Pembrolizumab vs Nivolumab as Initial Treatment for Advanced, Unresectable, or Metastatic Melanoma
Menée aux Etats-Unis à partir de données portant sur 742 patients atteints d'un mélanome de stade avancé, non résécable ou métastatique (âge médian : 73 ans ; durée médiane de suivi : 5,6 ans), cette étude compare l'efficacité, du point de vue du délai avant le traitement suivant, du pembrolizumab et du nivolumab en traitement initial
Introduction: Monoclonal antibodies targeting programmed cell death protein 1 (PD-1) are mainstays of modern cancer therapy. Pembrolizumab and nivolumab are the most used members of this class, but their comparative effectiveness and safety have not been established in a prospective randomized clinical trial. Comparative effectiveness and safety analyses in the few indications where both are used in the same manner may help support claims of the agents’ interchangeability.1 Initial retrospective analyses of clinical data with limited follow-up suggest the 2 agents’ comparative effectiveness and safety but have not been evaluated with extended follow-up in a national US health system.2,3 We therefore conducted a propensity score-adjusted comparison of the 2 agents’ effectiveness and safety outcomes in advanced, unresectable, or metastatic melanoma using data from the national Veterans Affairs (VA) health system, the largest integrated provider of cancer care in the US.
Methods: For this comparative effectiveness research study, we extracted all pembrolizumab and nivolumab administrations for advanced, unresectable, or metastatic melanoma (using International Classification of Diseases, Ninth Revision [ICD-9] or International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes and natural language processing [NLP]) from January 1, 2015, to July 1, 2025, from the VA’s Corporate Data Warehouse (eMethods in Supplement 1). We excluded patients with known BRAF variations at immunotherapy initiation and those who received ipilimumab or nivolumab. Baseline covariates for patient, temporal, and cancer characteristics thought to influence anti–PD-1 prescribing were balanced using propensity score adjustment, accounting for missing data via multiple imputation (eMethods, eFigures 1 and 2 in Supplement 1). The primary outcome was time-to-next treatment (TTNT); secondary outcomes were overall survival (OS) and prolonged, high-dose corticosteroids (a proxy for clinically significant all-cause immune-related adverse events).1 Propensity-weighted Cox proportional hazard models and Kaplan-Meier estimates were pooled across imputations using Rubin rules.
The VA Ann Arbor institutional review board deemed this study exempt and granted a waiver of informed consent for this analysis of existing administrative data. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines. Analysis was performed with R version 4.4.1 (R Project for Statistical Computing).
Results: The cohort included 742 patients with advanced or metastatic melanoma who received anti–PD-1 therapy with either pembrolizumab (413 [55.7%]) or nivolumab (329 [44.3%]); the median (IQR) age was 73 (68-80) years, and 723 (97.4%) were male (Table). Baseline characteristics were similar between treatment groups. Pembrolizumab recipients were older and were more likely to have initiated therapy in recent years. Median follow-up was 5.6 years (95% CI, 4.27-6.61 years) for pembrolizumab and 5.5 years (95% CI, 4.97-6.40 years) for nivolumab. Propensity score adjustment achieved excellent covariate balance on all variables (with a standardized difference below 0.05). Median TTNT was 14.6 months (95% CI, 11.8-18.6 months) for pembrolizumab and 13.2 months (95% CI, 9.95-16.1 months) for nivolumab (adjusted hazard ratio [aHR] for pembrolizumab vs nivolumab, 0.92; 95% CI, 0.78-1.10; P = .38) (Figure, panel A). Median OS was 27.9 months (95% CI, 21.3-32.4 months) for pembrolizumab and 25.3 months (95% CI, 19.6-34.3 months) for nivolumab (aHR, 0.96; 95% CI, 0.79-1.16; P = .66) (Figure, panel B). Two-year cumulative event rates of prolonged, high-dose corticosteroid use were 22.1% (95% CI, 17.3%-26.9%) for pembrolizumab and 23.5% (95% CI, 17.7%-29.2%) for nivolumab (aHR, 1.00; 95% CI, 0.70-1.44; P = .99) (Figure, panel C).
JAMA Network Open , résumé, 2026