ESMO 2017: Adjuvant Nivolumab Superior to Ipilimumab in Surgically Resected Stage III/IV Melanoma


Key Points

  • CheckMate 238 demonstrated that adjuvant nivolumab is superior to standard-of-care ipilimumab in patients with surgically resected stage III/IV melanoma who are at high risk of relapse.
  • Nivolumab led to better relapse-free survival, with fewer side effects than ipilimumab.
  • Similar results were observed across prespecified subgroups of patients.

Adjuvant nivolumab (Opdivo) is superior to standard-of-care ipilimumab (Yervoy) in patients with surgically resected stage III/IV melanoma who are at high risk of relapse, according to late-breaking results from the CheckMate 238 trial presented on September 11 at the European Society for Medical Oncology (ESMO) 2017 Congress in Madrid (Abstract LBA8_PR) and published in the The New England Journal of Medicine by Weber et al. The anti–programmed cell death 1 (PD-1) antibody nivolumab led to better relapse-free survival, with fewer side effects than ipilimumab.

Both nivolumab and ipilimumab are immune checkpoint inhibitors approved for the treatment of patients with metastatic melanoma. Ipilimumab is also the U.S. Food and Drug Administration–approved standard-of-care adjuvant therapy for resected stage III melanoma in the United States. Nivolumab was well tolerated and showed promising survival results when investigated as adjuvant therapy in a pilot study of 33 patients with resected stage IIIC and IV melanoma.

CheckMate 238 Details

The benefit shown for nivolumab in metastatic disease and those pilot data provided the impetus for CheckMate 238, a randomized, double-blind, phase III trial comparing adjuvant treatment with nivolumab vs standard-of-care ipilimumab. The trial included 906 patients with stages IIIB, IIIC, and IV resected melanoma who had a greater than 50% risk of relapse over 5 years. Patients were randomized 1:1 to either treatment.

The primary endpoint was relapse-free survival. Overall survival was a secondary endpoint, which will be complicated by the anticipation that patients will cross over to the alternative drug upon relapse.

The trial was stopped early by the data safety monitoring committee due to clear evidence of benefit for nivolumab. The planned interim analysis that occurred at a minimum follow-up of 18 months showed that the rate of relapse-free survival was significantly improved with nivolumab (66.4%) compared to ipilimumab (52.7%), with a hazard ratio of 0.65 (P < .0001). There were similar results across prespecified subgroups of patients.

There were fewer treatment-related, clinically relevant side effects (grade 3/4) in the group treated with nivolumab (14%) compared to those treated with ipilimumab (46%). Just 10% of patients taking nivolumab had to stop treatment due to side effects compared to 43% taking ipilimumab.

First author Jeffrey Weber, MD, Deputy Director, Perlmutter Cancer Center, NYU Langone Health, New York, said: “The results clearly show that relapse-free survival is more favorable with nivolumab. The majority of patients had higher-risk disease than in most prior adjuvant melanoma trials, which makes the findings even more encouraging.”

Additional Comments

“A previous trial found that ipilimumab had a significant relapse-free and overall survival advantage compared to placebo,” Dr. Weber continued. “CheckMate 238 shows that nivolumab is superior to ipilimumab, so extrapolating these results, nivolumab is far better than no adjuvant treatment for high-risk melanoma. It is also much less toxic than ipilimumab.”

He concluded: “Nivolumab looks like a superior adjuvant melanoma regimen compared to ipilimumab from every angle. It leads to better relapse-free survival, has fewer side effects, and is well tolerated.”

John Haanen, MD, PhD, Professor and Head, Division of Medical Oncology, Netherlands Cancer Institute, Amsterdam, said: “An adjuvant trial presented at the ESMO 2016 Congress showed that ipilimumab gave an overall survival advantage over placebo, but it was highly toxic. In the United States, it has become standard of care, but this is still being debated in Europe.”

Commenting on the findings presented at ESMO 2017, he said: “The results of CheckMate 238 are very exciting. They show for the first time that an anti–PD-1 drug is superior in the adjuvant setting, and because of its lower toxicity nivolumab is much easier to give than ipilimumab. The same occurs in the metastatic setting, where anti–PD-1 treatment is more efficacious, has a much better safety profile, and has replaced ipilimumab as first-line treatment.”

Another anti–PD-1 drug, pembrolizumab (Keytruda), is being tested as adjuvant therapy against placebo in patients with resected stage III melanoma in a phase III European Organisation for Research and Treatment of Cancer trial. Dr. Haanen said: “If relapse-free survival is better with pembrolizumab, it is likely that adjuvant anti–PD-1 will become standard of care for high-risk melanoma in the near future, provided an overall survival benefit is also shown.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.