Brentuximab vedotin combinations yield encouraging response rates in elderly Hodgkin’s lymphoma
ORLANDO, Fla. — Brentuximab vedotin conferred 100% objective response rates when combined with dacarbazine or bendamustine for the first-line treatment of older patients with Hodgkin’s lymphoma, according to results of an interim analysis presented at the ASH Annual Meeting and Exposition.
However, bendamustine (Treanda, Cephalon) appeared too toxic for the older patient population.
“This study shows tremendous progress for a patient population that has a significant unmet need,” Christopher A. Yasenchak, MD, a medical oncologist at Willamette Valley Cancer Institute and Research Center and U.S. Oncology Research in Springfield, Oregon, told HemOnc Today. “In elderly Hodgkin’s lymphoma, clinicians have little else to offer. Commonly, these patients are offered supportive care or hospice. Conventional multiagent chemotherapy in this patient population is poorly tolerated, and 3-year survival rates are terrible. So, to find an active therapy that is reasonably well tolerated that can improve quality of life and longevity is significant.”
An anti-CD30 antibody-drug conjugate, brentuximab vedotin (Adcetris, Seattle Genetics) has previously demonstrated safety and efficacy as a monotherapy in relapsed Hodgkin’s lymphoma. Among patients with Hodgkin’s lymphoma aged older than 60 years, front-line single-agent treatment with brentuximab vedotin conferred an objective response rate of 92%, a complete remission rate of 73% and a 10.5-month median PFS.
Further, data have also suggested improvements when brentuximab vedotin is used in combinations. It was highly active in preclinical models when combined with dacarbazine, and brentuximab vedotin plus bendamustine yielded an 82% complete remission rate in patients with relapsed Hodgkin’s lymphoma.
Based on these data, Yasenchak and colleagues conducted this phase 2 study to examine the efficacy and durability of brentuximab vedotin as a monotherapy and in combination with dacarbazine or bendamustine in treatment-naive older patients with Hodgkin’s lymphoma.
Yasenchak and colleagues planned to enroll 70 patients aged at least 60 years and assign them to treatment with brentuximab vedotin monotherapy (n = 30; 1.8 mg/kg every 3 weeks) or one of the two combinations (n = 20 for each; 375 mg/m2 dacarbazine for up to 12 cycles; 90 mg/m2 or 70 mg/m2 bendamustine for up to six cycles).
Objective response rate (ORR) served as the study’s primary endpoint.
At the time of interim analysis, 60 patients (median age, 76 years; range, 62-92 years) had been treated — 27 in the monotherapy arm, 22 in the brentuximab vedotin plus dacarbazine arm, and 20 in the brentuximab vedotin plus bendamustine arm.
Yasenchak presented data from the brentuximab plus dacarbazine, and plus bendamustine cohorts. Most patients had stage III/IV disease (dacarbazine, 73; bendamustine, 70%). Fifty percent of patients had B symptoms, and most (dacarbazine, 86%; bendamustine, 85%) were considered ineligible for standard chemotherapy.
At the interim analysis, patients in the dacarbazine arm received a median of 11.5 treatment cycles of dacarbazine and 12 cycles of brentuximab vedotin. Nine percent of these patients remain on single-agent brentuximab vedotin.
ORR in this cohort was 100% and the complete remission rate was 67%. The median PFS in this cohort had yet to be reached.
Although not a randomized study, the 12-month PFS rates of 66% was superior to the previously reported brentuximab vedotin single-agent PFS rate of 38%, Yasenchak said.
Treatment-related grade 3 or worse adverse events occurred in 36% of these patients, and serious adverse events occurred in 9%.
Patients in the bendamustine arm received a median of 3.5 cycles of bendamustine and brentuximab vedotin. Fifty-five percent of patients remain on single-agent brentuximab vedotin.
The dose of bendamustine was reduced from 90 mg/m2 to 70 mg/m2 to improve tolerability after the first 10 patients were enrolled. Following enrollment of 20 patients, bendamustine combination therapy was discontinued due to excessive toxicity.
The ORR among the 16 patients evaluable for efficacy who were treated with the bendamustine combination also reached 100%, with a complete response rate of 81%. However, the median follow-up of 4.6 months was too short to provide a reliable estimate of PFS, Yasenchak said.
“Bendamustine was far too toxic for this patient population,” Yasenchak said. “Unfortunately, there were many more adverse events, and even with dose reduction, we ended up having to remove bendamustine from the combination therapy and continue to treat with single-agent brentuximab vedotin. We’ll see how durable the response is with the median 3.5 cycles of bendamustine study subjects received.”
Sixty-five percent of patients experienced treatment-related grade 3 or worse adverse events, and 60% experienced serious adverse events.
Overall, 29 patients from the dacarbazine and bendamustine cohorts discontinued therapy due adverse events, progressive disease after complete or partial remission, or other reasons.
“We’re committed to finding additional active combinations that show a favorable toxicity profile and durable response,” Yasenchak said. “With the activity that we’re seeing with checkpoint inhibitors in classical Hodgkin’s lymphoma, a PD-1/PD-L1 inhibitor is going to be high on the list of possibilities.” – by Anthony SanFilippo
Yasenchak CA, et al. Abstract 587. Presented at: ASH Annual Meeting and Exposition; Dec. 5-8, 2015; Orlando, Fla.
Disclosure: The study included off-label use of brentuximab vedotin. Yasenchak reports research funding from Seattle Genetics. Please see the abstract for a list of all other researchers’ relevant financial disclosures.