Previous analyses of the CheckMate 067 study have shown the ability of the anti-PD1 agent nivolumab, whether used alone or in combination with ipilimumab, to induce durable disease control in patients with advanced melanoma. The final, 10-year results of the CheckMate 067 study continue to show long-term survival benefit with nivolumab plus ipilimumab and with nivolumab monotherapy, as compared with ipilimumab monotherapy.
The final efficacy and safety results from the CheckMate 067 study, with a minimum follow-up of 10 years are presented at the ESMO Congress 2024 along with a simultaneous publication by Dr. Jedd D. Wolchok of the Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine in New York, NY, US and colleagues on 15 September 2024 in The New England Journal of Medicine.
In the phase III CheckMate 067 study, after a minimum follow-up of 7.5 years, median overall survival (OS) was 72 months with nivolumab plus ipilimumab, as compared with less than 12 months before 2011, when ipilimumab became commercially available. Given that patients with advanced melanoma are living longer, new clinical questions have emerged. Clinically relevant outcomes now include OS, melanoma-specific survival (MSS), long-term outcomes among patients who had been alive and progression-free at 3 years, and patterns of first progression.
Some of these clinically relevant long-term outcomes have been assessed in the CheckMate 067 study. For example, 7.5-year MSS was numerically higher than 7.5-year OS in each study group (55% versus 48% with nivolumab plus ipilimumab, 47% versus 42% with nivolumab, and 26% versus 22% with ipilimumab). In addition, among patients who had been alive and progression-free at 3 years, 7.5-year MSS was 98% with nivolumab plus ipilimumab, 97% with nivolumab, and 95% with ipilimumab.
Follow-up data obtained beyond 7.5 years provide a unique opportunity to inform post-treatment surveillance imaging and follow-up schedules, as well as to assess any unexpected effects of immune checkpoint blockade on aging-associated conditions. Now, the study team is reporting the final efficacy and safety results from the CheckMate 067 study, with a minimum follow-up of 10 years.
The study team randomly assigned patients with previously untreated advanced melanoma, in a 1:1:1 ratio, to one of the following regimens: nivolumab (1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram) every 2 weeks; nivolumab (3 mg per kilogram) every 2 weeks plus placebo; or ipilimumab (3 mg per kilogram) every 3 weeks for four doses plus placebo.
Treatment was continued until the occurrence of disease progression, unacceptable side effects, or withdrawal of consent. Randomisation was stratified according to BRAF mutation status, metastasis stage, and PD-L1 expression.
With a minimum follow-up of 10 years, median OS was 71.9 months with nivolumab plus ipilimumab, 36.9 months with nivolumab, and 19.9 months with ipilimumab. The hazard ratio for death was 0.53 (95% confidence interval [CI] 0.44 to 0.65) for nivolumab plus ipilimumab as compared with ipilimumab and 0.63 (95% CI 0.52 to 0.76) for nivolumab as compared with ipilimumab.
Median MSS was more than 120 months with nivolumab plus ipilimumab (not reached, with 37% of the patients alive at the end of the study), 49.4 months with nivolumab, and 21.9 months with ipilimumab. Among patients who had been alive and progression-free at 3 years, 10-year MSS was 96% with nivolumab plus ipilimumab, 97% with nivolumab, and 88% with ipilimumab.
The survival benefits seen with nivolumab-containing therapies, as compared with ipilimumab monotherapy, persisted across all examined subgroups, including those stratified according to PD-L1 expression and BRAF mutation status.
Since the 5-year analysis, no new safety signals have been observed in any of the study groups, and no new deaths related to treatment have occurred.
The authors concluded that the final results from CheckMate 067 study continue to demonstrate a sustained, long-term survival benefit across subgroups in the nivolumab-containing arms, underscoring how immune checkpoint inhibitors (ICIs) have transformed the long-term prognosis for patients with advanced melanoma. There is now a potential for cure in patients responsive to these treatments.
However, despite the progress made in the treatment of advanced melanoma in the past 15 years, important gaps remain, including the higher incidence of treatment-related adverse events observed with ipilimumab-containing therapies than with nivolumab monotherapy. Emerging treatments, such as combination therapy with anti-PD1 and anti-LAG3 agents, may offer efficacy similar to that of ipilimumab-containing therapies but with fewer unacceptable side effects.
Furthermore, even with available combination therapy with ICIs, approximately 40% of patients do not have a response to treatment, and half die from melanoma. Triplet therapy with anti-CTLA4, anti-PD1, and anti-LAG3 agents may be more effective than the available combination therapies, as suggested by the 48-month OS of 72% with triplet therapy in the RELATIVITY-048 study, but larger studies are needed to confirm these data. The development of new treatments, such as improved targeted therapies, personalised vaccines, and adoptive cell transfer therapy, offers opportunities to enhance long-term outcomes in patients with advanced melanoma.
This study was supported by Bristol Myers Squibb, a grant from the US National Cancer Institute, and a grant from the National Institute for Health Research Biomedical Research Centre at the Royal Marsden National Health Service Foundation Trust and the Institute of Cancer Research.
References
- Wolchok JD, Chiarion-Sileni V, Rutkowski P, et al. for the CheckMate 067 Investigators. Final, 10-Year Outcomes with Nivolumab plus Ipilimumab in Advanced Melanoma. NEJM; Published online 15 September 2024. DOI: 10.1056/NEJMoa2407417
- LBA43 – Larkin J, Chiarion Sileni V, Gaudy Marqueste C, et al. 10-y survival outcomes from the phase III CheckMate 067 trial of nivolumab plus ipilimumab in advanced melanoma. Annals of Oncology 2024;35(Suppl 2):S1234-S1235.