Combination strategies involving brentuximab vedotin (Adcetris) plus checkpoint inhibitors yielded high rates of response and complete remission in relapsed and refractory Hodgkin’s lymphoma, according to findings from a phase I trial.
Responses among the 61 patients in the study, all of whom received brentuximab vedotin, reached 76% when the CD30-targeted antibody-drug conjugate was combined with ipilimumab (Yervoy), 89% with nivolumab (Opdivo), and 82% with the two checkpoint inhibitors together, reported Catherine Diefenbach, MD, of NYU Langone’s Perlmutter Cancer Center in New York City, and colleagues.
Complete response rates were 57% with the anti-CTLA-4 agent ipilimumab, 61% with the anti-PD-1 nivolumab, and 73% in patients treated with the triplet regimen, as described in the Lancet Haematology.
“[T]oxicity was highest for the triplet therapy group, but toxicity was manageable for most patients in all three treatment groups,” Diefenbach’s group wrote. “Of note, a higher response rate for all three treatment groups was observed in this trial compared with historical data for any of the drugs when used as monotherapy.”
Six dose-limiting toxicities were discovered among four patients in the study, and two treatment-related deaths from pneumonitis occurred — one in a heavily pretreated 72-year-old, but another in a younger patient with few risk factors.
Most toxicities were low grade, immune-related, and manageable, according to the authors. Grade 3/4 adverse events (AEs) were highest in the treatment arms that included ipilimumab, at 43% with the dual therapy and 50% with the triplet therapy, as compared to 16% in patients treated with nivolumab plus brentuximab vedotin alone.
Common grade 3/4 AEs among the three groups included rash in eight patients (13%), and arthritis, colitis, diabetic ketoacidosis, gastritis, and pancreatitis in one patient each (2%).
While the study was not powered for it, Diefenbach and colleagues found no increased toxicity among the 40% of patients who went on to receive hematopoietic cell transplantation.
Joshua Brody, MD, of the Icahn School of Medicine at Mount Sinai in New York City, called the findings an “important milestone” for the use of immunotherapy in relapsed or refractory Hodgkin’s lymphoma.
Doublet therapy of nivolumab plus brentuximab vedotin has already been shown to be highly effective, he told MedPage Today by email.
“The current study makes a logical next step of adding additional checkpoint blockade with inclusion of the anti-CTLA-4 antibody ipilimumab, promising insofar as ‘nivo+ipi’ has greater efficacy than nivolumab in melanoma, lung cancer and kidney cancer,” said Brody, who was not involved in the research.
“Importantly, the proportion of immune-related toxicities appeared higher with the triplet therapy, emphasizing the importance for close follow-up with this approach so that dosing and scheduling can be individualized for each patient,” he added. “A larger follow-up study will aim to confirm these exciting results and hopefully offer a compelling, chemo-free option of effective therapy for these patients with a difficult situation and profoundly unmet need.”
The study established maximum-tolerated doses for each arm, with 1.8 mg/kg brentuximab vedotin used across the board. For the ipilimumab and nivolumab groups, the maximum-tolerated dose was 3 mg/kg for each agent. In the triplet arm, nivolumab at a dose of 3 mg/kg along with a lower dose of ipilimumab (1 mg/kg) was established.
Only the nivolumab combination and triplet regimen will move forward to the phase II trial, however, based on median progression-free survival data, which was 1.2 years in the ipilimumab arm but not reached for the other arms.
Similarly, the median duration of response was 1.32 years with ipilimumab and not reached in the nivolumab and triplet therapy groups. A post-hoc analysis estimated that the probability of remaining relapse free at 1 year was 59%, 77%, and 87% for the three treatments, respectively.
“Since the triplet regimen might increase the risk of severe, life-threatening toxicities (like pneumonitis and myocarditis), it would need to be significantly more effective than doublet therapy with higher response rates and, more importantly, improved duration of response and survival,” wrote Franck Morschhauser, MD, of Centre Hospitalier Regional Universitaire in Lille, France, and colleagues in an accompanying editorial.
But ideally, the editorialists said, predictive biomarkers would be established to determine which patients might benefit from the added ipilimumab, or that could predict severe toxicity from the triplet regimen.
“If such biomarkers could identify patients who can achieve long-term remissions with doublet or triplet therapy without the need for consolidative stem cell transplantation, more upfront toxicity would be easier to accept,” they wrote.
For the phase I portion of this phase I/II study, 64 relapsed or refractory Hodgkin’s lymphoma patients were enrolled from 2014 to 2017. Among the 61 evaluable patients for the current analysis, all of whom were treated with brentuximab vedotin, 21 also received ipilimumab, 18 received nivolumab, and 22 received all three agents combined.
Median time to best response in the ipilimumab group was 72 days, and was 66 days in both the nivolumab and triplet therapy groups. Median overall survival was not reached for any of the arms, with follow-up ranging from 1.7 years in the triplet arm to 2.6 years in the ipilimumab arm.
Last Updated August 26, 2020
The study was funded by the Eastern Cooperative Oncology Group/American College of Radiology Imaging Network and the National Cancer Institute.
Diefenbach disclosed relationships with Seattle Genetics, Bristol-Myers Squibb, Genentech, Merck, and Genentech. Co-authors reported financial relationships with Seattle Genetics, Bristol-Myers Squibb, and various other industry entities.
Morschhauser reported honoraria from Bristol-Myers Squibb, AbbVie, Celgene, Epizyme, Gilead, Janssen, and Roche. One co-author reported honoraria from Bristol-Myers Squibb, Celgene, Gilead, Kite, Janssen, Merck Sharp & Dohme, Novartis, and Roche.