Nivolumab plus ipilimumab as first-line therapy achieve high response rate in advanced melanoma

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The immunotherapy drugs nivolumab and ipilimumab, given together as initial treatment in advanced melanoma, achieved a much higher response rate than treatment with ipilimumab alone, report investigators from Dana-Farber Cancer Institute in Boston.

The two-drug combination had a higher rate of complete responses and improved progression-free survival than with ipilimumab, the researchers said. Their report is being published in the New England Journal of Medicine simultaneously with a presentation of the results at the annual meeting of the American Association for Cancer Research in Philadelphia.

Treatment with ipilimumab (Yervoy) alone is a standard first-line treatment for such patients if their tumors contain a normal or “wild type” version of the BRAF gene. Nivolumab (Opdivo) is approved as a therapy following ipilimumab or a BRAF inhibitor for patients whose tumor harbor a BRAF mutation.

The double-blind trial included 142 previously untreated patients, of which 109 had the wild-type BRAF gene and 33 had the mutant form. The combination therapy achieved a 61 percent response rate in patients with wild type BRAF melanoma, compared with 10.8 percent in those who got only ipilimumab. In the BRAF mutant patients, nivolumab plus ipilumumab had a 52 percent response rate.

The combination eradicated all visible signs of the cancer — a “complete response” — in 16 of the 72 patients with “wild type” BRAF genes and five of 23 patients whose melanoma cells had BRAF mutations. There were no complete responses in either group treated with ipilimumab alone.

“These results confirm the effectiveness of the two-drug combination,” said F. Stephen Hodi, MD, director of the Melanoma Treatment Center and the Center for Immuno-Oncology at Dana-Farber. “It appears that the drugs are boosting the immune system’s response in a synergistic way, taking advantage of blocking two different brakes to the immune system.”

Hodi is senior author of the publication along with Jedd D. Wolchok, MD, PhD, of Memorial Sloan-Kettering Cancer Center.

At the time of publication the median response duration had not been reached with either of the drug regimens. Median progression-free survival was not reached for nivolumab plus ipilimumab; it was 4.4 months for ipilimumab alone.

Both drugs work by removing molecular “brakes” that cancer cells deploy to prevent the body’s immune system from attacking them. Ipilimumab is a monoclonal antibody targeting the CTLA-4 receptor, while nivolumab blocks the PD-1 protein on T cells to unleash their attack on the cancer.

The encouraging findings of the randomized, double-blind study confirmed and improved on the “hints” of the combination’s effectiveness observed in a previous phase 1 trial, noted Hodi.

The trial sponsor, Bristol-Myers Squibb, has established an expanded-access program in which previously untreated patients can receive the drug combination, said Hodi.

The added benefit of the combination, however, came at a cost of greater toxicity. Serious adverse events were reported in 54 percent of drug combination patients versus 23.9 percent in ipilimumab-only patients.

The symptoms, mainly colitis and diarrhea, were the result of “taking two brakes off the immune system” in the patients treated with both immunotherapy agents, Hodi said. In most cases immunosuppressive drugs dampened the immune reactions enough to alleviate the symptoms, apparently without negating the combination’s anticancer benefits, he added. “Following up patients in the current study over a longer period of time is an important step,” said Hodi.

The study was funded by Bristol Myers Squibb.

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