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Obinutuzumab, bendamustine significantly extend PFS in relapsed non-Hodgkin's lymphoma
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CHICAGO – The addition of the monoclonal antibody obinutuzumab to standard bendamustine chemotherapy significantly delayed the progression of relapsed indolent non-Hodgkin’s lymphoma, according to the results of an open-label phase 3 study presented at the ASCO Annual Meeting.
“Indolent non-Hodgkin’s lymphoma continues to be incurable with standard available therapies,” Laurie Helen Sehn, MD, MPH, of the BC Cancer Agency in Vancouver, Canada, said during a press conference. “Over the last decade, the addition of rituximab to chemotherapy has resulted in a significant improvement in both PFS and OS in these patients; however, patients who are rituximab-refractory … have a relatively poor outcome.”
Inadequate treatment options exist for patients with indolent non-Hodgkin’s lymphoma refractory to rituximab (Rituxan, Genentech/Biogen Idec), according to study background. Phase 2 trials indicated bendamustine (Treanda, Cephelon) monotherapy confers a median PFS of 9 months and a response duration of 10 months in this setting.
The analysis included 396 patients (median age, 63 years) with rituximab-refractory indolent non-Hodgkin’s lymphoma. Patients had received a median of two prior therapies.
Patients received bendamustine monotherapy (120 mg/m2; n = 202) or bendamustine (90 mg/m2) plus obinutuzumab (Gazyva, Genentech; 1,000 mg; n = 194) for up to six 28-day cycles. Eligible patients from the combination arm then received obinutuzumab monotherapy every 2 months for up to 2 years.
PFS served as the primary endpoint.
Median follow-up was 21 months.
Patients in the combination arm achieved a median PFS of 29 months, whereas patients who received bendamustine monotherapy had a 14-month median PFS (HR = 0.52; 95% CI, 0.39-0.7). Researchers observed no significant differences in overall response rate (69.1% vs. 63%), complete response (11.2% vs. 12.2%) or overall response up to 12 months from start of treatment (78.6% vs. 76.6%).
Fewer grade 3 or higher adverse events occurred with bendamustine monotherapy compared with the combination (62.1% vs. 68%), including neutropenia (26.3% vs. 33%) and infusion-related reactions (3.5% vs. 8.8%). However, grade 3 or higher thrombocytopenia (16.2% vs. 10.8%), anemia (10.1% vs. 7.7%) and pneumonia (5.6% vs. 2.6%) occurred more frequently among patients who received bendamustine monotherapy.
Researchers closed the trial early due to the positive outcomes.
“The safety profile revealed no new safety findings and was in keeping with what was expected with the combination of drugs,” Sehn said. “Based on the study results, we conclude that the combination of obinutuzumab and bendamustine, followed by obinutuzumab maintenance, represents a novel and effective treatment option for patients with who are refractory to rituximab.” – by Cameron Kelsall
For more information:
Sehn LH, et al. Abstract LBA8502. Presented at: ASCO Annual Meeting; May 29-June 2, 2015; Chicago.
Disclosure: The study was funded by Roche/Genentech. Sehn reports honoraria and research funding from and consultant roles with Amgen, Celgene, Gilead Sciences, Janssen, Lundbeck, Pfizer and Roche/Genentech. Please see the abstract for a list of all other authors’ relevant financial disclosures.
Perspective
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John P. Leonard, MD
Although this study design may lead to a regulatory approval, the approach and results unfortunately do not yield information that makes a meaningful difference for many patients encountered in practice. Rituximab-refractory indolent non-Hodgkin’s lymphoma represents an important clinical problem, but it is one that can be addressed by bendamustine (Treanda, Teva), radioimmunotherapy [Y-90 ibritumomab tiuxetan (Zevalin, Spectrum)] and the PI3 kinase inhibitor idelalisib (Zydelig, Gilead). When bendamustine is employed in this setting, it is generally used at a 90 mg/m2 dose level in combination with rituximab (Rituxan; Genentech, Biogen Idec). Such dosing seems to allow maintenance of dose intensity (bendamustine at 120 mg/m2 is less well tolerated). Adding rituximab to chemotherapy in this population allows for the possibility of synergy among agents, even in patients who fall into the arbitrarily defined category of “rituximab-refractory” disease. Therefore, the control arm in this study — single-agent bendamustine at 120 mg/m2 — does not represent a regimen that is commonly used in practice. In fact, I have not used it in my patients with lymphoma in more than 5 years.This trial demonstrated no significant differences in overall or complete response rates between the two arms. The treatment regimens were quite imbalanced, in that patients in the obinutuzumab arm received an additional 2 years of maintenance treatment. Importantly, the PFS curves seem to appear identical until the point of initiation of maintenance, suggesting the additional duration of treatment is responsible for any differences.
Although obinutuzumab seems to offer some advantages relative to rituximab in chronic lymphocytic leukemia, findings in non-Hodgkin’s subtypes (including indolent) have not yet suggested major differences. This area is currently under active investigation in several randomized trials. However, all of these appear to employ higher doses/frequency/duration of obinutuzumab vs. what is typically employed with rituximab. Unfortunately, until studies are performed that compare identical doses and schedules of obinutuzumab with standard doses of rituximab, physicians and patients will be left to wonder whether this agent represents a clinical advance in lymphoma.
Perspective
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Stefan Barta, MD
This is an interesting new anti-CD20 antibody, which has shown to be possibly more effective than rituximab (Rituxan, Genentech/Biogen Idec) in CLL. Furthermore, obinutuzumab has shown activity in T-cell lymphomas in rituximab-refractory patients as a single agent. In this trial, the investigators show that obinutuzumab when it is combined with bendamustine followed by obinutuzumab maintenance is superior to bendamustine alone. However, patients who only got bendamustine were not randomized to maintenance therapy. It has been interesting to see whether bendamustine vs. bendamustine plus obinutuzumab without maintenance would have led to a similar PFS benefit. In indolent lymphoma, PFS often does not translate into OS. Rituximab maintenance also shows a PFS benefit, but no OS benefit. Additionally, most patients with indolent lymphoma at this time and age have already received bendamustine treatment as upfront therapy. An interesting new study would compare bendamustine with rituximab vs. bendamustine plus obinutuzumab in the upfront setting.
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