Phase III Trial Shows Adding Obinutuzumab to Bendamustine Improves Progression-Free Survival in Rituximab-Refractory NHL

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Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory indolent non-Hodgkin lymphoma, with manageable toxicity.

—Laurie H. Sehn, MD, and colleagues

In the phase III GADOLIN trial reported in The Lancet Oncology, Laurie H. Sehn, MD, Chair, British Columbia Cancer Agency Lymphoma Tumor Group, and Clinical Associate Professor at the University of British Columbia, Vancouver, and colleagues, found that adding the anti-CD20 antibody obinutuzumab (Gazyva) to bendamustine increased progression-free survival in patients with rituximab (Rituxan)-refractory indolent non-Hodgkin lymphoma (NHL).1 Outcomes in patients with follicular lymphoma, who constituted the majority of the population, supported the recent approval of obinutuzumab in combination with bendamustine in patients refractory to or relapsing after a rituximab-containing regimen.

Study Details

In this open-label trial, patients aged ≥ 18 years with CD20-positive indolent NHL refractory to rituximab from 83 sites in 14 countries in Europe, Asia, and North and Central America were randomized between April 2010 and September 2014 to receive six 28-day cycles of induction therapy with intravenous (IV) obinutuzumab plus bendamustine (n = 194) or bendamustine (n = 202). Obinutuzumab plus bendamustine was given as obinutuzumab at 1,000 mg on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2 to 6 plus bendamustine at 90 mg/m²/d on days 1 and 2 in cycles 1 to 6); bendamustine monotherapy was given at 120 mg/m²/d on days 1 and 2 of all cycles. Patients in the obinutuzumab group without disease progression received obinutuzumab maintenance at 1,000 mg every 2 months for up to 2 years. The primary endpoint was progression-free survival in all patients as assessed by independent review committee.

The obinutuzumab/bendamustine and bendamustine groups were generally matched for baseline characteristics. Median age was 63 years in both, 57% and 58% were male, 81% had follicular lymphoma, and 95% had Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. Of 313 patients (79%) refractory to a previous rituximab-chemotherapy combination, 146 (47%) had relapsed during or within 6 months of completing rituximab maintenance; 365 patients (92%) were refractory to their last treatment, irrespective of whether it contained rituximab; and 311 (79%) were refractory to both rituximab and alkylator treatment. Patients had received a median of two previous treatments, and the median time from diagnosis was approximately 3 years.

Progression-Free Survival

The study was stopped after a preplanned interim analysis indicated that the primary endpoint had been met. At this analysis, median follow-up time was 21.9 months in the obinutuzumab/ bendamustine group and 20.3 months in the bendamustine group. At the time of analysis, 46 of 143 patients (32%) who had started obinutuzumab maintenance were still receiving maintenance therapy.

Update on Obinutuzumab and Bendamustine in Resistant NHL

  • Adding obinutuzumab to bendamustine significantly increased progression-free survival in rituximab-refractory indolent non-Hodgkin lymphoma.
  • The study supports the recent approval of obinutuzumab/bendamustine in rituximab-refractory follicular lymphoma.

Median progression-free survival was not reached (95% confidence interval [CI] = 22.5 months to not reached) in the obinutuzumab/bendamustine group vs 14.9 months (95% CI = 12.8–16.6 months) in the bendamustine group (hazard ratio [HR] = 0.55, P = .0001). On investigator assessment, median progression-free survival was 29.2 vs 14.0 months (HR = 0.52, P < .0001). Hazard ratios favored bendamustine consistently across subgroups. The hazard ratio among 75 patients without follicular lymphoma was 0.94 (95% CI = 0.46–1.90).

Objective response at the end of induction was observed in 69% vs 63% of patients (P = .31), with complete response in 11% vs 12% (P = .71); overall, response was observed in 79% vs 77% (P = .74), with complete response in 17% vs 17% (P = .99). At the time of analysis, median overall survival could not be estimated in either group.

Adverse Events

Adverse events of grade ≥ 3 occurred in 68% of the obinutuzumab/bendamustine group and in 62% of the bendamustine group, with the most common being neutropenia (33% vs 26%), thrombocytopenia (11% vs 16%), anemia (8% vs 10%) and infusion-related reactions (11% vs 6%). Serious adverse events occurred in 38% vs 33%, with the most common being febrile neutropenia (4% vs 3%), infusion-related reactions (4% vs 2%), and pneumonia (3% vs 5%). 

During induction, adverse events led to treatment withdrawal in 7% vs 16% of patients; 5% of patients in the obinutuzumab group stopped bendamustine but continued to receive obinutuzumab. Among 143 patients starting obinutuzumab maintenance, the most common adverse events of any grade were cough (15%), upper respiratory tract infection (12%), and neutropenia (10%); infusion-related reactions occurred in 8% (all grade 1 or 2). Adverse events led to treatment withdrawal in 6%. Death due to adverse events considered related to treatment occurred in three patients in the obinutuzumab group and five in the bendamustine group.

The investigators concluded: “Obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy in rituximab-refractory patients with indolent non-Hodgkin lymphoma, with manageable toxicity, and is a new treatment option for patients who have relapsed after or are no longer responding to rituximab-based therapy.” ■

Disclosure: The study was funded by F. Hoffmann-La Roche Ltd. For full disclosures of the study authors, visit


1. Sehn LH, Chua N, Mayer J, et al: Lancet Oncol. June 23, 2016 (early release online).

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