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Brentuximab vedotin combinations yield encouraging response rates in elderly Hodgkin’s lymphoma
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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.
Dacarbazine results
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%.
Bendamustine results
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
Reference:
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.
Perspective
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Peter Martin, MD
When we think of Hodgkin’s lymphoma, we think of it as a disease of younger people. But, there’s a bimodal distribution, and people who are older have an increased incidence of Hodgkin’s lymphoma — it takes off again after age 60 years. Still, the vast majority of studies have focused on younger patients.
In recent years, we have started to look at older patients and have realized they are not as well served with existing therapies. They may have a more aggressive form of Hodgkin’s lymphoma, and because they do not tolerate treatments as well, they have worse outcomes.
The question is, can we improve the efficacy of existing therapies while simultaneously reducing toxicity? It is not a new question, but it is a different bar when considering a 20-year-old who has a survival rate of 85% — and the focus is to reduce toxicity — vs. a 65-year-old with a differently expected outcome.
Brentuximab vedotin is clearly active based on other studies, and it can be combined with chemotherapy that is well tolerated by older people. Yasenchak and colleagues chose bendamustine based on the fact that it has well-defined activity in Hodgkin’s lymphoma, and they chose dacarbazine because it is also an alkylator and a vital part of the ABVD regimen (doxorubicin, bleomycin, vinblastine and dacarbazine). Both drugs have been combined with brentuximab vedotin in other studies.
The overall response rates were high in both arms at 100% and the complete response rate was higher in the bendamustine arm (81%) than in the dacarbazine arm (68%).
Interestingly, the investigators found that the combination with bendamustine was not as well tolerated as might have been expected. Sixty-percent of the patients in the bendamustine arm had a serious adverse event compared with 9% in the dacarbazine arm, and grade 3 to grade 4 toxicities also were significantly higher. That already is a bit of failure when you are trying to come up with a therapy that is better tolerated. In fact, they stopped the bendamustine arm because of the high rate of serious adverse events.
But what were those adverse events? That wasn’t entirely clear in the presentation at the ASH Annual Meeting. Although the bendamustine arm had a lot of toxicity, I still wonder if there is not a way to modify it and move forward with it because of the response rates. I am having a hard time writing off that combination completely.
It is still too early to say that the combination of brentuximab vedotin and chemotherapy should become the standard of care in this setting, but there is enough here to suggest that this approach is worthy of larger studies.
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