Sandra Horning, MD
The European Commission approved obinutuzumab (Gazyvaro, EU; Gazyva, US) for use in combination with bendamustine, followed by maintenance obinutuzumab, as a treatment for patients with follicular lymphoma who are refractory to or progress on a single-agent rituximab (MabThera) or rituximab-containing regimen.
The approval was based on findings from the phase III GADOLIN study, in which obinutuzumab plus bendamustine followed by obinutuzumab monotherapy reduced the risk of disease progression by 52% compared with bendamustine alone in patients with follicular lymphoma who progressed on rituximab-based therapy (HR, 0.48; 95% CI 0.34-0.68; P
“Today’s approval is a significant milestone in the treatment of people with follicular lymphoma in Europe,” Sandra Horning, MD, chief medical officer and head of Global Product Development at Roche, the company that develops obinutuzumab, said in a statement. “For those who fail to achieve durable disease control with MabThera-based treatment, Gazyvaro plus bendamustine is an important new treatment option that has been shown to reduce the risk of disease progression or death by more than half.”
The multicenter, open-label, phase III GADOLIN study involved 413 patients with rituximab-refractory indolent non-Hodgkin lymphoma, the most common being follicular lymphoma (n = 321). 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 plus chemotherapy).
Patients in the experimental arm (n = 155) received bendamustine (90 mg/m2
IV on days 2 and 3 of cycle 1, and days 1 and 2 of cycles 2-6) plus 6 cycles of obinutuzumab (1000 mg IV on days 1, 8, and 15 of cycle 1, and day 1 of cycles 2-6) followed by obinutuzumab every 2 months until disease progression for a maximum of 2 years. In the comparator group (n = 166), patients received 6 cycles of bendamustine monotherapy (120 mg/m2
IV on days 1 and 2 of cycles 1-6). The cycle length for both treatment arms was 28 days.
Clinical characteristics across both arms of the study were comparable: median patient age was 63 years, with a median of 2 prior lines of therapy (range, 1-10); approximately 4 months had elapsed since their last treatment. More than 90% of patients in each arm were refractory to their last treatment.
The primary endpoint of the study was progression-free survival (PFS). Secondary outcome measures included overall survival (OS), response, and safety.
The median PFS, as determined by an independent panel, was not reached in the obinutuzumab arm versus 13.8 months in the control arm. By investigator assessment, the median PFS with obinutuzumab was 29.2 versus 13.7 months with bendamustine alone (HR, 0.48; 95% CI, 0.35-0.67; P
At a median follow-up of 24.1 months, the risk of death was reduced by 38% with the obinutuzumab regimen compared with bendamustine alone (HR, 0.62; 95% CI, 0.39-0.98). Neither study arm has reached median OS.
The best overall response (BOR) rate for the obinutuzumab cohort was 78.7%, including complete response (CR) and partial response (PR) rates of 15.5% and 63.2%, respectively. The BOR was 74.7% for the control arm, with a CR rate of 18.7% and a PR rate of 56%. The median duration of response was not reached for the obinutuzumab arm versus 11.6 months with bendamustine alone.
The most frequently reported adverse events (AEs) in the obinutuzumab arm were infusion reactions (69%), low white blood cell counts (35%), nausea (54%), fatigue (39%), cough (26%), diarrhea (27%), constipation (19%), fever (18%), low platelet counts (15%), vomiting (22%), upper respiratory tract infection (13%), decreased appetite (18%), joint or muscle pain (12%), sinusitis (12%), low red blood cell counts (12%), general weakness (11%), and urinary tract infection (10%).
Low white blood cell counts (33%), infusion reactions (11%), and low platelet counts (10%), were the most common grade 3/4 AEs observed in patients receiving obinutuzumab. The most common serious AEs (>2%) included febrile neutropenia, neutropenia, infusion related reactions, sepsis, pneumonia, and pyrexia.
In the United States, the FDA approved obinutuzumab plus bendamustine followed by obinutuzumab alone in February 2016 for the treatment of patients with follicular lymphoma who relapse after, or are refractory to, a rituximab-containing regimen.
Obinutuzumab is also approved in the United States and European Union for use in combination with chlorambucil as a first-line treatment for patients with chronic lymphocytic leukemia.
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;33 (suppl; abstr LBA8502).