Obinutuzumab Effective in Follicular Lymphoma, but at a Cost

The standard first-line treatment for follicular lymphoma is the anti-CD20 antibody rituximab (Rituxan; Genentech) paired with chemotherapy. However, a recent study showed that replacing rituximab with another anti-CD20 antibody, obinutuzumab (Gazyva; Genentech), resulted in a 34% lower risk of progression, relapse, or death at 3 years; estimated 3-year rates of progression-free survival were 80.0% for obinutuzumab and 73.3% for rituximab. Unfortunately, obinutuzumab's greater effectiveness came at a price: It was associated with a roughly 15% increase in serious side effects.

“Obinutuzumab keeps patients in remission for longer than rituximab, but more careful follow-up is required,” says Robert Marcus, MBBS, of King's College Hospital in London, UK, the lead author of the study.

Loretta Nastoupil, MD, of The University of Texas MD Anderson Cancer Center in Houston, who was not involved in the study, says that the size of this phase III study—1,202 patients were enrolled—and the sound study design provide clinicians with valuable information about the drug's efficacy. However, she says that adoption of the drug may be affected by the higher rate of neutropenia, infusion reactions, infections, and cardiac events in the obinutuzumab arm.

An unexpected study finding involved bendamustine, one of the chemotherapies paired with the drugs of interest. Depending upon the study site, patients received one of three chemotherapy regimens: bendamustine; cyclophosphamide, vincristine, and prednisone; or cyclophosphamide, doxorubicin, vincristine, and prednisone. Non–relapse-related fatal adverse events were more than twice as common among patients who received bendamustine as among patients who received the other combinations. Marcus observes that, given the size of this study, these are the most rigorously analyzed safety data available for first-line bendamustine therapy.

“This is noteworthy, as bendamustine is considered a well-tolerated therapy,” explains Nastoupil. “The fatal adverse event rate is higher than we would like to see in a front-line follicular lymphoma study, given that life expectancy is high.” Because the fatal events occurred primarily during the maintenance phase of treatment, the findings raise questions as to whether maintenance should be pursued at all.

Additional research on obinutuzumab as a first-line treatment for follicular lymphoma is needed, Nastoupil says, particularly to investigate late-emerging toxicities and secondary cancer risk. “The study was reported with a relatively short median follow-up time, due to meeting the stopping rules.” Longer follow-up will also allow researchers to determine whether the drug improves overall survival relative to rituximab.

Cost-effectiveness research seems warranted as well, says Nastoupil. “Rituximab will soon be off patent, and with biosimilars anticipated, there may be financial considerations that impact treatment decisions.”

Although these questions remain, the study's conclusions could inform the treatment of related diseases. “We approach most indolent lymphomas as we do follicular lymphoma, so the implications will likely extend to other indolent non-Hodgkin lymphomas,” says Nastoupil. –Kristin Harper