Immunotherapy Combo Effective in Melanoma

Data from the phase III CheckMate 067 study suggest that for patients with previously untreated advanced melanoma, nivolumab (Opdivo; Bristol-Myers Squibb) combined with ipilimumab (Yervoy; Bristol-Myers Squibb) is significantly more effective than either checkpoint inhibitor alone. The results were presented by Jedd Wolchok, MD, PhD, chief of the Melanoma and Immunotherapeutics Service at Memorial Sloan Kettering Cancer Center in New York, NY, at the American Society of Clinical Oncology's Annual Meeting in Chicago, IL, May 29–June 2, and published concurrently in The New England Journal of Medicine.

Ipilimumab's target, CTLA-4, and nivolumab's, PD-1, “represent distinct and complementary pathways that negatively regulate antitumor immunity,” Wolchok said, “which provides a rationale for their simultaneous blockade.” By obstructing CTLA-4, ipilimumab unleashes a tumor-directed immune response in the form of cytotoxic T cells, while nivolumab prevents interactions between PD-1 and one of its ligands, PD-L1, exposing tumors to immune surveillance.

CheckMate 067 enrolled 945 patients with advanced melanoma, who were randomized to receive either ipilimumab or nivolumab as monotherapy, or both combined. The overall median progression-free survival (PFS) was 2.9 months for patients receiving ipilimumab alone, 6.9 months for the nivolumab-only group, and 11.5 months for those given the combination. The overall objective response rates (ORR) for the ipilimumab, nivolumab, and combination groups were 19%, 43.7%, and 57.6%, respectively. On average, the combination reduced patients' tumor burden by 52%, and nivolumab alone by 34%; in contrast, a 5% increase was seen with single-agent ipilimumab. The study's overall survival data will be reported at a later time.

In the context of high (>5%) PD-L1 expression, determined by immunohistochemistry, the median PFS for patients was the same (14 months) for the combination and nivolumab-only arms, and 3.9 months for those given ipilimumab alone; the respective ORRs were 72.1%, 57.5%, and 21.3%. The main side effects seen with CheckMate 067 included diarrhea, rash, fatigue, and nausea; these occurred most frequently in the combination group, resulting in 36.4% of patients discontinuing therapy.

“For frail patients with multiple comorbidities and high PD-L1 expression, we can tell them their average time to disease progression will be the same, whether on combination therapy with its increased toxicity, or nivolumab alone. On the other hand, fitter patients may wish to try the combination, which does have a higher response rate,” Wolchok said. He cautioned, however, that “PD-L1 expression is a first effort to introduce precision to immunotherapy, not a binary discriminator of absolute benefit.”

Interestingly, Wolchok noted, 67.5% of the patients who discontinued combination therapy due to side effects still developed a response, half of them after stopping treatment.

“There appears to be a margin of safety,” said Michael Atkins, MD, deputy director of Georgetown University's Lombardi Comprehensive Cancer Center in Washington, DC. “If one stops therapy and initiates immune modulators when significant immune-related adverse events are noted, toxicity can be controlled without eliminating treatment efficacy.”

“In my opinion, ipilimumab can no longer be considered a standard first-line immunotherapy for advanced melanoma,” Atkins added, “while ipilimumab and nivolumab combined are likely superior to nivolumab alone, although it behooves us to wait for the [overall] survival data before making this statement definitively. Meanwhile, I'm hopeful that these advances in melanoma will continue to pave the way for immunotherapy development in other cancers.”