“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% to 40% 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 a combination of ipilimumab and nivolumab could increase the percentage of patients who benefit from either of these immunotherapies alone.”
“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 Dr. 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.”
CheckMate 067 Findings
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%). It was 59% and 45% 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, patients randomly assigned nivolumab plus ipilimumab had a 12% 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 Dr. 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%, 21%, and 28%, respectively. The most common side effects in the combination group were diarrhea/colitis and hepatitis, which were generally manageable, as previously reported.
According to Dr. 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.