The 6.5-year data in the pivotal CheckMate 067 study show durable, improved clinical outcomes with nivolumab plus ipilimumab or nivolumab versus ipilimumab in patients with advanced melanoma and, in descriptive analyses, with the combination over nivolumab monotherapy. The data with the combination of first-line nivolumab plus ipilimumab include the longest median overall survival (OS) of 72.1 months reported to date in a phase III study of patients with advanced melanoma. For the first time, the researchers were also able to report melanoma-specific survival (MSS) in this population with median not reached at 77 months and 6.5-year rate of 56% with the combination, which is important, given the increasing competing risk of death from other causes that the durable control of melanoma with checkpoint inhibitors affords.
Prof. Jedd D. Wolchok of the Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College in New York, NY, US and colleagues reported on 24 November 2021 in the Journal of Clinical Oncology that at 6.5 years, median duration of response had yet to be reached with both nivolumab-containing regimens, and only three patients in either group had experienced progressive disease since the 5-year analysis. Durable clinical benefit was observed across clinically relevant subgroups, including those based on baseline BRAF mutation or baseline liver metastasis status. Of patients alive at 6.5 years, 77% treated with the combination and 69% treated with nivolumab were treatment-free. No new safety signals were observed, no treatment-related deaths had occurred since the 28-month analysis, and only 11 deaths of any cause had occurred across the three treatment groups since the 5-year analysis.
Previously, a 5-year follow-up analysis of the CheckMate 067 study demonstrated durable clinical benefit with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab monotherapy. At 5 years, median OS was not reached in patients in the combination therapy group and was 36.9 and 19.9 months in the nivolumab and ipilimumab monotherapy groups. The 5-year OS rates were 52%, 44%, and 26% in the three groups and among patients with BRAF-mutant advanced melanoma, 5-year OS rates were 60%, 46%, and 30%, respectively. The study was not designed to compare the nivolumab-containing treatment groups, but these results suggested improved clinical outcomes with combination therapy over nivolumab monotherapy. Compared with either monotherapy group, treatment with the combination also resulted in higher proportions of patients who were alive and treatment-free at 5 years.
The authors wrote that little is known about the long-term outcomes of nivolumab plus ipilimumab or nivolumab alone in melanoma beyond 5 years.
In CheckMate 067, patients with previously untreated unresectable stage III or stage IV melanoma were randomly assigned 1:1:1 to receive nivolumab plus ipilimumab once every 3 weeks (four doses) followed by nivolumab once every 2 weeks (n = 314), nivolumab once every 2 weeks (n = 316), or ipilimumab once every 3 weeks (four doses; n = 315). Co-primary endpoints were progression-free survival and OS with nivolumab plus ipilimumab or nivolumab versus ipilimumab. Secondary endpoints included objective response rate, descriptive efficacy assessments of nivolumab plus ipilimumab versus nivolumab alone, and safety. MSS which excludes deaths unrelated to melanoma, was also evaluated.
With minimum follow-up of 6.5 years, median OS was 72.1, 36.9, and 19.9 months in the combination, nivolumab, and ipilimumab groups, respectively. Median MSS was not reached, 58.7, and 21.9 months, respectively.
In patients with BRAF-mutated tumours, 6.5-year OS rates were 57%, 43%, 25% and 46%, 42%, 22% in those with BRAF-wild-type tumours.
In patients who discontinued treatment, the median treatment-free interval was 27.6, 2.3, and 1.9 months.
Since the 5-year analysis, no new safety signals were observed, and no treatment-related deaths had occurred since the 28-month analysis.
The authors concluded these 6.5-year data obtained with the combination of first-line nivolumab plus ipilimumab in patients with advanced melanoma in CheckMate 067 include the longest median OS reported to date in a phase III melanoma study, as well as a median MSS that had not been reached at 77 months. The majority of the patients are off treatment and have not yet started systemic subsequent therapy. These results represent a substantial development in the melanoma treatment landscape versus the standard median survival of 8 months a decade ago. This advance is supported by the ability to distinguish melanoma-specific from overall survival.
The study was supported by Bristol Myers Squibb.
Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. Long-Term Outcomes With Nivolumab Plus Ipilimumab or Nivolumab Alone Versus Ipilimumab in Patients With Advanced Melanoma. JCO; Published online 24 November 2021. DOI: 10.1200/JCO.21.02229