Obinutuzumab Breaks through to FDA Approval

On November 1, the U.S. Food and Drug Administration (FDA) approved a combination of Roche's monoclonal antibody obinutuzumab (Gazyva) with chlorambucil for patients with previously untreated chronic lymphocytic leukemia (CLL).

Also known as GA101, obinutuzumab is the first drug to receive FDA approval under the agency's breakthrough therapy designation, created in July 2012 to quicken the pace of development and review of drugs for serious or life-threatening conditions.

Like Roche's rituximab (Rituxan), a standard treatment for CLL, obinutuzumab is a monoclonal antibody that targets the CD20 antigen on B lymphocytes. Unlike rituximab, obinutuzumab is a fully humanized antibody which has a glycoengineered structure thought to provide a higher binding affinity for FcγRIII receptors. In turn, this may lead to greater antibody-dependent cellular toxicity.

FDA approval was based on the randomized phase III CLL11 trial, which compared the efficacy and safety profile of obinutuzumab plus chlorambucil, rituximab plus chlorambucil, or chlorambucil alone in 781 previously untreated people with CLL.

In the study's first stage, on which the approval was based, patients who received obinutuzumab in combination with chlorambucil experienced a median progression-free survival of 23 months compared with 11.1 months with chlorambucil alone.

On November 7, Roche announced results from the study's second stage comparing obinutuzumab with rituximab. Patients receiving obinutuzumab plus chlorambucil demonstrated longer progression-free survival that those receiving rituximab plus chlorambucil (a mean of 26.7 months compared with 15.2 months), higher complete response rates (21% compared with 7%) and much greater likelihood of showing no detectable disease in the blood after treatment (29.4% compared with 2.5%). Additional results will be presented at the American Society of Hematology's annual meeting in December.

The trial was unusual in that it studied an older population with a high prevalence of other health problems, notes trial leader Michael Hallek, MD, leader of the German CLL Study Group at the University Hospital of Cologne in Germany. Median age of the patients was 73 years, which “made it interesting and relevant for the real-world patient population with this leukemia,” he explains.

Richard Furman, MD, director of the CLL Research Center at Weill Cornell Medical College in New York, NY, says that physicians will be looking at the data to determine when and whether to transition patients to the new drug.

“One problem with the study leading to the approval of obinutuzumab is that chlorambucil, the chemotherapy used in the study, is not widely used in the US,” he points out. Additionally, although the new trial data demonstrate obinutuzumab's benefit over rituximab when both are used in combination with chlorambucil, the story for single-agent monoclonal antibody use is unknown.

Eliminating chemotherapy altogether from the treatment paradigm for CLL is an important goal, Furman says, and obinutuzumab is a welcome addition.

Hallek agrees that there's cause for optimism that obinutuzumab and several other CLL drugs in the pipeline will replace chemotherapy and eventually achieve more long-term remissions or cures. “These new agents will profoundly change the way we treat CLL in the next few years,” he predicts.