Intismeran Autogene plus Pembrolizumab for Resected Stage IIB to IV Melanoma

Intismeran autogene (intismeran) is an individualized neoantigen therapy that is designed to induce new T-cell responses and expand preexisting T-cell responses against patient-specific tumor neoantigens, which may potentially improve the efficacy of adjuvant therapy in patients with melanoma. In this phase 3, double-blind trial, we randomly assigned patients with completely resected stage IIB to IV cutaneous melanoma in a 2:1 ratio to receive intramuscular intismeran (at a dose of 1 mg) or placebo every 3 weeks for nine doses; all the patients received intravenous pembrolizumab (at a dose of 400 mg) every 6 weeks for nine cycles. The primary end point was investigator-determined recurrence-free survival, assessed in a time-to-event analysis. Key secondary end points included investigator-determined distant-metastasis-free survival (assessed in a time-to-event analysis) and safety. A total of 1137 patients underwent randomization: 757 to the intismeran-pembrolizumab group and 380 to the placebo-pembrolizumab group. The median follow-up was 24.6 months. Recurrence-free survival at 24 months was 82.2% in the intismeran-pembrolizumab group and 70.0% in the placebo-pembrolizumab group (two-sided P<0.001); the piecewise hazard ratio was 0.99 (95% confidence interval [CI], 0.66 to 1.49) before 6 months and 0.42 (95% CI, 0.30 to 0.58) after 6 months. Distant-metastasis-free survival at 24 months was 88.5% with intismeran-pembrolizumab and 80.2% with placebo-pembrolizumab (two-sided P = 0.002); the piecewise hazard ratio was 1.01 (95% CI, 0.58 to 1.79) before 6 months and 0.50 (95% CI, 0.34 to 0.73) after 6 months. Adverse events of grade 3 or higher occurred in 23.6% of the patients in the intismeran-pembrolizumab group and 20.3% of the patients in the placebo-pembrolizumab group. Eight patients (1.1%) in the intismeran-pembrolizumab group died from an adverse event; five of the deaths occurred before intismeran was administered. Adjuvant therapy with intismeran plus pembrolizumab significantly prolonged recurrence-free survival and distant-metastasis-free survival as compared with pembrolizumab alone in patients with completely resected, high-risk cutaneous melanoma. (Funded by Merck Sharp and Dohme and Moderna; ClinicalTrials.gov number, NCT05933577.).