The U.S. Food and Drug Administration (FDA) has approved a supplemental biologics license application orsBLA for obinutuzumab (Gazyva?; Genentech/Roche) in combination with chlorambucil chemotherapy in people with previously untreated chronic lymphocytic leukemia (CLL). The sBLA adds to the label data from Stage 2 of the CLL11 study showing significant improvements with Gazyva plus chlorambucil across multiple clinical endpoints when compared head-to-head with rituximab; Rituxan?; Genentech)plus chlorambucil.
Chronic lymphocytic leukemiais one of the most common forms of blood cancer and in 2014, it is expected that there will be nearly 5,000 deaths from CLL in the United States. Most cases of CLL (95%) start in white blood cells called B-cells that have a protein called CD20 on their surface.
This is the first and only medicine to significantly help people live without their disease worsening when combined with chlorambucil compared to rituximab and chlorambucil in people with previously untreated chronic lymphocytic leukemia or CLL
Engineered Monoclonal Antibody
Obinutuzumab is an engineered monoclonal antibody designed to attach to CD20, a protein found only on B-cells. It attacks targeted cells both directly and together with the body’s immune system. Obinutuzumabis thought to have an increased ability to induce direct cell death and induces greater activity in how it recruits the body?s immune system to attack B-cells (antibody dependent cellular cytotoxicity or ADCC) when compared to rituximab. The trial drug was discovered by Roche Glycart AG, a wholly owned, independent research unit of Roche. In the United States, the trial drug is being developed by Genentech in collaboration with Biogen Idec.
Obinutuzumab is currently in clinical trials. One of these trials is CLL11, a Phase III, multicenter, open-label, randomized three-arm study, conducted in cooperation with the German CLL Study Group, in 781 previously untreated people with CLL and co-existing medical conditions. Stage 1 (n=589) compared obinutuzumabplus chlorambucil to chlorambucil alone and rituximab plus chlorambucil to chlorambucil alone. Stage 2 (n=663) compared obinutuzumabplus chlorambucil directly with rituximab plus chlorambucil. The primary endpoint of the study was PFS with secondary endpoints including overall response rate (ORR), OS, CR, median duration of response, MRD and safety profile. Results from Stage 2 and updated data from Stage 1 were presented in 2013 during the Plenary Scientific Session of the American Society of Hematology (ASH) meeting and published in theNew England Journal of Medicinein 2014. 
The new approval includes complete response or CR and minimal residual disease or MRD data from Stage 2 of the study. Additionally, overall survival (OS) data was added from Stage 1 of the study comparing obinutuzumabplus chlorambucil to chlorambucil alone.
“Obinutuzumab is the first and only medicine to significantly help people live without their disease worsening when combined with chlorambucil compared to rituximab and chlorambucil in people with previously untreated chronic lymphocytic leukemia,? explained Sandra Horning, M.D., chief medical officer and head of Global Product Development. ?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 sBLA approval updated the obinutuzumabprescribing information with the following data:
- Obinutuzumab plus chlorambucil helped people with previously untreated CLL live nearly a year longer without their disease worsening or death (progression-free survival; PFS) than rituximab plus chlorambucil (median PFS: 26.7 months vs. 14.9 months, respectively. HR=0.42, 95% CI 0.33-0.54, p<0.0001).
- Obinutuzumabplus chlorambucil nearly tripled the number of people showing no evidence of disease (CR) compared to rituximab plus chlorambucil (26.1% vs. 8.8%, respectively).
- Of the people who achieved a complete response with or without complete recovery from abnormal blood cell counts (CR, CRi), 19% (18/94) of people in the obinutuzumabarm compared to 6% (2/34) of people in the rituximab arm were MRD negative in the bone marrow, and 41% (39/94) of people in the obinutuzumab arm compared to 12% (4/34) people in the rituximab arm were MRD negative in the peripheral blood. MRD negative means no residual traces of the cancer were found.
- Data from the first stage of the CLL11 study showed that at nearly two years, the rate of death was 9% (22/238) for people who received obinutuzumab plus chlorambucil compared to 20% (24/118) for those who received chlorambucil alone (HR=0.41, 95% CI 0.23-0.74). The median OS has not yet been reached.
Obinutuzumab can cause serious or life-threatening side effects including: Hepatitis B reactivation, progressive multifocal leukoencephalopathy (PML), infusion reactions, tumor lysis syndrome, infections, and low white blood cell counts. The most common side effects of obinutuzumab are infusion reactions, low white blood cell counts, low platelet counts, low red blood cell counts, fever, cough, nausea, and diarrhea.
The trial drug, first medicine approved with the FDA?s Breakthrough Therapy Designation, was approved for use in combination with chlorambucil in people with previously untreated CLL on November 1, 2013. In Europe the drug was approved by the European Commission for the same indication in July 2014. Obinutuzumabis also being investigated in a broad development program across various types of blood cancers, including multiple Phase III studies in non-Hodgkin?s lymphoma (NHL).
For more information:
 Goede V, Fischer K, Busch R, Engelke A, Eichhorst B, Wendtner CM, Chagorova T, et al. Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.N Engl J Med. 2014 Mar 20;370(12):1101-10. doi: 10.1056/NEJMoa1313984. Epub 2014 Jan 8.[Article][PubMed]
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