The European Medicines Agency's Committee for Medicinal Products for Human Use has recommended approval of obinutuzumab in the frontline setting for the treatment of patients with follicular lymphoma.
Sandra Horning, MD
The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has recommended approval of obinutuzumab (Gazyvaro, EU; Gazyva, US) in the frontline setting for the treatment of patients with follicular lymphoma, according to Roche, the manufacturer of the treatment.
The positive opinion from the CHMP is specifically for use of obinutuzumab in combination with chemotherapy, followed by obinutuzumab maintenance in patients who achieve a response. The recommendation is based on findings from the phase III GALLIUM study, in which combining obinutuzumab with chemotherapy in the first-line setting reduced the risk of disease progression or death by 34% versus rituximab plus chemotherapy in patients with follicular lymphoma.
“As follicular lymphoma is considered incurable, better initial treatment options are needed to prevent the disease from returning for as long as possible,” Sandra Horning, MD, chief medical officer and head of global product development, Genentech (Roche), said in a statement. “MabThera (rituximab) has been the standard of care for the past 20 years. Based on the GALLIUM study, Gazyvaro-based therapy provides superior progression-free survival compared to MabThera-based therapy, setting a new benchmark for what can be achieved with initial therapy for follicular lymphoma.”
The international phase III GALLIUM study included 1401 treatment-naive patients with indolent non-Hodgkin lymphoma, of whom 1202 had follicular lymphoma. Patients with follicular lymphoma were aged ≥18 years, had grade I to IIIa disease, and an ECOG performance status ≤2.
Patients were randomized to obinutuzumab plus chemotherapy, followed by obinutuzumab alone (n = 601), or rituximab plus chemotherapy, followed by rituximab alone (n = 601). The chemotherapy regimens used were CHOP, CVP, or bendamustine, based on the discretion of the physicians at each study location.
Patients specifically received rituximab at 375mg/m2 on day 1 of each cycle or obinutuzumab at 1000 mg on days 1, 8, and 15 of cycle 1 and day 1 of subsequent cycles, for either eight 21-day cycles (CHOP and CVP) or six 28-day cycles (bendamustine). Among patients randomized to chemotherapy, 57.1%, 33.1%, and 9.8%, received bendamustine, CHOP, and CVP, respectively.
The primary endpoint of the study was progression-free survival (PFS). Secondary outcome measures included response rate, overall survival (OS), disease-free survival, and safety. The study was unblinded per the recommendation of an independent data monitoring panel in January 2016 after a preplanned interim efficacy analysis.
At a median follow-up of 34.5 months, the hazard ratio (HR) for PFS by investigator assessment was 0.66 (95% CI, 0.51-0.85; P = .001). The 3-year PFS rate was 80% in the obinutuzumab arm versus 73.3% in the rituximab arm.
Per independent review, the HR for PFS was 0.71 (95% CI, 0.54-0.93; P = .014). The 3-year PFS rate was 81.9% in the obinutuzumab arm versus 77.9% in the rituximab arm.
The HR for OS was 0.75 (95% CI, 0.49-1.17; P = .21). The 3-year OS rates were 94% versus 92.1% in the obinutuzumab versus the rituximab arms, respectively.
In the obinutuzumab arm, the overall response rate was 88.5% versus 86.9% in the rituximab cohort. The complete remission rates were 19.5% versus 23.8% and the partial remission rates were 69.1% versus 63.1%, respectively. Ninety-two percent of patients in the obinutuzumab arm achieved MRD-negativity in the blood and/or bone marrow, compared with 84.9% in the control arm (P = .0041).
The safety analysis included 595 patients from the obinutuzumab arm and 597 patients from the rituximab arm. All-grade adverse events (AEs) occurred in 99.5% and 98.3% of the 2 arms, respectively.
Grade ≥3 AEs occurred in 74.6% of the obinutuzumab arm versus 67.8% of the rituximab arm. The most common grade ≥3 AEs occurring in the obinutuzumab arm versus the rituximab arm included neutropenia (43.9% vs 37.9%), leucopenia (8.6% vs 8.4%), febrile neutropenia (6.9% vs 4.9%), infusion-related reactions (6.7% vs 3.7%), and thrombocytopenia (6.1% vs 2.7%).
Serious AEs occurred in 46.1% of the obinutuzumab arm versus 39.9% of the rituximab arm. Discontinuations due to AEs occurred in 16.3% versus 14.2% of the 2 arms, respectively. Deaths related to AEs occurred in 4% of the obinutuzumab arm and 3.4% of the rituximab arm.
Obinutuzumab is a glycoengineered antibody against CD20. Through the glycoengineering process, sugar molecules are removed from immune-effector antibody cells in the posttranslational setting, significantly impacting antigen binding and function. Specifically, obinutuzumab is designed to lack fucose molecules.
Obinutuzumab is currently approved in the United States and EU for use in combination with bendamustine for patients with certain types of previously treated follicular lymphoma.
Shah, NN, Stetler-Stevenson M, Yuan CM, et al. Minimal residual disease negative complete remissions following anti-CD22 chimeric antigen receptor (CAR) in children and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Presented at: 58th ASH Annual Meeting and Exposition; San Diego, California; December 2-6, 2016. Abstract 650.