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FDA Updates Obinutuzumab Frontline CLL Label

Silas Inman @silasinman
Published: Thursday, Dec 25, 2014

Dr. Sandra Horning

Sandra Horning, MD

The FDA has updated the label for obinutuzumab (Gazyva) plus chlorambucil to include data from stage 2 of the phase III CLL11 study, which detailed an unprecedented improvement in progression-free survival (PFS) compared with rituximab (Rituxan) plus chlorambucil as a frontline treatment for patients with chronic lymphocytic leukemia (CLL). 

The combination of obinutuzumab plus chlorambucil was initially approved as a frontline therapy for patients with CLL in November 2013, based on data from stage 1 of the CLL11 trial. In this portion of the study, obinutuzumab plus chlorambucil reduced the risk of progression by 81% compared with chlorambucil alone (27.2 vs 11.2 months; HR = 0.19; 95% CI, 0.14-0.27; P <.0001). In stage 2 of the study, obinutuzumab plus chlorambucil led to a median PFS of 26.7 months compared with 14.9 months with rituximab and chlorambucil (HR = 0.42; 95% CI, 0.33-0.54; P <.0001). 

"Gazyva is the first and only medicine to significantly help people live without their disease worsening when combined with chlorambucil compared to Rituxan and chlorambucil in people with previously untreated chronic lymphocytic leukemia,” Sandra Horning, MD, chief medical officer and head of Global Product Development, said in a statement. “These new data enhance our understanding of the disease and its treatment, and this approval affirms an important treatment option for people with this difficult-to-treat disease.” 

The phase III CLL11 trial enrolled patients who had not received prior treatments for CLL with a median Cumulative Illness Rating Scale score of 8 and/or an estimated creatinine clearance <70 mL/min. The median age of patients was 73 years. In the three-arm study, 781 patients received six cycles every 28 days of chlorambucil (n = 118), chlorambucil plus obinutuzumab (n = 333), or chlorambucil plus rituximab (n = 330).

Chlorambucil was administered orally at 0.5 mg/kg on day 1 and 15 of each cycle and obinutuzumab was administered intravenously at 100 mg on day 1, 900 mg on day 2, and 1000 mg on day 8 and 15, for the first cycle of treatment, followed by 1000 mg on day 1 for cycles 2 through 6. Rituximab was administered at a standard dose of 375 mg/m2 on day 1 for the first cycle, followed by 500 mg/m2 on the first day of subsequent cycles.

In stage 2 of the study, the overall response rate in the obinutuzumab arm was 79.6% compared with 66.3% with rituximab. The complete response (CR) rate with obinutuzumab was 26.1% compared with 8.8% with rituximab. The median duration of response with obinutuzumab was 19.6 versus 9.7 months with rituximab.

Minimal residual disease (MRD) negativity in the bone marrow for patients who achieved a CR with or without complete recovery from abnormal blood cell counts (CR, CRi) was 19% with obinutuzumab versus 6% with rituximab. In peripheral blood, 41% of patients treated with obinutuzumab were MRD negative compared with 12% with rituximab.

The most common grade 3/4 adverse events with obinutuzumab versus rituximab were neutropenia (46% vs 41%), lymphopenia (39% vs 16%), leukopenia (35% vs 16%), and thrombocytopenia (13% vs 8%). Infusion reactions occurred in 65% of patients treated with obinutuzumab in the phase III study. Grade 3/4 infusion reactions were seen in 20% of patients, with 7% discontinuing therapy.

Altogether, 47 of the first 53 patients (89%) enrolled in the study experienced an infusion reaction, warranting an early adjustment to study protocol to require premedication with a corticosteroid, antihistamine, and acetamin along with dose adjustments. The FDA recommended dose for obinutuzumab is 100 mg on day 1 followed by 900 mg on day 2 and 1000 mg on day 8 and 15, for the first 28-day cycle followed by 1000 mg on day 1 of each subsequent cycle.

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