For Rituximab-Refractory NHL Patients, Adding Obinutuzumab to Bendamustine Improves Progression-Free Survival

Patients with indolent non-Hodgkin lymphoma (NHL) who do not respond to regimens containing rituximab have few subsequent treatment options and generally poor outcomes. Research has suggested that adding the monoclonal antibody obinutuzumab to bendamustine (considered a standard of care for rituximab-refractory NHL patients) improves outcomes in this patient population.

In the open-label, randomized, multicenter, phase III GADOLIN study, Laurie H. Sehn, MD, of the British Columbia Cancer Agency and the University of British Columbia in Vancouver, Canada, and authors compared the safety and efficacy of induction therapy with obinutuzumab plus bendamustine, followed by obinutuzumab maintenance therapy, with bendamustine alone. The study results, published in The Lancet Oncology, showed that progression-free survival (PFS; primary endpoint) was significantly longer in the combination cohort than in the monotherapy cohort (not reached vs. 14.9 months), for a 45 percent lower risk of disease progression (hazard ratio [HR] = 0.55; 95% CI 0.40-0.74; p=0.0001).

“Because all patients in this trial were unresponsive to rituximab or had progressed within six months of receiving it, the improvement in median PFS of more than 15 months with the addition of obinutuzumab is noteworthy,” the authors wrote, adding that “the HR is comparable to the benefit previously shown with the addition of rituximab to chemotherapy in rituximab-naive patients.”

In the GADOLIN trial, 396 adult patients were enrolled from 83 sites in 14 countries between April 15, 2010, and September 1, 2014. Patients were eligible for inclusion if they had:

  • histologically documented, CD20-positive indolent NHL (including follicular lymphoma of grades 1-3a, marginal zone lymphoma, small lymphocytic lymphoma, and Waldenström macroglobulinemia) that was refractory to rituximab
  • at least one bidimensionally measurable lesion (>1.5 cm in its largest dimension by computed tomography [CT] scan)
  • an estimated life expectancy of about 5 years
  • previously received anti-lymphoma treatment (including up to four chemotherapy-containing regimens)

Patients were excluded if they had used any monoclonal antibodies other than rituximab in the three months prior to the study, received chemotherapy or other investigational therapy within 28 days prior to the first treatment cycle, or received obinutuzumab or bendamustine within two years of the study’s first treatment cycle.

Patients were randomized 1:1 (stratified based on indolent NHL subtype, refractory type, number of previous therapies, and geographical region) to receive one of the following 28-day treatment cycles:

  • obinutuzumab 1,000 mg administered intravenously (IV) on days 1, 8, and 15 of cycle 1 and day 1 of cycles 2-6, plus bendamustine 90 mg/m2 on days 1 and 2 of cycles 1-6 (n=194)
  • bendamustine 120 mg/m2 on days 1 and 2 of each cycle for up to 6 cycles (n=202)

“The bendamustine monotherapy group did not include a maintenance phase because the cumulative toxicity of bendamustine restricts treatment duration,” Dr. Sehn and co-authors noted.

Patients in the combination cohort who did not experience disease progression continued to receive obinutuzumab 1,000 mg maintenance therapy every two months for two years, or until disease progression. Crossover was not allowed prior to primary analysis.

Clinical examinations, laboratory evaluations, CT scans, and bone marrow biopsy sampling (to confirm complete response) were collected, but positron emission tomography (PET) scans were not “because information about the usefulness of PET scans in indolent NHL was sparse when the study was designed,” the authors noted.

On January 24, 2015, noting that the study’s primary endpoint had been met, the Independent Data Monitoring Committee recommended that enrollment be halted. Therefore, 17 patients who were enrolled and randomized between the primary cutoff (September 1, 2014) and January 7, 2015, were not included in the published results.

Most trial participants had follicular lymphoma (n=321; 81%), and 92 percent (n=365) were refractory to their last treatment – irrespective of whether it contained rituximab. Patients had received a median of two previous treatment regimens, and the median time between diagnosis and study entry was 3.1 years in the combination cohort and three years in the monotherapy cohort.

At the time the study was halted, 19 patients who started induction therapy (six in the combination group and 13 in the monotherapy group) were still receiving induction therapy, while 46 patients in the combination cohort (32%) were still receiving maintenance therapy. The median duration of obinutuzumab maintenance therapy was 10.8 months (range = 3.7-21.4 months).

PFS was significantly longer in patients treated with the combination regimen, while there were no significant differences between treatment groups for some of the secondary endpoints, including overall response at the end of the induction phase (69% in the combination group vs. 63% in the monotherapy group; p=0.31), best overall response (79% vs. 77%; p=0.74), and overall survival (18% vs. 20%; p=0.4).

Nearly all patients (≥98%) reported at least one adverse event (AE), with grade 3-5 AEs reported in 68 percent of patients in the combination group (n=132/195) and 62 percent in the monotherapy group (n=123/198). The most frequent all-cause grade ≥3 AEs included neutropenia (33% vs. 26%), thrombocytopenia (11% vs. 16%), anemia (8% vs. 10%), and infusion-related reactions (IRRs; 11% vs. 6%).

Although more patients in the combination group had a grade 3 or 4 IRR, these were mainly managed supportively, and led to treatment withdrawal in only four patients, Dr. Sehn and colleagues reported. Overall, “obinutuzumab plus bendamustine was well tolerated with a similar safety profile to bendamustine monotherapy, despite treatment and adverse event reporting periods being much longer in the combination group.”

Deaths occurred in 18 percent of those in the combination group (n=34) and 21 percent of the monotherapy group (n=41). In the combination group, 22 deaths were related to disease progression (65%), compared with 29 patients in the bendamustine group (71%). AE-related deaths were similar in the two groups (n=12; 6% for each).

This study was designed to assess PFS benefit after induction and maintenance treatment as a whole, meaning that “the relative contribution of each treatment phase is difficult to assess, which is a limitation of this study,” the authors concluded. Future studies, they suggested, could include a second control group treated with obinutuzumab plus bendamustine induction only and no maintenance therapy.


Reference

Sehn LH, Chua N, Mayer J, et al. Obinutuzumab plus bendamustine versus bendamustine monotherapy in patients with rituximab-refractory indolent non-Hodgkin lymphoma (GADOLIN): A randomised, controlled, open-label, multicenter, phase 3 trial. J Clin Oncol. 2016;17:1081-93.

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