Frontline Obinutuzumab (Gazyva) Approved for CLL

Obinutuzumab is the first agent to gain approval under the FDA's new Breakthrough Therapy designation.

The approval was based on results from the CLL11 trial, which showed that intravenous obinutuzumab, a novel antibody that targets CD20, combined with chlorambucil significantly reduced the risk of progression by 84%, when compared to chlorambucil alone. The responses demonstrated with this agent resulted in both a priority review and breakthrough therapy designation from the FDA.

The approval of obinutuzumab comes with a Boxed Warning, similar to other monoclonal antibodies in this class, regarding hepatitis B reactivation and progressive multifocal leukoencephalopathy, a rare disorder affecting the brain.

“Today’s approval represents an important new addition to the treatments for patients with CLL,” said Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research. “This approval reflects the promise of the Breakthrough Therapy designation program, allowing us to work collaboratively with companies to expedite the development, review, and availability of important new drugs.”

The phase III CLL11 trial enrolled 781 patients who had not received prior treatments for CLL with a median Cumulative Illness Rating Scale score >6 and/or an estimated creatinine clearance <70 mL/min. The median age of patients was 73 years.

In the three-arm study, patients were randomized in a 1:2:2 ratio to receive six cycles every 28 days of chlorambucil (n = 118), chlorambucil plus obinutuzumab (n = 238), or chlorambucil plus rituximab (n = 233). Final data about the CLL11 trial, including the rituximab arm, will be presented at the American Society of Hematology&rsquo;s 55th Annual Meeting in December 2013.

The FDA approval was based on the stage of the trial that examined chlorambucil plus obinutuzumab compared with chlorambucil alone. In this segment, chlorambucil was administered orally at 0.5 mg/kg on day 1 and 15 of each 28-day 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.

According to unpublished data released by Genentech, the company that developed the drug, the obinutuzumab combination demonstrated a significantly higher prolongation in median PFS than chlorambucil monotherapy (23.0 months vs 11.1 months; hazard ratio [HR] = 0.16; 95% CI, 0.11-0.24;P< .0001). Moreover, the trial found a 75.9% overall response rate with the obinutuzumab combination compared with 32.1% with chlorambucil alone. Complete response rates were achieved in 27.8% of patients who received obinutuzumab plus chlorambucil versus 0.9% for chlorambucil alone.

The most common grade 3/4 adverse events for patients treated with obinutuzumab plus chlorambucil were neutropenia (34%), infusion reactions (21%), and thrombocytopenia (11%).

&ldquo;Gazyva is an important new medicine for people with newly diagnosed chronic lymphocytic leukemia as it more than doubled the time people lived without their disease worsening compared to chlorambucil alone,&rdquo; said Hal Barron, MD, the chief medical officer and head of Global Product Development at Genentech, in a statement. &ldquo;We have spent 20 years researching blood cancer medicines, and we will continue to study Gazyva to assess its efficacy in other types of blood cancers.

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.