The FDA has granted accelerated approval to the combination of the PD-1 inhibitor nivolumab and the CTLA-4 inhibitor ipilimumab to treat advanced melanoma, the first time the agency has approved any combination of immunotherapies to treat cancer.

The FDA has granted accelerated approval to the combination of Bristol-Myers Squibb's PD-1 inhibitor nivolumab (Opdivo) and CTLA-4 inhibitor ipilimumab (Yervoy) to treat advanced melanoma, the first approval of an immunotherapy combination to treat cancer.

The agency approved the combination for patients with BRAF V600 wild-type unresectable or metastatic melanoma, based on the pivotal phase II CheckMate 069 trial (N Engl J Med 2015;372:2006–17). In that study, patients with BRAF wild-type melanoma had objective response rates (ORR) of 61% with the combination therapy versus 11% with ipilimumab alone.

Later results from the phase III CheckMate 067 study, which will be taken into account for final approval, suggest that the combination may be an option for all melanoma patients with advanced disease (N Engl J Med 2015;373:23–34). Researchers enrolled 945 patients with untreated advanced melanoma regardless of mutation status and found that the nivolumab–ipilimumab combination extended progression-free survival (PFS) and improved ORR compared with either drug alone.

“This is a very exciting development for melanoma patients,” says Patrick Ott, MD, PhD, clinical director of the Melanoma Center and the Center for Immuno-Oncology at Dana-Farber Cancer Institute in Boston, MA. “Although the response rate of 60% with the combination compared to 40% with nivolumab alone seen in both the phase II and phase III trials comes at a price for these patients because the toxicity is substantially higher with the combination compared to anti–PD-1 therapy alone.”

In the phase III study, about 36% of patients in the combination therapy group dropped out due to side effects, compared with about 8% in the nivolumab group and 15% in the ipilimumab group. The most common adverse events were diarrhea and colitis.

When looking at response based on PD-L1 status, researchers in the phase III study noted that the greatest benefit with the combination of nivolumab and ipilimumab versus nivolumab alone may occur in the context of negative PD-L1 tumor expression, as the PFS was similar between combination therapy and monotherapy in patients with PD-L1–positive tumors. Expression of PD-L1 has been associated with increased response rates in previous studies using PD-1 inhibition alone.

“At Dana-Farber, we are offering the combination to most patients who we think can tolerate the toxicity, regardless of PD-L1 status,” says Ott, who has been treating patients for the past 8 months on an extended-access protocol. “Patients face a choice between taking a PD-1 inhibitor alone with lower toxicity or the combination with higher toxicity, but a better overall chance of response.”

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