Nivolumab Yields Durable Responses in Melanoma

Advanced melanoma is notoriously difficult to treat, and patients frequently develop resistance to existing therapies. That trend may be changing: In recent years, targeted and immunotherapeutic drugs have begun to improve outcomes for patients enrolled in clinical trials.

In 2012, an interim report of a large phase I trial suggested the experimental immunotherapeutic nivolumab (Bristol-Myers Squibb and Ono Pharmaceutical) can confer lasting benefits, including tumor regression, to patients with advanced melanoma. Now, after analyzing longer-term results in an expanded cohort, researchers report that responses can continue for months or, in some cases, years after treatment has stopped.

A monoclonal antibody, nivolumab targets PD-1, a receptor on activated T-cells that normally inhibits the immune response. By blocking PD-1, the drug frees up immune cells to attack cancer cells. Its action is like “releasing the brakes” on antitumor immunity, says Suzanne Topalian, MD, director of the melanoma program at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, MD, and lead author of the melanoma expansion study.

The original phase I trial was a large, multisite investigation assessing the drug's safety and effectiveness in five types of cancer. During that trial, researchers observed responses in more than a quarter of the patients with advanced melanoma, all of whom had received at least one and up to five prior systemic therapies.

“We realized after treating patients early in the trial that we were seeing reproducible evidence of responses in three of the five different cancers, including melanoma, lung, and kidney cancer,” says Topalian. “We realized that many of the clinical responses in melanoma patients were long lasting.”

The researchers expanded the trial, enrolling more patients and extending the study period. Retrospectively, they analyzed data to assess overall survival. Of the 107 patients with melanoma who received nivolumab, some of whom were treated for as long as 96 weeks, 33 experienced significant tumor regression with a median duration of about 2 years, the researchers reported in the Journal of Clinical Oncology. (In some patients, disease initially progressed but later stabilized or regressed, suggesting that the drug's effects may be delayed.) The median overall survival for the entire group was 16.8 months.

Although the treatments have not yet been compared head to head, phase II and III trials of Bristol-Myers Squibb's ipilimumab (Yervoy), an immunotherapeutic approved by the U.S. Food and Drug Administration in 2011, produced a median overall survival of less than a year.

Side effects of nivolumab, which included diarrhea and lymphopenia, tended to appear within the first 6 months and did not appear to accumulate over time. “If anything, toxicity decreased as time went on, but we don't know how to explain that yet,” notes Topalian.

The results from the expanded study were promising enough for researchers to launch three phase III clinical trials, including one assessing the combination of nivolumab and ipilimumab versus either drug as monotherapy, in melanoma last year. Phase III trials of nivolumab are also under way in lung and kidney cancers.