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FINDING CURES TOGETHER<sup>SM</sup>

Combination of Nivolumab and Ipilimumab Improved Overall Survival For Advanced Melanoma Patients

4/3/2017

​WASHINGTON — Among patients with advanced melanoma, those who received both nivolumab (Opdivo) and ipilimumab (Yervoy) had improved overall survival compared with those who received only ipilimumab and appeared to have more favorable survival outcomes compared with those who received nivolumab, according to results from the phase III CheckMate 067 clinical trial presented here at the AACR Annual Meeting 2017, April 1-5.

“The approval of checkpoint inhibitors like ipilimumab and nivolumab when used as monotherapies has transformed the treatment of advanced melanoma in the past few years, with about 30–40 percent of patients having remarkable and durable responses,” said James Larkin, PhD, FRCP, a consultant medical oncologist at The Royal Marsden in London. “This clinical trial set out to test whether treating patients with nivolumab alone, or a combination of ipilimumab and nivolumab could increase the percentage of patients who benefit when compared to the former standard of care comparitor, ipilimumab. James Larkin, PhD, FRCP

“Early results from the trial, published in 2015, showed that nivolumab alone or combined with ipilimumab resulted in significantly longer progression-free survival than ipilimumab alone and led the EMA [European Medicines Agency] and FDA [U.S. Food and Drug Administration] to grant approval for the use of nivolumab in combination with ipilimumab,” continued Larkin. “A condition of the FDA accelerated approval was that it was necessary to show that the progression-free survival data translated into improved overall survival, and here we show that: nivolumab alone or combined with ipilimumab resulted in significantly improved overall survival.”

Larkin and colleagues enrolled 945 patients with advanced melanoma who had not received prior treatment for advanced disease in the phase III clinical trial. They were randomly assigned 1:1:1 to nivolumab plus ipilimumab, nivolumab, or ipilimumab.

After a minimum follow-up of 28 months, median overall survival among those patients randomly assigned ipilimumab was 20.0 months. The median overall survival had not been reached for the nivolumab plus ipilimumab or the nivolumab plus placebo arms.

Two-year overall survival was highest among those randomly assigned nivolumab plus ipilimumab, 64 percent. It was 59 percent and 45 percent among those randomly assigned nivolumab plus placebo and ipilimumab alone, respectively. A similar trend was seen for median duration of response. Median duration of response had not been reached in the nivolumab plus ipilimumab arm, while it was 31.1 months and 18.2 months for the nivolumab plus placebo arm and ipilimumab alone arm, respectively. In descriptive analyses, meaning the study was not powered for this comparison, patients randomly assigned nivolumab plus ipilimumab had a 12 percent lower risk of death compared with those randomly assigned nivolumab plus placebo.

“It is exciting to see that initial results suggest that the nivolumab plus ipilimumab combination provides favorable survival outcomes compared with ipilimumab alone,” said Larkin. “However, the combination also results in a higher rate of severe adverse events than nivolumab or ipilimumab alone, so it is important to consider this when making treatment decisions for patients.”

As in previous reports, the frequency of grade 3/4 adverse events was higher among those randomly assigned nivolumab plus ipilimumab compared with those randomly assigned nivolumab plus placebo or ipilimumab alone: 58 percent, 21 percent, and 28 percent, respectively. The most common side effects in the combination group were diarrhea/colitis and hepatitis, which were generally manageable, as previously reported.

According to Larkin, the main limitation of this study is that it was not designed to compare the nivolumab plus ipilimumab combination with nivolumab alone and this is the first analysis that has been done for overall survival.

This study was funded by Bristol-Myers Squibb. Larkin declares institutional research support from Bristol-Myers Squibb, Merck Sharp & Dohme, Novartis, and Pfizer; and consultancy for Eisai, Bristol-Myers Squibb, Merck Sharp & Dohme, GlaxoSmithKline, Kymab, Pfizer, Novartis, Roche/Genentech, Secarna, Pierre Fabre, and EUSA Pharma.

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