Simultaneously giving a combination of two immunotherapies—ipilimumab (Yervoy; Bristol-Myers Squibb) and nivolumab (Opdivo; Bristol-Myers Squibb)—to patients with advanced melanoma who have received no prior therapies yields better responses than using ipilimumab alone. The downside is that patients have a higher risk of side effects, according to a study presented on April 20 at the American Association for Cancer Research Annual Meeting 2015 in Philadelphia, PA, and published the same day in The New England Journal of Medicine.
A standard, FDA-approved drug for melanoma, ipilimumab is used currently used as a monotherapy. In December, nivolumab, which has been shown to improve survival in BRAF wild-type melanoma, was approved for use in patients with melanoma whose disease has progressed after treatment with ipilimumab.
Based on preclinical studies in mice showing that giving the drugs in combination was more effective at controlling tumors than giving the therapies sequentially, researchers led by F. Stephen Hodi, MD, director of the melanoma center at Dana-Farber Cancer Institute in Boston, MA, launched a double-blind, phase I trial to test the combination in patients. They enrolled 142 patients with advanced melanoma who had not been treated previously; 109 had tumors with wild-type BRAF and 33 had BRAF V600 mutations.
Patients were randomly assigned, in a 2:1 ratio, to receive the ipilimumab–nivolumab combination (95 patients) or ipilimumab alone (47 patients) until their disease progressed or they experienced unacceptable side effects. Among the patients with wild-type BRAF who received the two-drug combination, the overall response rate (ORR) was 61%, compared with 11% in the group that received ipilimumab alone. In the two-drug group, 22% experienced a complete response and 39% experienced stable disease. In the ipilimumab-alone group, not one patient had a complete response; all of the responses were partial, Hodi reported.
The ORR with the drug combination was only slightly lower among patients whose tumors harbored BRAF V600 mutations—52%, with 22% complete responses and 30% partial responses—suggesting that the mutations do not dramatically hinder the effectiveness of the therapy. Again, the combination was still superior to ipilimumab alone, to which just 10% of patients had partial responses, Hodi said.
Among the BRAF wild-type patients, the progression-free survival time had not yet been reached among those on the combination therapy; with ipilimumab, the median PFS was 4.4 months. Among patients with BRAF V600 mutations, those times were 8.5 months and 2.7 months, respectively.
Nearly all patients experienced side effects, but serious adverse events were reported more frequently in those who received the combination regimen than ipilimumab monotherapy (54% vs. 24%), Hodi said. Three deaths were also associated with the combined therapy. The most common serious side effects included colitis, diarrhea, and elevated liver enzymes.
Side effects, whether minor or serious, led to a greater percentage of patients discontinuing treatment in the combination-therapy group compared with the ipilimumab-alone group (85% vs. 30%). Notably, said Hodi, 68% of the patients who discontinued therapy due to its toxic effects continued to experience a complete or partial response. Although Hodi said he wasn't sure why the patients continued to benefit, he said that further study is needed to determine whether the dosing regimen could be modified.
Commenting on the study's findings, Louis M. Weiner, MD, director of the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, said, “We are in the middle of a revolution, and I don't think that's hyperbolic speech at this point. The incredible advances that we're seeing in melanoma aren't the kinds of observations that we've seen in our business previously.”
- ©2015 American Association for Cancer Research.