Treatment with obinutuzumab in combination with bendamustine nearly doubled progression-free survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma.
Laurie Helen Sehn, MD, MPH
Treatment with the glycoengineered anti-CD20 antibody obinutuzumab (Gazyva) in combination with bendamustine nearly doubled progression-free survival (PFS) compared with bendamustine alone in patients with rituximab (Rituxan)-refractory indolent non-Hodgkin lymphoma (iNHL), according to findings of the phase III GADOLIN study presented at the 2015 ASCO Annual Meeting.
After a median follow-up of nearly 20 months, the median PFS was 14.9 months for patients in the bendamustine-only cohort, whereas for patients in the obinutuzumab combination arm the median PFS had not yet been reached (HR = 0.55;P< .0001). 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.
“Unfortunately, there is yet no cure for indolent lymphoma, so the overall goal of treatment is to increase the amount of time patients remain symptom-free and in remission. The fact that this new approach doubled average remission time marks a major step forward for our patients,” lead study author Laurie Helen Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency in Vancouver, Canada, said in a statement. “Obinutuzumab may offer patients the chance to stay well for a significantly longer period of time, putting off the need for additional 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/m2on 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/m2on 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).