CheckMate-915: Does Adjuvant CTLA-4 Blockade Play a Role in Resected Melanoma?

© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2023;11(10):370 | https://dx.doi.org/10.21037/atm-23-754 The CTLA-4 inhibitor ipilimumab is a vital component of the treatment armamentarium for patients with unresectable stage III/IV melanoma. Ipilimumab was Food and Drug Administration (FDA) approved in 2011 after demonstrating a survival benefit in advanced melanoma (1). The PD-1 inhibitor pembrolizumab subsequently prolonged overall survival (OS) compared to ipilimumab and was approved in 2014, as was nivolumab (2). Since then, PD-1 inhibitorbased therapies have persisted as the standard of care for advanced melanoma, often with the use of immune checkpoint inhibitor (ICI) doublets such as ipilimumab plus nivolumab, approved in 2015, or nivolumab plus the LAG3 inhibitor relatlimab, approved in 2022 (3,4). The success of ICI for patients with unresectable stage III/IV melanoma has led to investigation of these agents in earlier stages of disease, on the assumption of biological equivalence between residual microscopic versus macroscopic disease. In resected stage III melanoma, adjuvant ipilimumab was in i t ia l ly s tudied a t 10 mg/kg and improved recurrence-free survival (RFS) and OS compared to placebo (5). Subsequently, adjuvant PD-1 inhibition with pembrolizumab versus placebo (6), pembrolizumab versus interferon or ipilimumab (7), and nivolumab versus ipilimumab (8) improved RFS in resected stage III, IIIA(N2)-IV, and IIIB-IV melanoma, respectively. It is unknown whether the addition of adjuvant ipilimumab to nivolumab can improve outcomes in resected stage III/IV melanoma, however the benefit is clear in advanced melanoma. Ipilimumab 3 mg/kg plus nivolumab 1 mg/kg has numerically doubled OS compared to nivolumab monotherapy, as demonstrated in the 6.5 years follow-up of CheckMate-067 (3,9). Therefore, the purpose of CheckMate-915 by Weber et al. was to determine whether adjuvant ipilimumab plus nivolumab could improve RFS compared to adjuvant nivolumab monotherapy, which we review in this editorial. The study was entitled “Adjuvant Therapy of Nivolumab Combined With Ipilimumab Versus Nivolumab Alone in Patients With Resected Stage IIIB-D or Stage IV Melanoma” and was published in the Journal of Clinical Oncology in September 2022 (10). In CheckMate-915, there was no improvement in RFS for patients with resected stage IIIB-IV melanoma treated with combination therapy compared to adjuvant anti-PD-1 alone, the standard of care. Nor were there any differences in RFS for any of the examined subgroups, including stage. Twenty-four-month RFS was 64.6% in the combination group and 63.2% in the nivolumab group, which was unexpected given the superior activity of the combination in the metastatic setting (10). Importantly, the chosen ipilimumab dose in the trial was 1 mg/kg every 6 weeks. This dose and dosing interval has not been previously studied in melanoma and is a lower and less frequent dose than the standard 3 mg/kg administered every 3 weeks for up to 4 doses in advanced disease. The ipilimumab dosing Editorial Commentary