Phase I Trial of Nivolumab Shows Long-Term Efficacy Against Melanoma

A recent study by researchers at Dana-Farber Cancer Institute, Johns Hopkins University, Yale University, and allied institutions, published online in the Journal of Clinical Oncology, provides the longest-term look so far at how melanoma patients have fared since receiving the drug, nivolumab (Bristol-Myers Squibb). The Phase I clinical trial results indicate that the benefits of nivolumab occur quickly and persist, even in some cases where use of the drug is discontinued.

The clinical trial involved 107 patients with advanced melanoma that no longer responded to other treatments. Patients received nivolumab intravenously every other week for up to 96 weeks. After one year, 62 percent of the patients were alive. After two years, 43 percent were alive.

“These are striking results for patients with metastatic melanoma,” said the study's senior author F. Stephen Hodi, MD, director of the Melanoma Treatment Center at Dana-Farber, in a press release. “This study provides the first demonstration of the long-term benefits this treatment approach can produce.”

Nivolumab blocks PD-1, a protein on immune system T cells that restrains them from leading a charge on tumor cells. By interfering with PD-1, nivolumab allows the attack to proceed, according to researchers.

The side effects of the treatment were consistent with those observed in previous studies of the drug. The most common adverse experiences were fatigue, rash, and diarrhea, most of which occurred in the first six months of therapy. Prolonged exposure to the drug didn't produce cumulative negative effects, the investigators report.

One of the most noteworthy findings of the study is that, in many patients, tumors either remained the same size or continued to recede even after the treatment period was over. “This suggests that blockade PD-1 may reset the equilibrium between the immune system and the tumor, keeping tumor growth in check,” said Dr. Hodi, who is also the director of the Center for Immuno-Oncology at Dana-Farber.

Overall survival times for patients in the trial were considerably longer than the periods in which the disease did not worsen. In other words, even in patients who developed small new melanoma growths after treatment, the disease often remained under control. That is far different from the usual sequence of events, in which the appearance of new growths often heralds a full-scale return of the disease, Dr. Hodi explained.

The effectiveness of nivolumab in these patients suggests that combining the drug with other immune system-based therapies may prove even more potent, the authors indicate. Clinical trials are already under way to assess such a combined approach.

The lead author of the study is Suzanne Topalian, MD, of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins. Co-authors are William Sharfman, MD, Julie Brahmer, MD, Evan Lipson, MD, Janis Taube, MD, and Drew Pardoll, MD, PhD, of Johns Hopkins; Mario Sznol, MD, and Harriet Kluger, MD, of Yale University School of Medicine; David McDermott, MD, of Beth Israel Deaconess Medical Center; Donald Lawrence, MD, of Massachusetts General Hospital; Richard Carvajal, MD, of Memorial Sloan-Kettering Cancer Center; Michael Atkins, MD, of Georgetown-Lombardi Comprehensive Cancer Center, Washington, D.C.; John Powderly, MD, of Carolina BioOncology Institute; Philip Leming, MD, of Christ Hospital Cancer Center, Cincinnati, Oh.; Igor Puzanov, MD, and Jeffrey Sosman, MD, of Vanderbilt University Medical Center; David Smith, MD, of the University of Michigan; and Jon Wigginton, MD, Georgia Kollia, PhD, and Ashok Gupta, PhD, of Bristol-Myers Squibb.

Funding for the study was provided by Bristol-Myers Squibb.