The antibody–drug conjugate polatuzumab vedotin has been approved to treat relapsed or refractory diffuse large B-cell lymphoma. The drug recognizes the CD79b protein on B cells and kills them with a molecule that prevents tubulin polymerization.
The FDA has approved the first antibody–drug conjugate (ADC) for treating relapsed or refractory diffuse large B-cell lymphoma (DLBCL). The ADC, polatuzumab vedotin (Polivy; Genentech), may provide a new option for patients who are elderly and aren't eligible for stem-cell transplants, whose disease has progressed despite undergoing a transplant, or who are awaiting chimeric antigen receptor (CAR) T-cell therapy.
ADCs consist of a cytotoxic molecule fused to a monoclonal antibody that targets a specific protein expressed by cancer cells. Polatuzumab vedotin's antibody recognizes the CD79b protein that is associated with the B-cell receptor. After the antibody binds to CD79b, the ADC's toxic payload, monomethyl auristatin E, enters the B cell and then kills it by preventing tubulin polymerization.
The FDA approved the ADC for use with bendamustine and rituximab (Rituxan; Genentech) in patients with DLBCL who have previously received at least two therapies. “This is a big step forward for diffuse large B-cell lymphoma,” says Jonathan Friedberg, MD, of the Wilmot Cancer Institute, University of Rochester Medical Center, in New York. “So many drugs have been tried and failed in this area.”
The critical data supporting the approval came from a phase Ib/II trial. The phase II portion of the trial included 80 patients who received the ADC plus bendamustine and rituximab or only bendamustine and rituximab. As reported last year at the American Society of Hematology (ASH) Annual Meeting in San Diego, CA, the overall response rate was 45% in patients who received the triple therapy and 18% in the control patients. The ADC recipients also had a higher complete response rate, 40% versus 18%, respectively, and longer overall survival, 12.4 months versus 4.7 months, respectively.
The researchers noted that the safety results were similar to those they had previously reported, which indicated that addition of the ADC increased the rates of some side effects. At the 2017 ASH meeting, for instance, they revealed that 39% of patients who received the ADC developed peripheral neuropathy, whereas 3% of control patients did. Grade 3 or 4 cytopenias were also more common in those assigned to the ADC group—46% of them had neutropenia, for instance, versus 36% for the control group. Oncologists can manage those side effects, and “it doesn't look like the toxicity will be prohibitive here,” says Timothy Fenske, MD, of the Medical College of Wisconsin in Milwaukee.
CD79b was an “ideal” choice, he adds, for the ADC's target because it allows treatment flexibility. Rituximab targets CD20, whereas CAR T cells target CD19. Because the ADC recognizes a different cell-surface protein, it may be effective in patients whose cancers have become resistant to those other treatments, he says. In addition, he says, the ADC shouldn't cause resistance to anti-CD19 CAR T cells and preclude that treatment as a subsequent option for patients.
Friedberg says the ADC will be particularly useful for older patients who aren't candidates for stem-cell transplants or CAR T-cell infusion. The ADC could also be a bridge therapy for younger patients until they can receive CAR T cells. However, he notes that the overall importance of polatuzumab vedotin for treating DLBCL will depend on trials testing it as part of a first-line regimen and as a second-line treatment. –Mitch Leslie