A Second Anti-CD20 Drug for NHL

Data from the phase III GADOLIN study show that adding obinutuzumab (Gazyva; Genentech), a novel CD20-targeting monoclonal antibody, to standard chemotherapy considerably delays the progression of indolent non-Hodgkin lymphoma (NHL). The findings were presented by Laurie Sehn, MD, MPH, a medical oncologist at the BC Cancer Agency in Vancouver, Canada, at the American Society of Clinical Oncology's Annual Meeting in Chicago, IL, May 29–June 2.

“Indolent NHL is still incurable with current therapy,” Sehn noted. “Although patients progress relatively slowly, resistance to existing treatment is inevitable; with each cycle, they're less likely to respond, and the response duration is shorter.” The standard chemotherapy for NHL, bendamustine (Treanda; Cephalon), is “unfortunately associated with a brief remission period of 7 to 9 months,” she added.

Although adding rituximab (Rituxan; Genentech), another anti-CD20 drug, to the therapeutic regimen can significantly improve both progression-free survival (PFS) and overall survival, “some patients never respond to rituximab, or relapse early post-treatment,” said Sehn.

“Given the profound impact of anti-CD20 therapy on the natural history of virtually every B-cell lymphoma, [patients who develop] resistance present a substantial challenge,” said Owen O'Connor, MD, PhD, director of the Center for Lymphoid Malignancies at Columbia University Medical Center in New York, NY.

GADOLIN enrolled 396 patients with various forms of indolent NHL, primarily follicular, marginal zone, and small lymphocytic lymphomas. The patients, all rituximab-refractory, were randomized to receive bendamustine alone, or bendamustine with obinutuzumab followed by maintenance therapy with obinutuzumab. The investigator-assessed median PFS was 14 months for patients given bendamustine, and 29.2 months for those who received the combination. In an independent radiology review, the median PFS was 14.9 months in the bendamustine-only arm, and not yet reached in the combination arm.

The combination's safety profile was comparable to bendamustine alone, and no unexpected adverse events were noted. Neutropenia and thrombocytopenia were the main hematologic side effects; other side effects included infusion-related reactions and nausea. Because GADOLIN met its primary endpoint (PFS), the study is no longer recruiting patients.

Both obinutuzumab and rituximab target CD20 on B cells, but the former is “an example of improved antibody engineering,” said Grzegorz Nowakowski, MD, a medical oncologist at the Mayo Clinic in Rochester, MN. Obinutuzumab's cytotoxicity is enhanced by tighter binding to CD20, and its Fc region is also designed to better mediate antibody-dependent cellular cytotoxicity.

The benefit of adding obinutuzumab to bendamustine is significant, Nowakowski said, but based on standard Medicare reimbursement rates, it also doubles treatment costs. Nonetheless, he pointed out that “although the combination appears more expensive at first glance, the cost of subsequent therapy for patients relapsing earlier on bendamustine alone should be factored in.”

“Pharmacoeconomic analyses often overlook the total cost of care,” O'Connor agreed. “In my opinion, GADOLIN is a potentially practice-changing study that justifies a new drug combination for patients with relapsed, rituximab-refractory NHL.”