• Jeffrey S Weber, Matteo S Carlino, Adnan Khattak, Tarek Meniawy, George Ansstas, Matthew H Taylor, Kevin B Kim, Meredith McKean, Georgina V Long, Ryan J Sullivan, Mark Faries, Thuy T Tran, C Lance Cowey, Andrew Pecora, Montaser Shaheen, Jennifer Segar, Theresa Medina, Victoria Atkinson, Geoffrey T Gibney, Jason J Luke, Sajeve Thomas, Elizabeth I Buchbinder, Jane A Healy, Mo Huang, Manju Morrissey, Igor Feldman, Vasudha Sehgal, Celine Robert-Tissot, Peijie Hou, Lili Zhu, Michelle Brown, Praveen Aanur, Robert S Meehan, and Tal Zaks.
• Laura and Isaac Perlmutter Cancer Center at NYU Langone Health, New York, NY, USA. Electronic address: Jeffrey.Weber@nyulangone.org.
• Lancet. 2024 Feb 17; 403 (10427): 632644632-644.

BackgroundCheckpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.MethodsWe did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.FindingsFrom July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053), with lower recurrence or death event rate (24 [22%] of 107 vs 20 [40%] of 50); 18-month recurrence-free survival was 79% (95% CI 69·0-85·6) versus 62% (46·9-74·3). Most treatment-related adverse events were grade 1-2. Grade ≥3 treatment-related adverse events occurred in 25% of patients in the combination group and 18% of patients in the monotherapy group, with no mRNA-4157-related grade 4-5 events. Immune-mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups.InterpretationAdjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.FundingModerna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.Copyright © 2024 Elsevier Ltd. All rights reserved.

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