients in the RCB-3 category do poorly regardless of treatment (EFS of 34.6 % and 26.2% in the pembrolizumab and placebo arms, respectively).
“The RCB-3 population represents an unmet medical need, and they will need better drugs, and additional postoperative adjuvant therapy,” Dr. Pusztai said. The current standard of care is capecitabine for 6-8 cycles. Emerging new therapies, such as antibody drug conjugates, will be tested, he said.
In terms of limitations, adjuvant capecitabine was not allowed. “It remains uncertain how much better the RCB-2 and -3 patient outcomes would have been if capecitabine were administered,” he said.
The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Dr. Pusztai has received consulting fees and honoraria from Merck.
for improving survival in patients with early triple negative breast cancer (TNBC).
The findings were presented in Chicago June 4 and 5 at the annual meeting of the American Society of Clinical Oncology by study author Lajos Pusztai, MD, D.Phil, director of Breast Cancer Translational Research at Yale University, New Haven, Conn.
KEYNOTE-522 is the first prospective, randomized, placebo-controlled phase 3 trial of pembrolizumab for early-stage TNBC in the neoadjuvant and adjuvant setting.
The study included 1,174 patients (median age 49 years) with previously untreated stage II or III triple-negative breast cancer. Patients were randomly assigned to receive neoadjuvant therapy with four cycles of pembrolizumab (200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After surgery, patients received pembrolizumab or placebeo for 9 cycles or until recurrence or unacceptable toxicity. The primary end points were pathological complete response and event-free survival.
A total of 784 patients were treated with pembrolizumab and chemotherapy, and the second group of 390 patients received a placebo and chemotherapy. After surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo and chemotherapy for every 3 weeks for up to nine cycles.
The estimated event-free survival at 36 months was 84.5% in the pembrolizumab-chemotherapy group, compared with 76.8% in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% confidence interval, 0.48 to 0.82; P <0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy.
At the first interim analysis, 64.8% achieved pathological complete response in the pembrolizumab group versus 51.2% in the placebo group. At the fourth interim analysis at 36 months, event-free survival was 76.8% in the placebo arm and 84.5% in the pembrolizumab arm. RCB-0 status was achieved by 63.4% and 56.2% of patients in the pembrolizumab and placebo arms, respectively.
Pembrolizumab did contribute immune-related adverse events, mostly grades 1-2, in about 17% of patients with thyroid function abnormalities most common with most occurring 20 weeks prior to surgical treatment.
Treatment with pembrolizumab added to chemotherapy, compared with chemotherapy alone, shifted residual cancer burden to lower categories across the entire spectrum of patients in the trial.
The hazard ratio for event-free survival with RCB-0, which Dr. Pusztai said is equivalent to a pathologic complete response (pCR), was 0.70 (0.38-1.31). For RCB-1 (minimal residual disease) it was 0.92 (0.39-2.20); for RCB-2 (moderate residual disease) it was 0.52 (0.32-0.82); and for RCB-3 (extensive residual disease) it was 1.24 (0.69-2.23).
“The most important finding is that patients in RCB-2, a group with a moderate amount of residual disease, experienced significant improvement with pembrolizumab. This clearly indicates not only that pembrolizumab leads to higher pCR rates but also that the pembrolizumCR/RCB-0 ... extends to patients who do not achieve pCR,” Dr. Pusztai said.
The benefit, he suggested, could be a result of the adjuvant pembrolizumab maintenance phase.
Patients in the RCB-3 category do poorly regardless of treatment (EFS of 34.6 % and 26.2% in the pembrolizumab and placebo arms, respectively).
“The RCB-3 population represents an unmet medical need, and they will need better drugs, and additional postoperative adjuvant therapy,” Dr. Pusztai said. The current standard of care is capecitabine for 6-8 cycles. Emerging new therapies, such as antibody drug conjugates, will be tested, he said.
In terms of limitations, adjuvant capecitabine was not allowed. “It remains uncertain how much better the RCB-2 and -3 patient outcomes would have been if capecitabine were administered,” he said.
The study was funded by Merck Sharp and Dohme, a subsidiary of Merck. Dr. Pusztai has received consulting fees and honoraria from Merck.
FROM ASCO 2022
Tirzepatide powers ‘unprecedented’ weight loss in SURMOUNT-1
NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.
Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.
First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.
Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.
And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.
Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference.
She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”
Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”
A new era: Weight loss ‘in the range of bariatric surgery’
Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.
SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times.
Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.
The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.
The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.
Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.
An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”
“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.
Dual incretin agonism ‘enhances activity,’ says expert
Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.
Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.
Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.
The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.
“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.
Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked.
Weight-loss agents gain U.S. traction
There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.
His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.
With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels, an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.
“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.
SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m2 or more, or 27 kg/m2 or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.
The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.
The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively
The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”
Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”
Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.
SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.
Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.
First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.
Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.
And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.
Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference.
She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”
Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”
A new era: Weight loss ‘in the range of bariatric surgery’
Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.
SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times.
Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.
The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.
The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.
Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.
An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”
“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.
Dual incretin agonism ‘enhances activity,’ says expert
Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.
Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.
Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.
The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.
“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.
Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked.
Weight-loss agents gain U.S. traction
There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.
His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.
With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels, an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.
“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.
SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m2 or more, or 27 kg/m2 or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.
The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.
The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively
The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”
Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”
Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.
SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.
A version of this article first appeared on Medscape.com.
NEW ORLEANS – Treatment of people with obesity but no diabetes with the dual–incretin agonist tirzepatide safely produced “unprecedented” levels of weight loss in the vast majority of patients in SURMOUNT-1, a placebo-controlled trial with more than 2,500 people with obesity or overweight plus at least one weight-related complication.
Although the pivotal trial did not directly compare weekly subcutaneous injection with the twincretin tirzepatide (at 5 mg, 10 mg, or 15 mg) with either bariatric surgery or what has been the reigning champ of weight-loss agents, a 2.4-mg/week injection of semaglutide (Wegovy), the new findings are impressive because they eclipsed semaglutide’s past performance in at least three important ways, said Ania M. Jastreboff, MD, PhD, SURMOUNT-1’s lead investigator, at the annual scientific sessions of the American Diabetes Association.
First, the highest-tested dosage of tirzepatide, 15 mg/week, for 72 weeks, produced a 5% or greater loss in baseline weight in 91%-96% of patients, an effect “not previously seen” in any prior phase 3 trial of a weight-loss agent, noted Dr. Jastreboff, an endocrinologist and director of Weight Management & Obesity Prevention at Yale University in New Haven, Conn.
Second, the average level of weight loss among the 630 people who received 15 mg/week was 22.5% in the on-treatment analysis, and 20.9% in the intention-to-treat analysis, again a magnitude of effect never before seen with any other medical intervention.
And in an exploratory analysis, 40% of people who received the highest-tested tirzepatide dose of 15 mg/week had at least a 25% loss in baseline weight in the on-treatment analysis, another example of unprecedented weight-loss achievement, said Dr. Jastreboff.
Looking at the data another way, the average baseline weight of those in the trial was 104 kg (230 lb) at the start, and the average weight loss was between 35 and 52 lbs by 72 weeks on treatment, Dr. Jastreboff said in a press conference.
She noted, however, that not everyone will respond to tirzepatide, “but if you do respond to this medicine, you will feel full earlier, you won’t want to go back for seconds, and you may eat smaller amounts more often.”
Such weight-loss agents will need to be taken chronically, in the same way that medications are for hypertension or dyslipidemia, Dr. Jastreboff stressed. “If you stop the antiobesity medication then the body fat mass set point will go back up so this necessitates long-term treatment.”
A new era: Weight loss ‘in the range of bariatric surgery’
Tirzepatide, developed by Lilly, has recently been approved in the United States for the treatment of type 2 diabetes, under the brand name Mounjaro.
SURMOUNT-1 was designed to examine the effect of the agent in overweight/obesity, and the company will be filing for the additional indication of weight loss in the future. Top-line results of SURMOUNT-1 generated much excitement when Lilly reported them back in April, including a story in The New York Times.
Semaglutide, a Novo Nordisk drug, is approved in the United States for type 2 diabetes (as Ozempic at doses of either 1 mg or 2 mg per week) and also for weight loss, as Wegovy, at the higher dose of 2.4 mg per week. When Wegovy was given the green light by the Food and Drug Administration a year ago, it too was hailed as a “game changer” for obesity.
The weight-loss results seen in SURMOUNT-1 “put tirzepatide squarely in the range of weight loss achieved with bariatric surgery,” concluded Louis J. Aronne, MD, a coinvestigator on the trial, professor at Weill-Cornell Medicine in New York, and director of the Center for Weight Management and Metabolic Clinical Research of Weill-Cornell.
The results are “amazing,” and propel the weight-loss field into “a new era of obesity treatment,” commented Lee M. Kaplan, MD, who was not involved in the study and served as designated discussant for the trial.
Despite the lack of direct comparison, the findings indicate that “tirzepatide causes more weight loss than semaglutide,” and it provides “an opportunity to meet or exceed” the weight-loss effects of bariatric surgery, added Dr. Kaplan, director of the Obesity, Metabolism and Nutrition Institute at Massachusetts General Hospital in Boston.
Simultaneously with Dr. Jastreboff’s report at the meeting, the results were published online in The New England Journal of Medicine.
An accompanying editorial agrees with Dr. Kaplan: “It is remarkable that the magnitude of weight loss with tirzepatide was similar to that with gastric bypass, which raises the potential for alternative medical approaches to the treatment of obesity.”
“The tides are shifting, and there are now more options for people with obesity to lose weight,” write Clifford J. Rosen, MD, of Tufts University, Boston, and Julie R. Ingelfinger, MD, of Harvard University and Massachusetts General Hospital, Boston.
Dual incretin agonism ‘enhances activity,’ says expert
Tirzepatide is the first agent on the U.S. market from a novel class of dual-incretin agonists, with a molecular structure engineered to activate both the glucagonlike protein-1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP), the two predominant incretins in the human gut. This combined activity has led to the twincretin nickname for tirzepatide.
Semaglutide is a single-incretin agonist, with its activity focused exclusively on the GLP-1 receptor.
Dr. Aronne tied the apparently superior efficacy of tirzepatide relative to semaglutide directly to the added incretin activity of tirzepatide. “The dual approach enhances efficacy,” he proposed during his presentation at the meeting.
The impressive efficacy and reassuring safety profile reported from SURMOUNT-1 opens the door to a new approach to treating obesity, which in the past has often taken a back seat to treatments for dyslipidemia, hypertension, and diabetes.
“Now that we can treat obesity safely and effectively, it makes sense to treat obesity first,” Dr. Aronne recommended.
Dr. Jastreboff agreed: “Perhaps we can prevent diabetes by treating obesity head-on,” she remarked.
Weight-loss agents gain U.S. traction
There have been concerns about patient access to these newer weight-loss drugs in the United States, given that the retail cost of semaglutide for obesity exceeds $1,000/month, but Dr. Aronne reported data that painted a more optimistic picture.
His numbers showed that during the first months that semaglutide was on the U.S. market as a weight-loss agent, the number of U.S. prescriptions written for branded antiobesity medications roughly doubled, a spike that seemed mostly driven by the introduction and growing use of semaglutide.
With tirzepatide, every prespecified cardiometabolic parameter assessed in the trial showed clinically meaningful improvements, reported Dr. Jastreboff, including an average 17% reduction in waist circumference in patients on either of the highest two dosages, a 34% average drop in total fat mass, an average 0.5–percentage point cut in baseline hemoglobin A1c at the highest two dosages, substantial cuts in fasting plasma glucose and fasting insulin levels, an average 28% drop in triglyceride levels, and an average systolic blood pressure reduction of about 8 mm Hg that occurred within 24 weeks on treatment.
“I think that insurers will sign up” for tirzepatide coverage based on benefits like this, Dr. Aronne predicted.
SURMOUNT-1 randomized 2,539 patients with obesity or with overweight plus at least one weight-related complication at any of 119 sites in nine countries. They had a body mass index of 30 kg/m2 or more, or 27 kg/m2 or more and at least one weight-related complication, excluding diabetes. They were randomized in a 1:1:1:1 ratio to receive once-weekly, subcutaneous tirzepatide (5 mg, 10 mg, or 15 mg) or placebo for 72 weeks, including a 20-week dose-escalation period.
The study’s two primary endpoints were the average percentage change in body weight from entry to 72 weeks, and the percentage of participants reaching at least a 5% reduction in their baseline body weight by 72 weeks.
The most common adverse events with tirzepatide were gastrointestinal, and most were mild to moderate in severity, occurring primarily during dose escalation. Adverse events caused treatment discontinuation in 4.3%, 7.1%, 6.2%, and 2.6% of participants receiving 5-mg, 10-mg, and 15-mg tirzepatide doses and placebo, respectively
The trial ran from December 2019 to April 2022, so during the peak of the COVID-19 pandemic, which Dr. Jastreboff described as an “amazing feat.”
Jamy Ard, MD, who chaired the SURMOUNT-1 session quipped, after hearing the results, “Wow; that’s exciting. If you’re not excited by the results, you’d better check your pulse.”
Dr. Ard is a professor at Wake Forest University, Winston-Salem, N.C., and codirector of the Wake Forest Baptist Health Weight Management Center in Winston-Salem.
SURMOUNT-1 was sponsored by Eli Lilly, the company that markets tirzepatide (Mounjaro). Dr. Jastreboff has been an advisor or consultant to Eli Lilly, as well as to Boehringer Ingelheim, Intellihealth, Novo Nordisk, Pfizer, Rhythm Pharmaceuticals, Scholar Rock, and Weight Watchers, and she has received research funding from Eli Lilly and Novo Nordisk. Dr. Aronne has been a consultant or advisor to, speaker on behalf of, or received research funding from Eli Lilly as well as from Altimmune, Amgen, Allurion, Intellihealth, Janssen, Novo Nordisk, Pfizer, and United Health group; he has an ownership interest in ERX, Gelesis, and Intellihealth; and he serves on the board of ERX, Jamieson Wellness, and Intellihealth. Dr. Kaplan has been a consultant to Eli Lilly, as well as to Amgen, Boehringer Ingelheim, Gelesis, Gilead, Novo Nordisk, Optum Health, Pfizer, Rhythm Pharmaceuticals, the Obesity and Nutrition Institute, and Xeno Biosciences. Dr. Ard has been a consultant to Eli Lilly, as well as to Nestle Health Sciences and Novo Nordisk, and he has received research funding from Boehringer Ingelheim, Epitomee, Medical, and United Health Group.
A version of this article first appeared on Medscape.com.
AT ADA 2022
‘Very impressive’ data promise new blood cancer option
“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.
Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.
After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.
The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.
“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.
The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.
A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.
A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).
The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.
Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.
“The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”
However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.
As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
Be ready to manage infections
Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.
Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.
A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.
He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.
Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.
The study was funded by Janssen Research and Development.
Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.
“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.
Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.
After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.
The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.
“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.
The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.
A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.
A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).
The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.
Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.
“The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”
However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.
As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
Be ready to manage infections
Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.
Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.
A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.
He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.
Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.
The study was funded by Janssen Research and Development.
Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.
“We have limited treatment options for triple-class exposed and refractory multiple myeloma patients, especially for use in the community,” coauthor Dr. Saad Z. Usmani, of Memorial Sloan Kettering Cancer Center, New York, said in an interview. “Teclistamab is a BCMA directed bispecific antibody that is showing high response rates at the recommended subcutaneous phase 2 doses (RP2D),” and has a strong safety profile, he explained.
Teclistamab tackles two targets – both CD3 on the surface of T cells and B-cell maturation antigen (BCMA) on the surface of myeloma cells – said Dr. Ajay K. Nooka of Emory University, Atlanta, in the meeting presentation. The study was published simultaneously in the New England Journal of Medicine.
After teclistamab showed promising efficacy and an acceptable level of side effects in phase 1, researchers enrolled 165 adults aged 33-84 years with relapsed or refractory multiple myeloma (MM). The patients had experienced at least three previous lines of therapy (LOT). All patients received a weekly subcutaneous injection of 1.5 mg/kg of body weight following step-up doses of 0.06 mg/kg and 0.3 mg/kg. The primary endpoint of the study was overall response.
The median age of the patients was 64 years; 58% were male, 81.2% were White. The median prior LOT was 5; all of the patients were triple-class exposed (100%); 70% were penta-drug exposed, 78% were triple-class refractory, and 30% penta-drug refractory.
The overall response rate (ORR) was 63% over a median follow-up period of approximately 14.1 months. In addition, 39.4% of patients had a complete response or better, and 26.7% had no minimal residual disease, for a negative minimal residual disease rate of 46.2% in patients with complete response. The median durations of response and progression-free survival were 18.4 months and 11.3 months, respectively.
“The ORR was consistent across clinically relevant subgroups, including high cytogenetic risk and penta-drug refractory subgroups,” Dr. Nooka said in his presentation.
The most common adverse event was cytokine release syndrome, which occurred in 72.1% of patients; however, only 0.6% of these events were grade 3, and none were grade 4. Other adverse events included neutropenia in 70.9% (64.2% of events were grade 3 or 4), anemia (52.1%, 37.0% of events were grade 3 or 4, respectively) and thrombocytopenia (40%, 21.2% of events were grade 3 or 4). Infections occurred in 76.4% of patients overall, 44.8% of which were grade 3 or 4, and neurotoxic events occurred in 24 patients (14.5%). The five cases of immune effector cell–associated neurotoxicity syndrome (CRS) were grade 1 or 2.
A total of 2 patients (1.2%) discontinued the study because of adverse events, but no discontinuations or dose reductions occurred as a result of neurotoxic events.
A total of 5 deaths attributed to teclistamab occurred during the study: 2 caused by COVID-19, 1 pneumonia, 1 hepatic failure, and 1 progressive multifocal leukoencephalopathy (PML).
The responses were durable and persisted over time, said Dr. Nooka. At the point of data cutoff, 64.4% of patients who responded maintained that response.
Overall, the data support teclistamab as “a promising new, off-the-shelf, T-cell redirecting therapy targeting BCMA for patients with relapsed or refractory MM,” with phase 3 studies ongoing and early access programs in progress, Dr. Nooka concluded.
“The ORR and durability of response seen with teclistamab is very impressive when one sees the data for other single agents approved for relapsed/refractory MM in the past,” Dr. Usmani said in an interview. “I hope the current data will help get a regulatory approval for the triple class exposed MM population.”
However, potential barriers to widespread use of teclistamab in practice include logistics and a learning curve for practicing hematologists/oncologists, Dr. Usmani noted. “While the CRS appears to be grade 1 or 2 and very manageable, the logistics of giving bispecific antibodies in the community setting and managing CRS during the first cycle of therapy in the community will need to be worked out, and partnership with academic centers that have experience in managing these patients will be needed, he added.
As for additional research, “teclistamab is being combined with other MM therapies and being explored in earlier lines of treatment,” Dr. Usmani said.
Be ready to manage infections
Despite promising early findings, the use of teclistamab and other BCMA-targeting biospecific therapies is “not a free lunch” for refractory and relapsed MM patients, said discussant Dr. Madhav V. Dhodapkar of Emory University, Atlanta, during the discussion period after the ASCO presentation.
Although the risk of CRS and ICANS appears low, “infections are emerging as a major adverse event” that need to be recognized and managed, he said.
A distinct pattern of infections may be emerging, based on data from the current study and other studies of similar therapies, with infections such as Pneumocystis jirovecii (PJP) and cytomegalovirus (CMV) reactivation, Dr. Dhodapkar added.
He noted other considerations for studies of teclistamab and similar therapies, including the need to address both host-related and tumor-related factors, as well as seasonal and opportunistic threats such as COVID-19.
Future research questions include whether there is a role for pathogen-specific surveillance to help mitigate infection risk, including COVID-19 risk management strategies, he emphasized.
The study was funded by Janssen Research and Development.
Dr. Usmani disclosed relationships as a consultant or advisor, speakers’ bureau member, and/or recipient of research funding from serving as a consultant or advisor for Abbvie, Amgen, Bristol-Myers Squibb/Celgene, Celgene, Genentech, Gilead Sciences, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Merck, Oncopeptides, Seattle Genetics, Skyline Diagnostics, and Takeda. Lead author of the New England Journal paper Dr. Philippe Moreau disclosed relationships with companies including Abbvie, Amgen, Celgene, GlaxoSmithKline, Janssen-Cilag, Oncopeptides, and Sanofi. ASCO presenting author Dr. Nooka disclosed relationships with companies including Adaptive Biotechnologies, Amgen, BeyondSpring Pharmaceuticals, Bristol-Myers Squibb/Celgene, Genzyme, GlaxoSmithKline, Janssen Oncology, Karyopharm Therapeutics, Oncopeptides, Secura Bio, Arch Oncology, and Takeda.
FROM ASCO 2022
European AxSpA guidelines reflect recent changes in drug therapy
COPENHAGEN – European recommendations and overarching principles for the management of patients with axial spondyloarthritis (axSpA) have remained largely unchanged since 2016 – with a few notable but very important exceptions.
The 2022 updated recommendations include a new point regarding which biologic agents to use for patients with recurrent uveitis, active inflammatory bowel disease (IBD), or significant psoriasis, as well as new advice to reevaluate the diagnosis and consider the presence of comorbidities if the disease doesn’t respond to current therapies, reported Sofia Ramiro, MD, PhD, from Leiden (Netherlands) University Medical Center.
She summarized the 2022 updates at the annual European Congress of Rheumatology on behalf of colleagues in the ASAS (Assessment of SpondyloArthritis International Society)/EULAR committee.
Among other significant updates are a recommendation for managing patients with persistently high disease activity despite conventional therapy, and a recommendation as to what to do when a first biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) fails, Dr. Ramiro said at the meeting.
“Although we have more changes in the pharmacological part, I would like to emphasize the importance of nonpharmacological treatment in axial SpA,” she said.
Overarching principles
The members of the committee that created the recommendations were in complete agreement that axSpA, as they state in the overarching principles, “is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.”
They also universally acknowledged that “the primary goal of treating the patient with axSpA is to maximize health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, preservation/normalization of function, and social participation.”
The overarching principles include the aforementioned emphasis on both pharmacologic and nonpharmacologic management, shared decision-making between patients and rheumatologists, and awareness of the potential financial toxicities and societal problems that patients face.
A closer look: New recommendations
As noted before, there are two new recommendations since the 2016 iteration.
Recommendation No. 10 states, “If there is a history of recurrent uveitis or active IBD, preference should be given to a monoclonal antibody against TNF-alpha [tumor necrosis factor–alpha]. For patients with significant psoriasis, an IL-17 [interleukin-17] inhibitor may be preferred.”
This recommendation stipulates that it refers only to IL-17A inhibitors.
The other new recommendation, No. 11, seems like plain common sense. It states, “Absence of response to treatment should trigger reevaluation of the diagnosis and consideration of the presence of comorbidities.”
Revised recommendations
The two significantly revised recommendations deal with drug therapy.
Recommendation No. 9 holds that for patients with persistently high disease activity despite conventional therapy, a TNF inhibitor, including the pegylated humanized antigen-binding fragment certolizumab pegol (Cimzia), an IL-17 inhibitor, or Janus kinase (JAK) inhibitor, should be considered.
Recommendation No. 12 states that if the first biologic or targeted synthetic DMARD fails, switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor should be considered.
Transatlantic similarities, differences
Lianne Gensler, MD, a rheumatologist and professor of medicine at the University of California, San Francisco, who served on the committee that developed the 2019 American College of Rheumatology guidelines for the treatment of ankylosing spondylitis and nonradiographic axSpA, said that, while there are similarities between some of the recommendations promulgated on each side of the Atlantic, there are significant differences and even opposing viewpoints.
A primary difference between the two is the methodology used to arrive at the recommendations in the first place, she said in an interview with this news organization.
“ACR uses a very robust approach to guideline development, where each question is addressed by a ‘PICO’ ” population, intervention, control, and outcomes – and that’s good if you have good evidence, but sometimes – often, in fact – we don’t have strong evidence that would lead everyone to choose the same approach every time, and that’s true especially in inflammatory arthritis, where there’s a lot of shared decision-making, so many of the recommendations out of ACR are conditional,” she said.
In contrast, the ASAS/EULAR recommendations are based largely on broader levels of evidence and on consensus. In developing the European recommendations, the authors were able to take into account drugs that were newly approved since the 2019 ACR guidelines were issued, she noted.
Although many of the broader recommendations are similar, they diverge when it comes to specific issues, such as whether to treat to target.
“ACR guidelines say, ‘Do not treat to target.’ EULAR guidelines say it’s okay to treat to target. ACR guidelines made that decision because at that time, there was no treat-to-target data,” Dr, Gensler said.
“I think, as rheumatologists, we always want to aim for a goal in a patient, so it’s not unreasonable, but I think we shouldn’t attach too much to a number,” she said.
Another difference is that the ACR guidelines recommend against switching to a biosimilar agent when a patient’s condition is stable with the originator biologic.
Dr. Gensler said that she particularly appreciated the new EULAR recommendation (No. 11) to reconsider the diagnosis for patients for whom therapies have failed.
“The sense that nonresponse means ongoing disease activity and therefore drug escalation or change needs to happen is not always the right answer,” she said.
The process for developing the recommendations was supported by EULAR. Dr. Ramiro has received research grants and consulting and/or speaking fees from AbbVie, Eli Lilly, Galapagos, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and UCB. Dr. Gensler has received research grant support from Novartis, Pfizer, and UCB and has consulting relationships with AbbVie, Gilead, Janssen, MoonLake, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
COPENHAGEN – European recommendations and overarching principles for the management of patients with axial spondyloarthritis (axSpA) have remained largely unchanged since 2016 – with a few notable but very important exceptions.
The 2022 updated recommendations include a new point regarding which biologic agents to use for patients with recurrent uveitis, active inflammatory bowel disease (IBD), or significant psoriasis, as well as new advice to reevaluate the diagnosis and consider the presence of comorbidities if the disease doesn’t respond to current therapies, reported Sofia Ramiro, MD, PhD, from Leiden (Netherlands) University Medical Center.
She summarized the 2022 updates at the annual European Congress of Rheumatology on behalf of colleagues in the ASAS (Assessment of SpondyloArthritis International Society)/EULAR committee.
Among other significant updates are a recommendation for managing patients with persistently high disease activity despite conventional therapy, and a recommendation as to what to do when a first biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) fails, Dr. Ramiro said at the meeting.
“Although we have more changes in the pharmacological part, I would like to emphasize the importance of nonpharmacological treatment in axial SpA,” she said.
Overarching principles
The members of the committee that created the recommendations were in complete agreement that axSpA, as they state in the overarching principles, “is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.”
They also universally acknowledged that “the primary goal of treating the patient with axSpA is to maximize health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, preservation/normalization of function, and social participation.”
The overarching principles include the aforementioned emphasis on both pharmacologic and nonpharmacologic management, shared decision-making between patients and rheumatologists, and awareness of the potential financial toxicities and societal problems that patients face.
A closer look: New recommendations
As noted before, there are two new recommendations since the 2016 iteration.
Recommendation No. 10 states, “If there is a history of recurrent uveitis or active IBD, preference should be given to a monoclonal antibody against TNF-alpha [tumor necrosis factor–alpha]. For patients with significant psoriasis, an IL-17 [interleukin-17] inhibitor may be preferred.”
This recommendation stipulates that it refers only to IL-17A inhibitors.
The other new recommendation, No. 11, seems like plain common sense. It states, “Absence of response to treatment should trigger reevaluation of the diagnosis and consideration of the presence of comorbidities.”
Revised recommendations
The two significantly revised recommendations deal with drug therapy.
Recommendation No. 9 holds that for patients with persistently high disease activity despite conventional therapy, a TNF inhibitor, including the pegylated humanized antigen-binding fragment certolizumab pegol (Cimzia), an IL-17 inhibitor, or Janus kinase (JAK) inhibitor, should be considered.
Recommendation No. 12 states that if the first biologic or targeted synthetic DMARD fails, switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor should be considered.
Transatlantic similarities, differences
Lianne Gensler, MD, a rheumatologist and professor of medicine at the University of California, San Francisco, who served on the committee that developed the 2019 American College of Rheumatology guidelines for the treatment of ankylosing spondylitis and nonradiographic axSpA, said that, while there are similarities between some of the recommendations promulgated on each side of the Atlantic, there are significant differences and even opposing viewpoints.
A primary difference between the two is the methodology used to arrive at the recommendations in the first place, she said in an interview with this news organization.
“ACR uses a very robust approach to guideline development, where each question is addressed by a ‘PICO’ ” population, intervention, control, and outcomes – and that’s good if you have good evidence, but sometimes – often, in fact – we don’t have strong evidence that would lead everyone to choose the same approach every time, and that’s true especially in inflammatory arthritis, where there’s a lot of shared decision-making, so many of the recommendations out of ACR are conditional,” she said.
In contrast, the ASAS/EULAR recommendations are based largely on broader levels of evidence and on consensus. In developing the European recommendations, the authors were able to take into account drugs that were newly approved since the 2019 ACR guidelines were issued, she noted.
Although many of the broader recommendations are similar, they diverge when it comes to specific issues, such as whether to treat to target.
“ACR guidelines say, ‘Do not treat to target.’ EULAR guidelines say it’s okay to treat to target. ACR guidelines made that decision because at that time, there was no treat-to-target data,” Dr, Gensler said.
“I think, as rheumatologists, we always want to aim for a goal in a patient, so it’s not unreasonable, but I think we shouldn’t attach too much to a number,” she said.
Another difference is that the ACR guidelines recommend against switching to a biosimilar agent when a patient’s condition is stable with the originator biologic.
Dr. Gensler said that she particularly appreciated the new EULAR recommendation (No. 11) to reconsider the diagnosis for patients for whom therapies have failed.
“The sense that nonresponse means ongoing disease activity and therefore drug escalation or change needs to happen is not always the right answer,” she said.
The process for developing the recommendations was supported by EULAR. Dr. Ramiro has received research grants and consulting and/or speaking fees from AbbVie, Eli Lilly, Galapagos, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and UCB. Dr. Gensler has received research grant support from Novartis, Pfizer, and UCB and has consulting relationships with AbbVie, Gilead, Janssen, MoonLake, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
COPENHAGEN – European recommendations and overarching principles for the management of patients with axial spondyloarthritis (axSpA) have remained largely unchanged since 2016 – with a few notable but very important exceptions.
The 2022 updated recommendations include a new point regarding which biologic agents to use for patients with recurrent uveitis, active inflammatory bowel disease (IBD), or significant psoriasis, as well as new advice to reevaluate the diagnosis and consider the presence of comorbidities if the disease doesn’t respond to current therapies, reported Sofia Ramiro, MD, PhD, from Leiden (Netherlands) University Medical Center.
She summarized the 2022 updates at the annual European Congress of Rheumatology on behalf of colleagues in the ASAS (Assessment of SpondyloArthritis International Society)/EULAR committee.
Among other significant updates are a recommendation for managing patients with persistently high disease activity despite conventional therapy, and a recommendation as to what to do when a first biologic or targeted synthetic disease-modifying antirheumatic drug (DMARD) fails, Dr. Ramiro said at the meeting.
“Although we have more changes in the pharmacological part, I would like to emphasize the importance of nonpharmacological treatment in axial SpA,” she said.
Overarching principles
The members of the committee that created the recommendations were in complete agreement that axSpA, as they state in the overarching principles, “is a potentially severe disease with diverse manifestations, usually requiring multidisciplinary management coordinated by the rheumatologist.”
They also universally acknowledged that “the primary goal of treating the patient with axSpA is to maximize health-related quality of life through control of symptoms and inflammation, prevention of progressive structural damage, preservation/normalization of function, and social participation.”
The overarching principles include the aforementioned emphasis on both pharmacologic and nonpharmacologic management, shared decision-making between patients and rheumatologists, and awareness of the potential financial toxicities and societal problems that patients face.
A closer look: New recommendations
As noted before, there are two new recommendations since the 2016 iteration.
Recommendation No. 10 states, “If there is a history of recurrent uveitis or active IBD, preference should be given to a monoclonal antibody against TNF-alpha [tumor necrosis factor–alpha]. For patients with significant psoriasis, an IL-17 [interleukin-17] inhibitor may be preferred.”
This recommendation stipulates that it refers only to IL-17A inhibitors.
The other new recommendation, No. 11, seems like plain common sense. It states, “Absence of response to treatment should trigger reevaluation of the diagnosis and consideration of the presence of comorbidities.”
Revised recommendations
The two significantly revised recommendations deal with drug therapy.
Recommendation No. 9 holds that for patients with persistently high disease activity despite conventional therapy, a TNF inhibitor, including the pegylated humanized antigen-binding fragment certolizumab pegol (Cimzia), an IL-17 inhibitor, or Janus kinase (JAK) inhibitor, should be considered.
Recommendation No. 12 states that if the first biologic or targeted synthetic DMARD fails, switching to another biologic DMARD (TNF inhibitor or IL-17 inhibitor) or JAK inhibitor should be considered.
Transatlantic similarities, differences
Lianne Gensler, MD, a rheumatologist and professor of medicine at the University of California, San Francisco, who served on the committee that developed the 2019 American College of Rheumatology guidelines for the treatment of ankylosing spondylitis and nonradiographic axSpA, said that, while there are similarities between some of the recommendations promulgated on each side of the Atlantic, there are significant differences and even opposing viewpoints.
A primary difference between the two is the methodology used to arrive at the recommendations in the first place, she said in an interview with this news organization.
“ACR uses a very robust approach to guideline development, where each question is addressed by a ‘PICO’ ” population, intervention, control, and outcomes – and that’s good if you have good evidence, but sometimes – often, in fact – we don’t have strong evidence that would lead everyone to choose the same approach every time, and that’s true especially in inflammatory arthritis, where there’s a lot of shared decision-making, so many of the recommendations out of ACR are conditional,” she said.
In contrast, the ASAS/EULAR recommendations are based largely on broader levels of evidence and on consensus. In developing the European recommendations, the authors were able to take into account drugs that were newly approved since the 2019 ACR guidelines were issued, she noted.
Although many of the broader recommendations are similar, they diverge when it comes to specific issues, such as whether to treat to target.
“ACR guidelines say, ‘Do not treat to target.’ EULAR guidelines say it’s okay to treat to target. ACR guidelines made that decision because at that time, there was no treat-to-target data,” Dr, Gensler said.
“I think, as rheumatologists, we always want to aim for a goal in a patient, so it’s not unreasonable, but I think we shouldn’t attach too much to a number,” she said.
Another difference is that the ACR guidelines recommend against switching to a biosimilar agent when a patient’s condition is stable with the originator biologic.
Dr. Gensler said that she particularly appreciated the new EULAR recommendation (No. 11) to reconsider the diagnosis for patients for whom therapies have failed.
“The sense that nonresponse means ongoing disease activity and therefore drug escalation or change needs to happen is not always the right answer,” she said.
The process for developing the recommendations was supported by EULAR. Dr. Ramiro has received research grants and consulting and/or speaking fees from AbbVie, Eli Lilly, Galapagos, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi, and UCB. Dr. Gensler has received research grant support from Novartis, Pfizer, and UCB and has consulting relationships with AbbVie, Gilead, Janssen, MoonLake, Novartis, and Pfizer.
A version of this article first appeared on Medscape.com.
THE EULAR 2022 CONGRESS
New treatment outperforms chemo in HER2-low breast cancer
CHICAGO -- Breast cancer patients with low levels of HER2 expression, previously considered untreatable with HER2-targeted therapies, benefited from the anti-HER2 antibody drug conjugate trastuzumab deruxtecan.
“Overall, these results establish HER2 low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” said Shanu Modi, MD, during a press conference held in Chicago at the annual meeting of the American Society of Clinical Oncology, where she presented the results.
“I think the results of this trial clearly will be practice changing,” said ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, during the press conference. “I think what this trial does is really extend the benefits of this agent to a whole new group of patients that traditionally is really quite difficult to treat. I think this will offer a wonderful new option for patients and also will really fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients,” Dr. Meisel added.
The conjugate includes the anti-HER2 antibody trastuzumab and the topoisomerase I inhibitor deruxtecan, which interferes with DNA replication. Trastuzumab has demonstrated efficacy in patients with high levels of HER2 expression, and trastuzumab-deruxtecan received FDA approval in May 2022 for the treatment of HER2-positive breast cancer in patients who had previously received an anti-HER2 regimen.
However, anti-HER2 agents had not been shown to benefit HER2-low patients, defined as immunohistochemistry (IHC) 1+ or 2+. About 60% of breast cancer patients traditionally thought of HER2 negative could be classified as HER2 low, according to Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, New York.
Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies failed in this population, Dr. Modi highlighted the nature of the drug conjugate, including a high drug payload and the use of a topoisomerase inhibitor, which is rarely employed against breast cancer. Once released from the antibody, the drug retains its ability to cross cell membranes and enter the tumor microenvironment. That ‘knock on’ effect might allow it to reach neighboring cells that don’t express HER2. “We know HER2 expression is very heterogeneous. I think that’s why, for the first time, we’re seeing activity for a targeted agent,” Dr. Modi said.
The DESTINY-Breast04 study included 557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer. Patients were randomized to trastuzumab deruxtecan or physician’s choice of several standard chemotherapy drugs. After a median follow-up of 18.4 months, compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in risk of progression and a 36% reduction in mortality. The group also had longer progression-free survival (10.1 months vs. 5.4 months) and overall survival (23.9 months vs. 17.5 months).
Although adverse events were similar between the two groups (52.6% in trastuzumab deruxtecan, 67.4% in chemotherapy), lung toxicity occurred in 12% of the group, and there were 3 fatalities as a result (0.8%). Interstitial lung disease/pneumonitis has been linked to trastuzumab treatment in the past, with one meta-analysis finding a frequency of 2.4% and fatality rate of 0.2%.
Additional studies are in progress to determine the minimum threshold of HER2 expression needed to gain a benefit from trastuzumab deruxtecan treatment.
The study was funded by Daiichi Sankyo, and AstraZeneca. Dr. Modi has advised, consulted for, or received honoraria from Daiichi Sankyo, and AstraZeneca. Dr. Meisel has advised or consulted for Medscape and AstraZeneca.
CHICAGO -- Breast cancer patients with low levels of HER2 expression, previously considered untreatable with HER2-targeted therapies, benefited from the anti-HER2 antibody drug conjugate trastuzumab deruxtecan.
“Overall, these results establish HER2 low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” said Shanu Modi, MD, during a press conference held in Chicago at the annual meeting of the American Society of Clinical Oncology, where she presented the results.
“I think the results of this trial clearly will be practice changing,” said ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, during the press conference. “I think what this trial does is really extend the benefits of this agent to a whole new group of patients that traditionally is really quite difficult to treat. I think this will offer a wonderful new option for patients and also will really fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients,” Dr. Meisel added.
The conjugate includes the anti-HER2 antibody trastuzumab and the topoisomerase I inhibitor deruxtecan, which interferes with DNA replication. Trastuzumab has demonstrated efficacy in patients with high levels of HER2 expression, and trastuzumab-deruxtecan received FDA approval in May 2022 for the treatment of HER2-positive breast cancer in patients who had previously received an anti-HER2 regimen.
However, anti-HER2 agents had not been shown to benefit HER2-low patients, defined as immunohistochemistry (IHC) 1+ or 2+. About 60% of breast cancer patients traditionally thought of HER2 negative could be classified as HER2 low, according to Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, New York.
Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies failed in this population, Dr. Modi highlighted the nature of the drug conjugate, including a high drug payload and the use of a topoisomerase inhibitor, which is rarely employed against breast cancer. Once released from the antibody, the drug retains its ability to cross cell membranes and enter the tumor microenvironment. That ‘knock on’ effect might allow it to reach neighboring cells that don’t express HER2. “We know HER2 expression is very heterogeneous. I think that’s why, for the first time, we’re seeing activity for a targeted agent,” Dr. Modi said.
The DESTINY-Breast04 study included 557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer. Patients were randomized to trastuzumab deruxtecan or physician’s choice of several standard chemotherapy drugs. After a median follow-up of 18.4 months, compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in risk of progression and a 36% reduction in mortality. The group also had longer progression-free survival (10.1 months vs. 5.4 months) and overall survival (23.9 months vs. 17.5 months).
Although adverse events were similar between the two groups (52.6% in trastuzumab deruxtecan, 67.4% in chemotherapy), lung toxicity occurred in 12% of the group, and there were 3 fatalities as a result (0.8%). Interstitial lung disease/pneumonitis has been linked to trastuzumab treatment in the past, with one meta-analysis finding a frequency of 2.4% and fatality rate of 0.2%.
Additional studies are in progress to determine the minimum threshold of HER2 expression needed to gain a benefit from trastuzumab deruxtecan treatment.
The study was funded by Daiichi Sankyo, and AstraZeneca. Dr. Modi has advised, consulted for, or received honoraria from Daiichi Sankyo, and AstraZeneca. Dr. Meisel has advised or consulted for Medscape and AstraZeneca.
CHICAGO -- Breast cancer patients with low levels of HER2 expression, previously considered untreatable with HER2-targeted therapies, benefited from the anti-HER2 antibody drug conjugate trastuzumab deruxtecan.
“Overall, these results establish HER2 low metastatic breast cancer as a targetable population of breast cancer with trastuzumab deruxtecan as a new standard of care in this setting,” said Shanu Modi, MD, during a press conference held in Chicago at the annual meeting of the American Society of Clinical Oncology, where she presented the results.
“I think the results of this trial clearly will be practice changing,” said ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, during the press conference. “I think what this trial does is really extend the benefits of this agent to a whole new group of patients that traditionally is really quite difficult to treat. I think this will offer a wonderful new option for patients and also will really fundamentally change the way we think about HER2 status and how we classify this in our metastatic patients,” Dr. Meisel added.
The conjugate includes the anti-HER2 antibody trastuzumab and the topoisomerase I inhibitor deruxtecan, which interferes with DNA replication. Trastuzumab has demonstrated efficacy in patients with high levels of HER2 expression, and trastuzumab-deruxtecan received FDA approval in May 2022 for the treatment of HER2-positive breast cancer in patients who had previously received an anti-HER2 regimen.
However, anti-HER2 agents had not been shown to benefit HER2-low patients, defined as immunohistochemistry (IHC) 1+ or 2+. About 60% of breast cancer patients traditionally thought of HER2 negative could be classified as HER2 low, according to Dr. Modi, who is a medical oncologist at Memorial Sloan Kettering Cancer Center, New York.
Asked why she thought trastuzumab deruxtecan succeeded where other anti-HER2 therapies failed in this population, Dr. Modi highlighted the nature of the drug conjugate, including a high drug payload and the use of a topoisomerase inhibitor, which is rarely employed against breast cancer. Once released from the antibody, the drug retains its ability to cross cell membranes and enter the tumor microenvironment. That ‘knock on’ effect might allow it to reach neighboring cells that don’t express HER2. “We know HER2 expression is very heterogeneous. I think that’s why, for the first time, we’re seeing activity for a targeted agent,” Dr. Modi said.
The DESTINY-Breast04 study included 557 patients in Asia, Europe, and North America with HR-negative or HR-positive, HER2-low, unresectable, and/or metastatic breast cancer. Patients were randomized to trastuzumab deruxtecan or physician’s choice of several standard chemotherapy drugs. After a median follow-up of 18.4 months, compared with the chemotherapy group, patients in the trastuzumab deruxtecan arm had a 49% reduction in risk of progression and a 36% reduction in mortality. The group also had longer progression-free survival (10.1 months vs. 5.4 months) and overall survival (23.9 months vs. 17.5 months).
Although adverse events were similar between the two groups (52.6% in trastuzumab deruxtecan, 67.4% in chemotherapy), lung toxicity occurred in 12% of the group, and there were 3 fatalities as a result (0.8%). Interstitial lung disease/pneumonitis has been linked to trastuzumab treatment in the past, with one meta-analysis finding a frequency of 2.4% and fatality rate of 0.2%.
Additional studies are in progress to determine the minimum threshold of HER2 expression needed to gain a benefit from trastuzumab deruxtecan treatment.
The study was funded by Daiichi Sankyo, and AstraZeneca. Dr. Modi has advised, consulted for, or received honoraria from Daiichi Sankyo, and AstraZeneca. Dr. Meisel has advised or consulted for Medscape and AstraZeneca.
AT ASCO 2022
New treatment meets unmet need in breast cancer
CHICAGO -- An antibody drug conjugate that targets a cell-surface antigen found on most breast and bladder cancers demonstrated improved progression-free survival over standard chemotherapy in patients with endocrine-resistant hormone receptor positive/HER2 negative metastatic breast cancer.
The agent, called sacituzumab govitecan (Trodelvy, Gilead), was approved on an accelerated basis in 2020 by the Food and Drug Administration for patients with unresectable locally advanced or metastatic triple-negative breast cancer. It received regular approval in 2021.
The conjugate includes an antibody that targets the Trop-2 protein. The antibody is bound to govitecan, which is the active metabolite of the topoisomerase inhibitor 1 irinotecan.
“Sacituzumab demonstrated significant and clinically meaningful benefit, compared with chemotherapy in patients with heavily pretreated endocrine resistant hormone receptor positive, HER2 negative, advanced breast cancer and should be considered a potential treatment in this heavily pretreated patient population,” said lead author Hope S. Rugo, MD, during a press conference held June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology. Dr. Rugo is director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco comprehensive cancer center.
The results drew praise from ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, since patients with HR+/HER2- metastatic breast cancer who become resistant to endocrine therapy are left with only sequential, single-agent chemotherapy. “We’ve all been eagerly awaiting the results of this trial. These estrogen positive endocrine negative resistant patients really are an area of great unmet clinical need, and their cancers can be very difficult to treat,” Dr. Meisel said during the press conference.
Approximately, 74% of all breast cancers are HR positive/HER2 negative. And, of these, 92% of patients live beyond five years, according to the American Cancer Society.
The study found a relatively small 1.5 months difference in median progression-free survival, but the results are nevertheless clinically important, especially given that 21% of patients were progression-free at one year, compared with 7% in the chemotherapy arm. “When you look at the patients who do respond on sacituzumab govitecan, it seems that they tend to respond better and longer. The idea that someone with such heavily pretreated disease could walk into your clinic and you could offer them an option that would allow them a one in five chance of still not having progressed at one year is really huge from a clinical standpoint,” Dr. Meisel said.
“This is what we need, incremental options that may be different or better than chemotherapy, so I think this really represents a step forward for the field,” he said.
Two other antibody-drug conjugates that are FDA approved for HER2-positive breast cancer include ado-trastuzumab emtansine (Kadcyla, Genentech) and fam-trastuzumab deruxtecan (Enhertu, AstraZeneca, and Daiichi Sankyo). This new wave of therapies is exciting, according to Julie Gralow, MD, who is chief medical officer and executive vice president of ASCO. “I think this way of delivering chemotherapy inside the cancer cell by having an antibody directed to something on the cell surface and then internalization is really, really very interesting,” Dr. Gralow said during the press conference.
The study included 543 patients from 113 international centers who had previously received endocrine therapy, CDK4/6 inhibitors, and at least two previous regimens of chemotherapy. Median progression-free survival (PFS) was 5.5 months in the sacituzumab govitecan group and 4.0 months in the chemotherapy group (hazard ratio, 0.66; P <.001). PFS was more frequent at 6 months (46% vs. 30%) and 12 months (21% vs. 7%). There was no significant improvement in overall survival (13.9 months vs. 12.3 months). The sacituzumab govitecan group had higher rates of overall response (21% vs. 14%) and clinical benefit (34% vs. 22%), as well as a longer median duration of response (7.4 vs. 5.6 months).
Adverse events were more common with sacituzumab govitecan (74% vs. 60%), including low white blood cell counts (51% vs. 39%) and diarrhea (10% vs. 1%). Both groups had low rates of treatment discontinuation due to adverse events (6% in sacituzumab govitecan vs. 4% in chemotherapy).
Dr. Rugo has received honoraria from Puma Biotechnology and Samsung Bioepis, has consulted for Napo Pharmaceuticals, and has received funding from Astellas Pharma, AstraZeneca, Ayala Pharmaceuticals, Daiichi Sankyo, Genentech, Gilead Sciences, Lilly, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Sermonix Pharmaceuticals. Dr. Meisel has advised or consulted for Medscape and Total Health Conferencing. She has advised or consulted for AstraZeneca, Curio Science, Genentech, GlaxoSmithKline, Novartis, and SeaGen. She has received research funding from Pfizer and Seattle Genetics. She has received travel, accommodation, or expenses from Pfizer, Puma Biotechnology, and Total Health Conferencing.
CHICAGO -- An antibody drug conjugate that targets a cell-surface antigen found on most breast and bladder cancers demonstrated improved progression-free survival over standard chemotherapy in patients with endocrine-resistant hormone receptor positive/HER2 negative metastatic breast cancer.
The agent, called sacituzumab govitecan (Trodelvy, Gilead), was approved on an accelerated basis in 2020 by the Food and Drug Administration for patients with unresectable locally advanced or metastatic triple-negative breast cancer. It received regular approval in 2021.
The conjugate includes an antibody that targets the Trop-2 protein. The antibody is bound to govitecan, which is the active metabolite of the topoisomerase inhibitor 1 irinotecan.
“Sacituzumab demonstrated significant and clinically meaningful benefit, compared with chemotherapy in patients with heavily pretreated endocrine resistant hormone receptor positive, HER2 negative, advanced breast cancer and should be considered a potential treatment in this heavily pretreated patient population,” said lead author Hope S. Rugo, MD, during a press conference held June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology. Dr. Rugo is director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco comprehensive cancer center.
The results drew praise from ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, since patients with HR+/HER2- metastatic breast cancer who become resistant to endocrine therapy are left with only sequential, single-agent chemotherapy. “We’ve all been eagerly awaiting the results of this trial. These estrogen positive endocrine negative resistant patients really are an area of great unmet clinical need, and their cancers can be very difficult to treat,” Dr. Meisel said during the press conference.
Approximately, 74% of all breast cancers are HR positive/HER2 negative. And, of these, 92% of patients live beyond five years, according to the American Cancer Society.
The study found a relatively small 1.5 months difference in median progression-free survival, but the results are nevertheless clinically important, especially given that 21% of patients were progression-free at one year, compared with 7% in the chemotherapy arm. “When you look at the patients who do respond on sacituzumab govitecan, it seems that they tend to respond better and longer. The idea that someone with such heavily pretreated disease could walk into your clinic and you could offer them an option that would allow them a one in five chance of still not having progressed at one year is really huge from a clinical standpoint,” Dr. Meisel said.
“This is what we need, incremental options that may be different or better than chemotherapy, so I think this really represents a step forward for the field,” he said.
Two other antibody-drug conjugates that are FDA approved for HER2-positive breast cancer include ado-trastuzumab emtansine (Kadcyla, Genentech) and fam-trastuzumab deruxtecan (Enhertu, AstraZeneca, and Daiichi Sankyo). This new wave of therapies is exciting, according to Julie Gralow, MD, who is chief medical officer and executive vice president of ASCO. “I think this way of delivering chemotherapy inside the cancer cell by having an antibody directed to something on the cell surface and then internalization is really, really very interesting,” Dr. Gralow said during the press conference.
The study included 543 patients from 113 international centers who had previously received endocrine therapy, CDK4/6 inhibitors, and at least two previous regimens of chemotherapy. Median progression-free survival (PFS) was 5.5 months in the sacituzumab govitecan group and 4.0 months in the chemotherapy group (hazard ratio, 0.66; P <.001). PFS was more frequent at 6 months (46% vs. 30%) and 12 months (21% vs. 7%). There was no significant improvement in overall survival (13.9 months vs. 12.3 months). The sacituzumab govitecan group had higher rates of overall response (21% vs. 14%) and clinical benefit (34% vs. 22%), as well as a longer median duration of response (7.4 vs. 5.6 months).
Adverse events were more common with sacituzumab govitecan (74% vs. 60%), including low white blood cell counts (51% vs. 39%) and diarrhea (10% vs. 1%). Both groups had low rates of treatment discontinuation due to adverse events (6% in sacituzumab govitecan vs. 4% in chemotherapy).
Dr. Rugo has received honoraria from Puma Biotechnology and Samsung Bioepis, has consulted for Napo Pharmaceuticals, and has received funding from Astellas Pharma, AstraZeneca, Ayala Pharmaceuticals, Daiichi Sankyo, Genentech, Gilead Sciences, Lilly, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Sermonix Pharmaceuticals. Dr. Meisel has advised or consulted for Medscape and Total Health Conferencing. She has advised or consulted for AstraZeneca, Curio Science, Genentech, GlaxoSmithKline, Novartis, and SeaGen. She has received research funding from Pfizer and Seattle Genetics. She has received travel, accommodation, or expenses from Pfizer, Puma Biotechnology, and Total Health Conferencing.
CHICAGO -- An antibody drug conjugate that targets a cell-surface antigen found on most breast and bladder cancers demonstrated improved progression-free survival over standard chemotherapy in patients with endocrine-resistant hormone receptor positive/HER2 negative metastatic breast cancer.
The agent, called sacituzumab govitecan (Trodelvy, Gilead), was approved on an accelerated basis in 2020 by the Food and Drug Administration for patients with unresectable locally advanced or metastatic triple-negative breast cancer. It received regular approval in 2021.
The conjugate includes an antibody that targets the Trop-2 protein. The antibody is bound to govitecan, which is the active metabolite of the topoisomerase inhibitor 1 irinotecan.
“Sacituzumab demonstrated significant and clinically meaningful benefit, compared with chemotherapy in patients with heavily pretreated endocrine resistant hormone receptor positive, HER2 negative, advanced breast cancer and should be considered a potential treatment in this heavily pretreated patient population,” said lead author Hope S. Rugo, MD, during a press conference held June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology. Dr. Rugo is director of Breast Oncology and Clinical Trials Education at the University of California, San Francisco comprehensive cancer center.
The results drew praise from ASCO spokesperson and breast cancer expert Jane Lowe Meisel, MD, since patients with HR+/HER2- metastatic breast cancer who become resistant to endocrine therapy are left with only sequential, single-agent chemotherapy. “We’ve all been eagerly awaiting the results of this trial. These estrogen positive endocrine negative resistant patients really are an area of great unmet clinical need, and their cancers can be very difficult to treat,” Dr. Meisel said during the press conference.
Approximately, 74% of all breast cancers are HR positive/HER2 negative. And, of these, 92% of patients live beyond five years, according to the American Cancer Society.
The study found a relatively small 1.5 months difference in median progression-free survival, but the results are nevertheless clinically important, especially given that 21% of patients were progression-free at one year, compared with 7% in the chemotherapy arm. “When you look at the patients who do respond on sacituzumab govitecan, it seems that they tend to respond better and longer. The idea that someone with such heavily pretreated disease could walk into your clinic and you could offer them an option that would allow them a one in five chance of still not having progressed at one year is really huge from a clinical standpoint,” Dr. Meisel said.
“This is what we need, incremental options that may be different or better than chemotherapy, so I think this really represents a step forward for the field,” he said.
Two other antibody-drug conjugates that are FDA approved for HER2-positive breast cancer include ado-trastuzumab emtansine (Kadcyla, Genentech) and fam-trastuzumab deruxtecan (Enhertu, AstraZeneca, and Daiichi Sankyo). This new wave of therapies is exciting, according to Julie Gralow, MD, who is chief medical officer and executive vice president of ASCO. “I think this way of delivering chemotherapy inside the cancer cell by having an antibody directed to something on the cell surface and then internalization is really, really very interesting,” Dr. Gralow said during the press conference.
The study included 543 patients from 113 international centers who had previously received endocrine therapy, CDK4/6 inhibitors, and at least two previous regimens of chemotherapy. Median progression-free survival (PFS) was 5.5 months in the sacituzumab govitecan group and 4.0 months in the chemotherapy group (hazard ratio, 0.66; P <.001). PFS was more frequent at 6 months (46% vs. 30%) and 12 months (21% vs. 7%). There was no significant improvement in overall survival (13.9 months vs. 12.3 months). The sacituzumab govitecan group had higher rates of overall response (21% vs. 14%) and clinical benefit (34% vs. 22%), as well as a longer median duration of response (7.4 vs. 5.6 months).
Adverse events were more common with sacituzumab govitecan (74% vs. 60%), including low white blood cell counts (51% vs. 39%) and diarrhea (10% vs. 1%). Both groups had low rates of treatment discontinuation due to adverse events (6% in sacituzumab govitecan vs. 4% in chemotherapy).
Dr. Rugo has received honoraria from Puma Biotechnology and Samsung Bioepis, has consulted for Napo Pharmaceuticals, and has received funding from Astellas Pharma, AstraZeneca, Ayala Pharmaceuticals, Daiichi Sankyo, Genentech, Gilead Sciences, Lilly, Merck, Novartis, OBI Pharma, Odonate Therapeutics, Pfizer, and Sermonix Pharmaceuticals. Dr. Meisel has advised or consulted for Medscape and Total Health Conferencing. She has advised or consulted for AstraZeneca, Curio Science, Genentech, GlaxoSmithKline, Novartis, and SeaGen. She has received research funding from Pfizer and Seattle Genetics. She has received travel, accommodation, or expenses from Pfizer, Puma Biotechnology, and Total Health Conferencing.
AT ASCO 2022
ctDNA spots breast cancer recurrence
CHICAGO -- Circulating tumor DNA successfully identified minimal residual disease in patients with hormone receptor-positive (HR+) breast cancer who are at high risk for recurrence – generally years before metastases occurs. The findings come from the CHiRP study, which included patients who were at least 5 years post diagnosis.
The researchers and other groups previously showed that minimal residual disease (MRD) status is associated with distant-recurrence free survival, “yet little is known about ctDNA in the late adjuvant setting in hormone receptor-positive breast cancer,” said Marla Lipsyc-Sharf, MD, a clinical fellow in medicine at Dana-Farber Cancer Institute, Boston. Dr. Lipsyc-Sharf presented her findings June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology.
The study was simultaneously published online in the Journal of Clinical Oncology.
Plasma samples were collected at follow-up visits every 6-12 months, and a personalized version of the RaDaR assay was used to detect ctDNA associated with MRD. Although the technology is currently only useful for research, the team hopes it can soon provide clinical guidance. “The CHiRP study is an important first step toward an understanding of the baseline prevalence and role of ctDNA in this setting. Multiple prospective clinical trials are underway or beginning to establish the clinical utility of ctDNA assays in this setting and understand whether intervention after MRD detection improves patient outcomes, such as survival or quality of life,” she said.
Ben Ho Park, MD, PhD, an oncologist with Vanderbilt University Medical Center, Nashville, Tenn., described the findings as encouraging.
“I think most of us saw this very striking data that you could actually predict who’s going to recur and that all patients who did recur were ctDNA positive. The numbers are really, indeed very encouraging that we can develop assays now that detect minimal residual disease with serum monitoring. It really opens up the floodgates for designing studies [to determine] who to treat with additional adjuvant therapies while they’re still in the adjuvant phase of breast cancer therapy,” Dr. Park said during a discussion that followed the presentation.
The study included 83 patients with high-risk HR+ breast cancer and no evidence of recurrence within 5 years of diagnosis. High risk was defined as T3/T4 and/or N2/N3 disease; T1/N1 disease with 3 or more lymph nodes involved; or T2N1 disease with Ki67 ≥ 20%, grade 3, or oncotype DX score ≥ 26.
For each patient, clinicians designed a tumor-informed liquid biopsy assay to detect plasma ctDNA. A total of 68.7% of participants had stage 3 disease. A total of 90.4% received curative-intent chemotherapy, and all received endocrine therapy. A total of 47% remained on endocrine therapy at their last follow-up.
A total of 93.2% of patients who completed adjuvant endocrine therapy had at least 5 years of treatment. A median of 8.4 years elapsed between diagnosis and first ctDNA sample, and the median follow-up was 10.4 years from diagnosis and 1.8 years from the first sample.
A total of 5% of patients had MRD when they entered the study, and 10% were found to have MRD at any time. Of 6 patients (7.2%) who experienced a metastatic recurrence, all were MRD+, and ctDNA evidence appeared as soon as 37.6 months before diagnosis (median 12.4 months). Of eight patients who were MRD+ at some point, two of them had not had a recurrence at the latest follow-up, and one patient had no follow-up at all, and the other had a follow-up 15.4 months after ctDNA detection.
Limitations of the study included a limited follow-up period and low rate of recurrence, as well as infrequent plasma sampling.
Dr. Lipsyc-Sharf has no relevant financial disclosures. Dr. Park has financial relationships and/or has received funding from Celcuity, Loxo, Casdin Capital, EQRx, Guardant Health, Hologic, Horizon Discovery, Jackson Laboratory for Genomic Medicine, Sermonix Pharmaceuticals, Abbvie, GE Healthcare, Lilly, Pfizer, Horizon Discovery, and Tempus.
CHICAGO -- Circulating tumor DNA successfully identified minimal residual disease in patients with hormone receptor-positive (HR+) breast cancer who are at high risk for recurrence – generally years before metastases occurs. The findings come from the CHiRP study, which included patients who were at least 5 years post diagnosis.
The researchers and other groups previously showed that minimal residual disease (MRD) status is associated with distant-recurrence free survival, “yet little is known about ctDNA in the late adjuvant setting in hormone receptor-positive breast cancer,” said Marla Lipsyc-Sharf, MD, a clinical fellow in medicine at Dana-Farber Cancer Institute, Boston. Dr. Lipsyc-Sharf presented her findings June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology.
The study was simultaneously published online in the Journal of Clinical Oncology.
Plasma samples were collected at follow-up visits every 6-12 months, and a personalized version of the RaDaR assay was used to detect ctDNA associated with MRD. Although the technology is currently only useful for research, the team hopes it can soon provide clinical guidance. “The CHiRP study is an important first step toward an understanding of the baseline prevalence and role of ctDNA in this setting. Multiple prospective clinical trials are underway or beginning to establish the clinical utility of ctDNA assays in this setting and understand whether intervention after MRD detection improves patient outcomes, such as survival or quality of life,” she said.
Ben Ho Park, MD, PhD, an oncologist with Vanderbilt University Medical Center, Nashville, Tenn., described the findings as encouraging.
“I think most of us saw this very striking data that you could actually predict who’s going to recur and that all patients who did recur were ctDNA positive. The numbers are really, indeed very encouraging that we can develop assays now that detect minimal residual disease with serum monitoring. It really opens up the floodgates for designing studies [to determine] who to treat with additional adjuvant therapies while they’re still in the adjuvant phase of breast cancer therapy,” Dr. Park said during a discussion that followed the presentation.
The study included 83 patients with high-risk HR+ breast cancer and no evidence of recurrence within 5 years of diagnosis. High risk was defined as T3/T4 and/or N2/N3 disease; T1/N1 disease with 3 or more lymph nodes involved; or T2N1 disease with Ki67 ≥ 20%, grade 3, or oncotype DX score ≥ 26.
For each patient, clinicians designed a tumor-informed liquid biopsy assay to detect plasma ctDNA. A total of 68.7% of participants had stage 3 disease. A total of 90.4% received curative-intent chemotherapy, and all received endocrine therapy. A total of 47% remained on endocrine therapy at their last follow-up.
A total of 93.2% of patients who completed adjuvant endocrine therapy had at least 5 years of treatment. A median of 8.4 years elapsed between diagnosis and first ctDNA sample, and the median follow-up was 10.4 years from diagnosis and 1.8 years from the first sample.
A total of 5% of patients had MRD when they entered the study, and 10% were found to have MRD at any time. Of 6 patients (7.2%) who experienced a metastatic recurrence, all were MRD+, and ctDNA evidence appeared as soon as 37.6 months before diagnosis (median 12.4 months). Of eight patients who were MRD+ at some point, two of them had not had a recurrence at the latest follow-up, and one patient had no follow-up at all, and the other had a follow-up 15.4 months after ctDNA detection.
Limitations of the study included a limited follow-up period and low rate of recurrence, as well as infrequent plasma sampling.
Dr. Lipsyc-Sharf has no relevant financial disclosures. Dr. Park has financial relationships and/or has received funding from Celcuity, Loxo, Casdin Capital, EQRx, Guardant Health, Hologic, Horizon Discovery, Jackson Laboratory for Genomic Medicine, Sermonix Pharmaceuticals, Abbvie, GE Healthcare, Lilly, Pfizer, Horizon Discovery, and Tempus.
CHICAGO -- Circulating tumor DNA successfully identified minimal residual disease in patients with hormone receptor-positive (HR+) breast cancer who are at high risk for recurrence – generally years before metastases occurs. The findings come from the CHiRP study, which included patients who were at least 5 years post diagnosis.
The researchers and other groups previously showed that minimal residual disease (MRD) status is associated with distant-recurrence free survival, “yet little is known about ctDNA in the late adjuvant setting in hormone receptor-positive breast cancer,” said Marla Lipsyc-Sharf, MD, a clinical fellow in medicine at Dana-Farber Cancer Institute, Boston. Dr. Lipsyc-Sharf presented her findings June 4 in Chicago at the annual meeting of the American Society of Clinical Oncology.
The study was simultaneously published online in the Journal of Clinical Oncology.
Plasma samples were collected at follow-up visits every 6-12 months, and a personalized version of the RaDaR assay was used to detect ctDNA associated with MRD. Although the technology is currently only useful for research, the team hopes it can soon provide clinical guidance. “The CHiRP study is an important first step toward an understanding of the baseline prevalence and role of ctDNA in this setting. Multiple prospective clinical trials are underway or beginning to establish the clinical utility of ctDNA assays in this setting and understand whether intervention after MRD detection improves patient outcomes, such as survival or quality of life,” she said.
Ben Ho Park, MD, PhD, an oncologist with Vanderbilt University Medical Center, Nashville, Tenn., described the findings as encouraging.
“I think most of us saw this very striking data that you could actually predict who’s going to recur and that all patients who did recur were ctDNA positive. The numbers are really, indeed very encouraging that we can develop assays now that detect minimal residual disease with serum monitoring. It really opens up the floodgates for designing studies [to determine] who to treat with additional adjuvant therapies while they’re still in the adjuvant phase of breast cancer therapy,” Dr. Park said during a discussion that followed the presentation.
The study included 83 patients with high-risk HR+ breast cancer and no evidence of recurrence within 5 years of diagnosis. High risk was defined as T3/T4 and/or N2/N3 disease; T1/N1 disease with 3 or more lymph nodes involved; or T2N1 disease with Ki67 ≥ 20%, grade 3, or oncotype DX score ≥ 26.
For each patient, clinicians designed a tumor-informed liquid biopsy assay to detect plasma ctDNA. A total of 68.7% of participants had stage 3 disease. A total of 90.4% received curative-intent chemotherapy, and all received endocrine therapy. A total of 47% remained on endocrine therapy at their last follow-up.
A total of 93.2% of patients who completed adjuvant endocrine therapy had at least 5 years of treatment. A median of 8.4 years elapsed between diagnosis and first ctDNA sample, and the median follow-up was 10.4 years from diagnosis and 1.8 years from the first sample.
A total of 5% of patients had MRD when they entered the study, and 10% were found to have MRD at any time. Of 6 patients (7.2%) who experienced a metastatic recurrence, all were MRD+, and ctDNA evidence appeared as soon as 37.6 months before diagnosis (median 12.4 months). Of eight patients who were MRD+ at some point, two of them had not had a recurrence at the latest follow-up, and one patient had no follow-up at all, and the other had a follow-up 15.4 months after ctDNA detection.
Limitations of the study included a limited follow-up period and low rate of recurrence, as well as infrequent plasma sampling.
Dr. Lipsyc-Sharf has no relevant financial disclosures. Dr. Park has financial relationships and/or has received funding from Celcuity, Loxo, Casdin Capital, EQRx, Guardant Health, Hologic, Horizon Discovery, Jackson Laboratory for Genomic Medicine, Sermonix Pharmaceuticals, Abbvie, GE Healthcare, Lilly, Pfizer, Horizon Discovery, and Tempus.
AT ASCO 2022
TNF placental transfer makes little difference in offspring infections
COPENHAGEN – Here’s reassuring news for pregnant women with rheumatic diseases treated with tumor necrosis factor (TNF)–alpha inhibitors: Although the drugs vary widely in their transmissibility across the placenta, there appears to be no excess risk for serious infections in children exposed in utero to TNF inhibitors with high, compared with low, placental transfer.
That’s according to investigators at McGill University in Montreal, who studied outcomes for nearly 3,000 infants who were exposed to TNF inhibitors during gestation.
“Our data are reassuring as we saw no strong signal, which suggests that there is no need to switch the mother’s drugs. More studies are needed, but this is a step in the right direction to reduce maternal stress and reassure physicians,” said Leah K. Flatman, MSc, a PhD candidate in epidemiology at McGill.
Ms. Flatman presented the findings in an oral abstract session at the annual European Congress of Rheumatology.
Not without risks
Approximately 20% of pregnant women with chronic inflammatory diseases are prescribed a TNF inhibitor, a class of drug that is effective for disease control but also increases risk for infection because of immunosuppressive effects.
“Similarly, offspring exposed in utero to TNF inhibitors may also experience immunosuppression and subsequent serious infections in their first year of life. This is the result of the TNF inhibitor entering the fetal bloodstream at different concentrations,» Ms. Flatman said.
Anti-TNF monoclonal immunoglobulins, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and golimumab (Simponi) have the highest placental transfer, reaching higher levels in fetal circulation than in maternal circulation, she noted.
In contrast, certolizumab (Cimzia), a pegylated humanized antigen-binding fragment, and etanercept (Enbrel and biosimilars), a fusion protein, have the lowest placental penetration, Ms. Flatman said.
Population study
The investigators conducted a population cohort study using the IBM MarketScan database of commercial claims from employer-provided health insurance plans in the United States.
They looked at data on offspring of mothers with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and/or inflammatory bowel diseases (IBD; Crohn’s disease, and ulcerative colitis). The children were born from Jan. 1, 2011 through Dec. 31, 2019.
The exposure was at least one filled prescription and/or infusion procedure claim for TNF inhibitors in the 6 months before delivery. The exposures were divided into high and low placental-transfer categories.
A total of 26,088 offspring were identified, of whom 2,902 (11.1%) were exposed to a TNF inhibitor in utero. A little more than half of these children were born to mothers treated with TNF inhibitors for IBD.
For the primary outcome of serious infections (based on at least one hospitalization with infection in the first year of life), the investigators plotted Kaplan-Meier curves, which showed that the survival probability of serious infections in the high and low groups overlapped, indicating no large differences.
Of 2,105 offspring of mothers treated with a high–placental-transfer drug, 38 (1.8%) had serious infections, compared with 10 of 797 offspring (1.3%) of mothers who received low–placental-transfer drugs.
In multivariable analysis that controlled for maternal age at delivery, any RA diagnosis without an IBD diagnosis, and IBD diagnosis, gestational or pregestational diabetes, maternal asthma, preterm delivery, corticosteroid use, and disease-modifying antirheumatic drug use, the investigators saw that the hazard ratio for risk for serious infection in the high–, compared with the low–placental-transfer group was 1.20, with a confidence interval crossing 1, indicating nonsignificance.
Similar results reported
Frauke Förger, MD, professor of rheumatology and immunology at the University of Bern (Switzerland), who comoderated the oral abstract session where the data were presented, told this news organization that the findings were in line with those of a recent meta-analysis looking at the safety of biologic agents in pregnant women with IBD.
She added, however, that although the meta-analysis also showed little difference in outcomes for the children of women treated with high– compared with low–placental-transfer drugs, “we need more data to be sure about this.”
Comoderator Gabriela Riemekasten, MD, director of the clinic for rheumatology and clinical immunology at University Hospital in Lübeck, Germany, told this news organization that she was surprised to see that more women received high– than low–placental-transfer drugs.
Although there was a 20% difference between the groups, the numbers were relatively low, and “I would consider this in my practice and give my patients the advice of these data,” she said.
The study was supported by an Arthritis Society PhD Salary Award, and a Canadian Institutes of Health Project grant. Ms. Flatman, Dr. Förger, and Dr. Riemekasten reported having no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
COPENHAGEN – Here’s reassuring news for pregnant women with rheumatic diseases treated with tumor necrosis factor (TNF)–alpha inhibitors: Although the drugs vary widely in their transmissibility across the placenta, there appears to be no excess risk for serious infections in children exposed in utero to TNF inhibitors with high, compared with low, placental transfer.
That’s according to investigators at McGill University in Montreal, who studied outcomes for nearly 3,000 infants who were exposed to TNF inhibitors during gestation.
“Our data are reassuring as we saw no strong signal, which suggests that there is no need to switch the mother’s drugs. More studies are needed, but this is a step in the right direction to reduce maternal stress and reassure physicians,” said Leah K. Flatman, MSc, a PhD candidate in epidemiology at McGill.
Ms. Flatman presented the findings in an oral abstract session at the annual European Congress of Rheumatology.
Not without risks
Approximately 20% of pregnant women with chronic inflammatory diseases are prescribed a TNF inhibitor, a class of drug that is effective for disease control but also increases risk for infection because of immunosuppressive effects.
“Similarly, offspring exposed in utero to TNF inhibitors may also experience immunosuppression and subsequent serious infections in their first year of life. This is the result of the TNF inhibitor entering the fetal bloodstream at different concentrations,» Ms. Flatman said.
Anti-TNF monoclonal immunoglobulins, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and golimumab (Simponi) have the highest placental transfer, reaching higher levels in fetal circulation than in maternal circulation, she noted.
In contrast, certolizumab (Cimzia), a pegylated humanized antigen-binding fragment, and etanercept (Enbrel and biosimilars), a fusion protein, have the lowest placental penetration, Ms. Flatman said.
Population study
The investigators conducted a population cohort study using the IBM MarketScan database of commercial claims from employer-provided health insurance plans in the United States.
They looked at data on offspring of mothers with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and/or inflammatory bowel diseases (IBD; Crohn’s disease, and ulcerative colitis). The children were born from Jan. 1, 2011 through Dec. 31, 2019.
The exposure was at least one filled prescription and/or infusion procedure claim for TNF inhibitors in the 6 months before delivery. The exposures were divided into high and low placental-transfer categories.
A total of 26,088 offspring were identified, of whom 2,902 (11.1%) were exposed to a TNF inhibitor in utero. A little more than half of these children were born to mothers treated with TNF inhibitors for IBD.
For the primary outcome of serious infections (based on at least one hospitalization with infection in the first year of life), the investigators plotted Kaplan-Meier curves, which showed that the survival probability of serious infections in the high and low groups overlapped, indicating no large differences.
Of 2,105 offspring of mothers treated with a high–placental-transfer drug, 38 (1.8%) had serious infections, compared with 10 of 797 offspring (1.3%) of mothers who received low–placental-transfer drugs.
In multivariable analysis that controlled for maternal age at delivery, any RA diagnosis without an IBD diagnosis, and IBD diagnosis, gestational or pregestational diabetes, maternal asthma, preterm delivery, corticosteroid use, and disease-modifying antirheumatic drug use, the investigators saw that the hazard ratio for risk for serious infection in the high–, compared with the low–placental-transfer group was 1.20, with a confidence interval crossing 1, indicating nonsignificance.
Similar results reported
Frauke Förger, MD, professor of rheumatology and immunology at the University of Bern (Switzerland), who comoderated the oral abstract session where the data were presented, told this news organization that the findings were in line with those of a recent meta-analysis looking at the safety of biologic agents in pregnant women with IBD.
She added, however, that although the meta-analysis also showed little difference in outcomes for the children of women treated with high– compared with low–placental-transfer drugs, “we need more data to be sure about this.”
Comoderator Gabriela Riemekasten, MD, director of the clinic for rheumatology and clinical immunology at University Hospital in Lübeck, Germany, told this news organization that she was surprised to see that more women received high– than low–placental-transfer drugs.
Although there was a 20% difference between the groups, the numbers were relatively low, and “I would consider this in my practice and give my patients the advice of these data,” she said.
The study was supported by an Arthritis Society PhD Salary Award, and a Canadian Institutes of Health Project grant. Ms. Flatman, Dr. Förger, and Dr. Riemekasten reported having no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
COPENHAGEN – Here’s reassuring news for pregnant women with rheumatic diseases treated with tumor necrosis factor (TNF)–alpha inhibitors: Although the drugs vary widely in their transmissibility across the placenta, there appears to be no excess risk for serious infections in children exposed in utero to TNF inhibitors with high, compared with low, placental transfer.
That’s according to investigators at McGill University in Montreal, who studied outcomes for nearly 3,000 infants who were exposed to TNF inhibitors during gestation.
“Our data are reassuring as we saw no strong signal, which suggests that there is no need to switch the mother’s drugs. More studies are needed, but this is a step in the right direction to reduce maternal stress and reassure physicians,” said Leah K. Flatman, MSc, a PhD candidate in epidemiology at McGill.
Ms. Flatman presented the findings in an oral abstract session at the annual European Congress of Rheumatology.
Not without risks
Approximately 20% of pregnant women with chronic inflammatory diseases are prescribed a TNF inhibitor, a class of drug that is effective for disease control but also increases risk for infection because of immunosuppressive effects.
“Similarly, offspring exposed in utero to TNF inhibitors may also experience immunosuppression and subsequent serious infections in their first year of life. This is the result of the TNF inhibitor entering the fetal bloodstream at different concentrations,» Ms. Flatman said.
Anti-TNF monoclonal immunoglobulins, such as infliximab (Remicade and biosimilars), adalimumab (Humira and biosimilars), and golimumab (Simponi) have the highest placental transfer, reaching higher levels in fetal circulation than in maternal circulation, she noted.
In contrast, certolizumab (Cimzia), a pegylated humanized antigen-binding fragment, and etanercept (Enbrel and biosimilars), a fusion protein, have the lowest placental penetration, Ms. Flatman said.
Population study
The investigators conducted a population cohort study using the IBM MarketScan database of commercial claims from employer-provided health insurance plans in the United States.
They looked at data on offspring of mothers with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and/or inflammatory bowel diseases (IBD; Crohn’s disease, and ulcerative colitis). The children were born from Jan. 1, 2011 through Dec. 31, 2019.
The exposure was at least one filled prescription and/or infusion procedure claim for TNF inhibitors in the 6 months before delivery. The exposures were divided into high and low placental-transfer categories.
A total of 26,088 offspring were identified, of whom 2,902 (11.1%) were exposed to a TNF inhibitor in utero. A little more than half of these children were born to mothers treated with TNF inhibitors for IBD.
For the primary outcome of serious infections (based on at least one hospitalization with infection in the first year of life), the investigators plotted Kaplan-Meier curves, which showed that the survival probability of serious infections in the high and low groups overlapped, indicating no large differences.
Of 2,105 offspring of mothers treated with a high–placental-transfer drug, 38 (1.8%) had serious infections, compared with 10 of 797 offspring (1.3%) of mothers who received low–placental-transfer drugs.
In multivariable analysis that controlled for maternal age at delivery, any RA diagnosis without an IBD diagnosis, and IBD diagnosis, gestational or pregestational diabetes, maternal asthma, preterm delivery, corticosteroid use, and disease-modifying antirheumatic drug use, the investigators saw that the hazard ratio for risk for serious infection in the high–, compared with the low–placental-transfer group was 1.20, with a confidence interval crossing 1, indicating nonsignificance.
Similar results reported
Frauke Förger, MD, professor of rheumatology and immunology at the University of Bern (Switzerland), who comoderated the oral abstract session where the data were presented, told this news organization that the findings were in line with those of a recent meta-analysis looking at the safety of biologic agents in pregnant women with IBD.
She added, however, that although the meta-analysis also showed little difference in outcomes for the children of women treated with high– compared with low–placental-transfer drugs, “we need more data to be sure about this.”
Comoderator Gabriela Riemekasten, MD, director of the clinic for rheumatology and clinical immunology at University Hospital in Lübeck, Germany, told this news organization that she was surprised to see that more women received high– than low–placental-transfer drugs.
Although there was a 20% difference between the groups, the numbers were relatively low, and “I would consider this in my practice and give my patients the advice of these data,” she said.
The study was supported by an Arthritis Society PhD Salary Award, and a Canadian Institutes of Health Project grant. Ms. Flatman, Dr. Förger, and Dr. Riemekasten reported having no relevant financial disclosures.
A version of this article first appeared on Medscape.com.
THE EULAR 2022 CONGRESS
‘Encouraging’ results of baricitinib in juvenile idiopathic arthritis
COPENHAGEN – Baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, significantly increases time to disease flare and decreases frequency of flares in patients with juvenile idiopathic arthritis (JIA), according to the results of a phase 3, placebo-controlled study.
The results support use of baricitinib when biologic or conventional synthetic disease-modifying antirheumatic drugs (DMARDs) fail.
The difference in the proportion of patients who flared between baricitinib and placebo was seen as soon as 4 weeks after half of the patients switched from active drug to placebo, at 3.7% versus 23.5% respectively, reported Athimalaipet Ramanan, MD, from the University of Bristol (England) who presented the findings of the withdrawal, efficacy, and safety study at the annual European Congress of Rheumatology.
“Our patients and parents have been waiting for alternative drugs for JIA, so JAK inhibitors have come at the right time,” he said. “These are really very encouraging findings for families, caregivers, and patients with JIA, to have an effective oral JAK inhibitor for managing these children.”
In reporting the key findings, Dr. Ramanan added that the majority of patients (76%) achieved a JIA-ACR (American College of Rheumatology) 30 score during the 12-week open-label phase and went on to enter the double-blind withdrawal phase of the trial.
Baricitinib 2-mg tablets are already Food and Drug Administration approved for the treatment of adults with moderately to severely active rheumatoid arthritis. This study, sponsored by the drug manufacturer Eli Lilly, aimed to investigate the efficacy and safety in pediatric patients with JIA who have shown an inadequate response to conventional synthetic or biologic DMARDs.
“For juvenile patients we need to make a dose adjustment [from the adult dosing], especially because we don’t have long-term safety data from JAK inhibitors in general,” said Osama Elfayad, MD, rheumatologist from Mouwasat Hospital, Dammam, Saudi Arabia who attended the presentation and commented on the findings.
He emphasized that safety was of primary concern in the pediatric population who have a long life expectancy. “For me it is essential to have good long-term safety data in juvenile patients. If we start with 4 mg and if the patient is controlled, we should shift to 2 mg which will be much better. I understand some clinicians are asking for 1 mg.”
Study details
The study population included patients aged from 2 to 17 years old with extended oligo- or polyarticular JIA, enthesitis-related juvenile idiopathic arthritis (ERA) and juvenile psoriatic arthritis.
The trial was divided into three periods: a 2-week safety assessment, a 12-week open-label lead-in phase, and an up-to 32-week double-blind withdrawal phase. After confirmation of dose and safety, children were enrolled in the open-label phase receiving age-based, oral, once daily doses of baricitinib.
“The primary endpoint is really concerned with the next phase of the study [double-blind withdrawal phase] looking at the proportion of patients who have shown a response at week 12 [achieved JIA-ACR30] but when switched from active drug to placebo have a flare,” explained Dr. Ramanan.
Patients were randomized 1:1 to continuing baricitinib or newly starting placebo until disease flare or up to week 32. The time to flare during the double-blind phase was the primary endpoint, while secondary endpoints included JIA-ACR30/50/70/90 response rates at week 12, and the proportion of patients with a flare during the double-blind phase.
“These secondary endpoints are more relevant to the clinic,” noted Dr. Ramanan.
A total of 219 patients entered the open-label phase, and of these, 163 achieved a JIA-ACR 30. These 163 children entered the double-blind stage and were randomized to baricitinib four times a day (56 completed), or placebo (32 completed).
Two-thirds of patients were female, which is typical of the disease, explained Dr. Ramanan, and over two-thirds were White. “Most patients had had disease for around 4 years, and about half had had prior biologic therapy. About half were on baseline methotrexate and almost one-third had used corticosteroids although at doses of under 0.2mg/kg.
“It’s gratifying to see that over 75% achieved a JIA-ACR 30 [76.3%]. More importantly, two-thirds of the patients have a JIA-ACR 50 [63.5%], and almost half of the patients have a JIA-ACR 70 [46.1%]. This is pretty significant at 12 weeks only,” he remarked.
The key finding, however, was in the withdrawal phase, said Dr. Ramanan. “We see that those patients who had a response at week 12 and were then switched to placebo, about half [50.6%] flared on placebo, compared to only 17% of those who continued with baricitinib. So not only do those who switch to placebo have a higher frequency of flares but they are more likely to flare quickly, as early as 4 weeks.”
With respect to safety, he said: “This shows short-term safety, but what we really need is medium and long-term safety data. It is no surprise that most of the events seen were as expected in children including nasopharyngitis, upper respiratory tract infections, and nausea.”
In the baricitinib versus placebo phase, 4.9% had serious adverse events in the baricitinib group compared to 3.7% in the placebo group. “There was nothing we didn’t expect to see which was mainly infection,” said Dr. Ramanan.
Dr. Elfayad has no disclosures. Professor Ramanan is a consultant for Eli Lilly, Abbvie, Roche, UCB, Novartis, Pfizer, and Sobi. He has received grant/research support from Eli Lilly.
COPENHAGEN – Baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, significantly increases time to disease flare and decreases frequency of flares in patients with juvenile idiopathic arthritis (JIA), according to the results of a phase 3, placebo-controlled study.
The results support use of baricitinib when biologic or conventional synthetic disease-modifying antirheumatic drugs (DMARDs) fail.
The difference in the proportion of patients who flared between baricitinib and placebo was seen as soon as 4 weeks after half of the patients switched from active drug to placebo, at 3.7% versus 23.5% respectively, reported Athimalaipet Ramanan, MD, from the University of Bristol (England) who presented the findings of the withdrawal, efficacy, and safety study at the annual European Congress of Rheumatology.
“Our patients and parents have been waiting for alternative drugs for JIA, so JAK inhibitors have come at the right time,” he said. “These are really very encouraging findings for families, caregivers, and patients with JIA, to have an effective oral JAK inhibitor for managing these children.”
In reporting the key findings, Dr. Ramanan added that the majority of patients (76%) achieved a JIA-ACR (American College of Rheumatology) 30 score during the 12-week open-label phase and went on to enter the double-blind withdrawal phase of the trial.
Baricitinib 2-mg tablets are already Food and Drug Administration approved for the treatment of adults with moderately to severely active rheumatoid arthritis. This study, sponsored by the drug manufacturer Eli Lilly, aimed to investigate the efficacy and safety in pediatric patients with JIA who have shown an inadequate response to conventional synthetic or biologic DMARDs.
“For juvenile patients we need to make a dose adjustment [from the adult dosing], especially because we don’t have long-term safety data from JAK inhibitors in general,” said Osama Elfayad, MD, rheumatologist from Mouwasat Hospital, Dammam, Saudi Arabia who attended the presentation and commented on the findings.
He emphasized that safety was of primary concern in the pediatric population who have a long life expectancy. “For me it is essential to have good long-term safety data in juvenile patients. If we start with 4 mg and if the patient is controlled, we should shift to 2 mg which will be much better. I understand some clinicians are asking for 1 mg.”
Study details
The study population included patients aged from 2 to 17 years old with extended oligo- or polyarticular JIA, enthesitis-related juvenile idiopathic arthritis (ERA) and juvenile psoriatic arthritis.
The trial was divided into three periods: a 2-week safety assessment, a 12-week open-label lead-in phase, and an up-to 32-week double-blind withdrawal phase. After confirmation of dose and safety, children were enrolled in the open-label phase receiving age-based, oral, once daily doses of baricitinib.
“The primary endpoint is really concerned with the next phase of the study [double-blind withdrawal phase] looking at the proportion of patients who have shown a response at week 12 [achieved JIA-ACR30] but when switched from active drug to placebo have a flare,” explained Dr. Ramanan.
Patients were randomized 1:1 to continuing baricitinib or newly starting placebo until disease flare or up to week 32. The time to flare during the double-blind phase was the primary endpoint, while secondary endpoints included JIA-ACR30/50/70/90 response rates at week 12, and the proportion of patients with a flare during the double-blind phase.
“These secondary endpoints are more relevant to the clinic,” noted Dr. Ramanan.
A total of 219 patients entered the open-label phase, and of these, 163 achieved a JIA-ACR 30. These 163 children entered the double-blind stage and were randomized to baricitinib four times a day (56 completed), or placebo (32 completed).
Two-thirds of patients were female, which is typical of the disease, explained Dr. Ramanan, and over two-thirds were White. “Most patients had had disease for around 4 years, and about half had had prior biologic therapy. About half were on baseline methotrexate and almost one-third had used corticosteroids although at doses of under 0.2mg/kg.
“It’s gratifying to see that over 75% achieved a JIA-ACR 30 [76.3%]. More importantly, two-thirds of the patients have a JIA-ACR 50 [63.5%], and almost half of the patients have a JIA-ACR 70 [46.1%]. This is pretty significant at 12 weeks only,” he remarked.
The key finding, however, was in the withdrawal phase, said Dr. Ramanan. “We see that those patients who had a response at week 12 and were then switched to placebo, about half [50.6%] flared on placebo, compared to only 17% of those who continued with baricitinib. So not only do those who switch to placebo have a higher frequency of flares but they are more likely to flare quickly, as early as 4 weeks.”
With respect to safety, he said: “This shows short-term safety, but what we really need is medium and long-term safety data. It is no surprise that most of the events seen were as expected in children including nasopharyngitis, upper respiratory tract infections, and nausea.”
In the baricitinib versus placebo phase, 4.9% had serious adverse events in the baricitinib group compared to 3.7% in the placebo group. “There was nothing we didn’t expect to see which was mainly infection,” said Dr. Ramanan.
Dr. Elfayad has no disclosures. Professor Ramanan is a consultant for Eli Lilly, Abbvie, Roche, UCB, Novartis, Pfizer, and Sobi. He has received grant/research support from Eli Lilly.
COPENHAGEN – Baricitinib (Olumiant), a Janus kinase (JAK) inhibitor, significantly increases time to disease flare and decreases frequency of flares in patients with juvenile idiopathic arthritis (JIA), according to the results of a phase 3, placebo-controlled study.
The results support use of baricitinib when biologic or conventional synthetic disease-modifying antirheumatic drugs (DMARDs) fail.
The difference in the proportion of patients who flared between baricitinib and placebo was seen as soon as 4 weeks after half of the patients switched from active drug to placebo, at 3.7% versus 23.5% respectively, reported Athimalaipet Ramanan, MD, from the University of Bristol (England) who presented the findings of the withdrawal, efficacy, and safety study at the annual European Congress of Rheumatology.
“Our patients and parents have been waiting for alternative drugs for JIA, so JAK inhibitors have come at the right time,” he said. “These are really very encouraging findings for families, caregivers, and patients with JIA, to have an effective oral JAK inhibitor for managing these children.”
In reporting the key findings, Dr. Ramanan added that the majority of patients (76%) achieved a JIA-ACR (American College of Rheumatology) 30 score during the 12-week open-label phase and went on to enter the double-blind withdrawal phase of the trial.
Baricitinib 2-mg tablets are already Food and Drug Administration approved for the treatment of adults with moderately to severely active rheumatoid arthritis. This study, sponsored by the drug manufacturer Eli Lilly, aimed to investigate the efficacy and safety in pediatric patients with JIA who have shown an inadequate response to conventional synthetic or biologic DMARDs.
“For juvenile patients we need to make a dose adjustment [from the adult dosing], especially because we don’t have long-term safety data from JAK inhibitors in general,” said Osama Elfayad, MD, rheumatologist from Mouwasat Hospital, Dammam, Saudi Arabia who attended the presentation and commented on the findings.
He emphasized that safety was of primary concern in the pediatric population who have a long life expectancy. “For me it is essential to have good long-term safety data in juvenile patients. If we start with 4 mg and if the patient is controlled, we should shift to 2 mg which will be much better. I understand some clinicians are asking for 1 mg.”
Study details
The study population included patients aged from 2 to 17 years old with extended oligo- or polyarticular JIA, enthesitis-related juvenile idiopathic arthritis (ERA) and juvenile psoriatic arthritis.
The trial was divided into three periods: a 2-week safety assessment, a 12-week open-label lead-in phase, and an up-to 32-week double-blind withdrawal phase. After confirmation of dose and safety, children were enrolled in the open-label phase receiving age-based, oral, once daily doses of baricitinib.
“The primary endpoint is really concerned with the next phase of the study [double-blind withdrawal phase] looking at the proportion of patients who have shown a response at week 12 [achieved JIA-ACR30] but when switched from active drug to placebo have a flare,” explained Dr. Ramanan.
Patients were randomized 1:1 to continuing baricitinib or newly starting placebo until disease flare or up to week 32. The time to flare during the double-blind phase was the primary endpoint, while secondary endpoints included JIA-ACR30/50/70/90 response rates at week 12, and the proportion of patients with a flare during the double-blind phase.
“These secondary endpoints are more relevant to the clinic,” noted Dr. Ramanan.
A total of 219 patients entered the open-label phase, and of these, 163 achieved a JIA-ACR 30. These 163 children entered the double-blind stage and were randomized to baricitinib four times a day (56 completed), or placebo (32 completed).
Two-thirds of patients were female, which is typical of the disease, explained Dr. Ramanan, and over two-thirds were White. “Most patients had had disease for around 4 years, and about half had had prior biologic therapy. About half were on baseline methotrexate and almost one-third had used corticosteroids although at doses of under 0.2mg/kg.
“It’s gratifying to see that over 75% achieved a JIA-ACR 30 [76.3%]. More importantly, two-thirds of the patients have a JIA-ACR 50 [63.5%], and almost half of the patients have a JIA-ACR 70 [46.1%]. This is pretty significant at 12 weeks only,” he remarked.
The key finding, however, was in the withdrawal phase, said Dr. Ramanan. “We see that those patients who had a response at week 12 and were then switched to placebo, about half [50.6%] flared on placebo, compared to only 17% of those who continued with baricitinib. So not only do those who switch to placebo have a higher frequency of flares but they are more likely to flare quickly, as early as 4 weeks.”
With respect to safety, he said: “This shows short-term safety, but what we really need is medium and long-term safety data. It is no surprise that most of the events seen were as expected in children including nasopharyngitis, upper respiratory tract infections, and nausea.”
In the baricitinib versus placebo phase, 4.9% had serious adverse events in the baricitinib group compared to 3.7% in the placebo group. “There was nothing we didn’t expect to see which was mainly infection,” said Dr. Ramanan.
Dr. Elfayad has no disclosures. Professor Ramanan is a consultant for Eli Lilly, Abbvie, Roche, UCB, Novartis, Pfizer, and Sobi. He has received grant/research support from Eli Lilly.
AT THE EULAR 2022 CONGRESS
Izokibep improves multiple psoriatic arthritis symptoms in phase 2 study
A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.
Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.
There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.
Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”
He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”
Small and potent, a novel IL-17 inhibitor
Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.
Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.
Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.”
So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.
Testing two doses of izokibep in psoriatic arthritis
The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.
Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.
ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.
“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.
Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.
More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.
There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.
“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.
“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.
“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.
As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.
Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.
Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.
Dr. Behrens and Dr. Taylor were investigators in the study.
Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche
Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.
A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.
Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.
There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.
Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”
He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”
Small and potent, a novel IL-17 inhibitor
Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.
Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.
Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.”
So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.
Testing two doses of izokibep in psoriatic arthritis
The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.
Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.
ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.
“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.
Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.
More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.
There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.
“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.
“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.
“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.
As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.
Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.
Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.
Dr. Behrens and Dr. Taylor were investigators in the study.
Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche
Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.
A host of psoriatic arthritis symptoms can be improved by the investigational interleukin (IL)-17 blocker izokibep, according to the results of a phase 2 trial presented at the annual European Congress of Rheumatology.
Around half of all participants in the trial who were treated with izokibep achieved a 50% or higher improvement in American College of Rheumatology response criteria (ACR50) at week 16, the trial’s primary endpoint. This was highly significant (P = .0003) when compared to the control group, where only 13% of patients given a placebo achieved an ACR50.
There was also a significant improvement in skin symptoms, as assessed by the Psoriasis Area and Severity Index (PASI) and resolution of enthesitis in 88% of patients given the highest dose of izokibep.
Aurelie Najm, MD, PhD, of the Institute of Infection, Immunity and Inflammation at the University of Glasgow, who tweeted about the main results, said that the data also looked “promising for the enthesitis domain” with a “safety profile similar to that observed in PsO [psoriasis].”Peter Taylor, MA, PhD, FRCP, FRCPE, of the University of Oxford in England, said: “The improvements demonstrated in arthritis, psoriasis, and enthesitis are exciting relative to responses reported for the current standard of care.”
He continued, in a statement issued jointly by Affibody, Acelyrin, and Immagene Biopharmaceuticals – the three companies assessing izokibep’s therapeutic potential – that the drug “seems promising” and that he was “eager to see its continued development for patients.”
Small and potent, a novel IL-17 inhibitor
Izokibep is an antibody mimetic that inhibits IL-17A designed to “overcome the limitations of monoclonal antibodies,” according to its developers.
Due to its small molecular size – reportedly about one-tenth of the size of a monoclonal antibody – they say that levels of high drug exposure can be achieved from a single, subcutaneous injection rather than an intravenous infusion, which is needed for monoclonal antibodies.
Moreover, izokibep’s small size means it could potentially reach target tissues “that may otherwise be inaccessible to the much larger monoclonal antibodies.”
So far more than 300 patients have been treated with izokibep, some for up to 3 years, but not all have had psoriatic arthritis. Indeed, the drug has been tested in patients with psoriasis, and there are a few actively recruiting trials including one in ankylosing spondylitis, another in noninfective uveitis, and one in the rare and painful skin condition hidradenitis suppurativa.
Testing two doses of izokibep in psoriatic arthritis
The trial presented at the EULAR 2022 Congress tested two doses of izokibep – 40 mg and 80 mg – given by subcutaneous injection every 2 weeks – against placebo in 135 adult patients with active psoriatic arthritis. For inclusion in the trial patients had to have at least three swollen and at least three tender joints and have had an inadequate response to prior therapy including nonsteroidal anti-inflammatory drugs, conventional synthetic disease-modifying antirheumatic drugs, or tumor necrosis factor inhibitors.
Principle investigator Frank Behrens, MD, of Goethe University Frankfurt, Germany, reported that it was a multicenter effort conducted at 22 European sites with the primary endpoint being an ACR50 response at 16 weeks. This was met by 52% of patients given the 80-mg dose of izokibep, 48% of patients given the 40-mg dose of izokibep, and just 13% of patients who had been randomized to placebo.
ACR20 and ACR70 response were one of several key secondary endpoints tested, again at 16 weeks, with a respective 75%, 60%, and 20% of patients in each group achieving the lower response target and 20%, 32%, and 5%, achieving the more stringent response target.
“Izokibep demonstrated a robust efficacy in the musculoskeletal arthritic domains, but also in the extra-articular musculoskeletal domain,” Dr. Behrens said.
Not only that, but the values were “at the top end” of what’s been demonstrated for drugs currently regarded as the standard of care.
More than 80% of patients achieved a PASI75 response and 57% a PASI50 response with the two doses of izokibep, and 63%-88% achieved a resolution of enthesitis. The latter was measured using the Leeds Enthesitis Index.
There was also improvement in quality of life, measured using the Psoriatic Impact of Disease questionnaire, with a percentage increase beyond the MCID of 31%-41% with izokibep versus 12% for placebo.
“These are the first data of the phase 2 study in psoriatic arthritis,” Dr. Behrens reported.
“The safety profile was consistent with placebo,” with the only “standout aspect” being a higher number of injection-site reactions with izokibep versus placebo; but there were no serious infections, no serious adverse events,” he added.
“The interesting thing is from the preclinical research there was no dose-limiting toxicity with izokibep, therefore, I think the plan in the future is maybe to increase the dose to optimize treatment outcome based on the really robust effectiveness we see here in the first study in this clinical trial,” he said.
As a small study, stratifying results by gender wasn’t an option, Dr. Behrens noted in answering a question during the discussion period, but might be something that will be included in future and larger trials based on the post-hoc findings of other IL-17 trials.
Moving forward, the next step will involve a phase 2b/3 pivotal study which will likely include a higher dosing regimen of 160 mg once weekly alongside the twice-weekly dosing used in this trial.
Izokibep is an investigational treatment being developed by Affibody AB, Sweden, and ACELYRIN, USA. All three companies funded the phase 2 trial and were involved in the study design, conduct and reporting of results.
Dr. Behrens and Dr. Taylor were investigators in the study.
Dr. Behrens disclosed he was a shareholder of Pfizer, Sanofi, GlaxoSmithKline, Gilead Sciences, Inc. and Novartis; part of the speakers’ bureau for Amgen, Horizon, Lilly, Novartis, Pfizer, Sanofi, Genzyme, Flexion and AbbVie; a consultant of AbbVie, Boehringer Ingelheim, Flexion, Janssen, Pfizer, Sanofi, Regeneron, SUN Pharma Advanced Research, Gilead Sciences, Inc.; and had received grant or research support from Pfizer, Janssen, Chugai, Celgene and Roche
Dr. Taylor acknowledged grant or research support from: Celgene and Galapagos, and acted as a consultant for AbbVie, Biogen, Bristol Myers Squibb, Fresenius, Galapagos, Gilead, GlaxoSmithKline, Janssen, Lilly, Nordic Pharma, Pfizer, Roche, Sanofi and UCB.
FROM THE EULAR 2022 CONGRESS