Patients with relapsed indolent non-Hodgkin lymphoma experienced a doubling of progression-free survival when treated with a combination of the anti-CD20 agent obinutuzumab and bendamustine.
Laurie H. Sehn, MD, MPH
Patients with relapsed indolent non-Hodgkin lymphoma (iNHL) experienced a doubling of progression-free survival (PFS) when treated with a combination of the anti-CD20 agent obinutuzumab (Gazyva) and bendamustine compared with bendamustine alone, according to findings of the phase III GADOLIN study.
The interim obinutuzumab results were so positive that the trial closed early, noted lead study author Laurie Helen Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency in Vancouver, Canada, who reported the late-breaking data at the 2015 ASCO Annual Meeting.
The study involved rituximab-refractory patients. Data showed that after a median follow-up of just over 20 months, median PFS as assessed by an independent radiology facility (IRF)—the study’s primary endpoint—was 14.9 months for patients in the bendamustine-only cohort, whereas for patients in the obinutuzumab combination arm, median PFS had not yet been reached (HR = 0.55; P < .0001), a result indicative of a 45% reduction in the rate of progression with the dual therapy, Sehn reported.
“The fact that this new approach doubled average remission time marks a major step forward for our patients. Obinutuzumab may offer patients the chance to stay well for a significantly longer period of time, putting off the need for chemotherapy.”
Currently, the standard initial treatment for iNHL is a combination of chemotherapy and rituximab, but most patients become rituximab-resistant, leaving them few options for further treatment. Bendamustine is effective in these patients, but remission duration is only approximately 7-9 months.
Obinutuzumab, which is currently FDA-approved in combination with chemotherapy for patients with chronic lymphocytic leukemia, is a novel glycoengineered antibody that targets the CD20 protein located on the surface of all B cells, including B-cell lymphoma cells. Preclinical studies have suggested that when monoclonal antibodies attach to this protein, some lymphoma cells die, and others appear to become more responsive to chemotherapy.
The multicenter, open-label GADOLIN study involved 413 patients with rituximab-refractory iNHL. Patients in the trial had various forms of NHL, the most common being follicular lymphoma.
Those randomly assigned to the experimental arm (n = 194) received bendamustine (90 mg/m2 on days 1 and 2 of cycles 1-6) plus 6 cycles of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6). Patients showing benefit from this regimen followed it with maintenance obinutuzumab at the same 1000-mg dose administered once every 2 months for 2 years or until progression.
In the comparator group (n= 202), patients received 6 cycles of bendamustine monotherapy (120 mg/m2 on days 1 and 2 of cycles 1-6). The cycle length for both treatment arms was 28 days.
Patients were considered rituximab-refractory if they did not respond to either rituximab monotherapy or rituximab in combination with chemotherapy, or had relapsed within 6 months of completion of the last dose of a rituximab-based regimen (rituximab monotherapy or rituximab + chemotherapy).
Clinical characteristics across both arms of the study were comparable: median patient age was 63 years, with a median two prior lines of therapy; approximately 4 months had elapsed since their last treatment. More than 90% of patients in each arm were refractory to their last treatment, Sehn added.
Investigator-assessed PFS was a secondary endpoint, and results were similar to those assessed through IRF: a median PFS of 29.2 months was seen with the combination versus 14.0 months in the control arm (HR = 0.52; P < .0001).
Safety was another important secondary endpoint of the study, Sehn said. Adverse events (AEs) of all grades and withdrawals from therapy were similar in both arms, and no new safety signals were observed.
In the obinutuzumab-bendamustine and bendamustine-only arms, the most common hematologic AEs were neutropenia (35% vs 29%) and thrombocytopenia (15% vs 24%). The most common nonhematologic AEs were infusion-related reactions (69% vs 63%), nausea (54% vs 61%), fatigue (39% vs 33%), and diarrhea (27% vs 30%).
Sehn said that the trial findings were not only statistically significant but clinically meaningful:
“This study is remarkable, because it demonstrates the first randomized evidence of a clinical benefit of a novel anti-CD20 monoclonal antibody for patients who are rituximab-refractory.”
“It’s encouraging to see such impressive results for a novel anti-CD20 monoclonal antibody in a difficult-to-treat population …” concurred Merry-Jennifer Markham, MD, an ASCO expert on the targeted therapies press briefing panel where the findings were announced. “That this approach stalled cancer progression by more than a year will be good news for patients who urgently need additional treatment options.”
The drug’s manufacturer, Genentech, announced that it will be submitting data from this study to the FDA, the European Medicines Agency, and other international health authorities for approval of obinutuzumab in this setting.
Obinutuzumab also is being studied in a large clinical program, the manufacturer said, including two phase III studies: the GOYA trial is comparing obinutuzumab with rituximab plus chemotherapy as first-line treatment for diffuse large B-cell lymphoma, and the GALLIUM trial is comparing obinutuzumab with rituximab plus chemotherapy as first-line treatment in iNHL.
Genentech noted that additional combination studies are planned or underway investigating obinutuzumab with other approved or investigational medicines, including cancer immunotherapies and small molecule inhibitors, across a range of blood cancers.
Sehn LH, Chua N, Mayer J, et al. GADOLIN: Primary results from a phase III study of obinutuzumab plus bendamustine compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma. J Clin Oncol. 2015;(suppl; abstr LBA8502).