Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study

• Published in: The Lancet (British edition) 2024-02, Vol.403 (10427), p.632-644
• Main Authors: Weber, Jeffrey S, Carlino, Matteo S, Khattak, Adnan, Meniawy, Tarek, Ansstas, George, Taylor, Matthew H, Kim, Kevin B, McKean, Meredith, Long, Georgina V, Sullivan, Ryan J, Faries, Mark, Tran, Thuy T, Cowey, C Lance, Pecora, Andrew, Shaheen, Montaser, Segar, Jennifer, Medina, Theresa, Atkinson, Victoria, Gibney, Geoffrey T, Luke, Jason J, Thomas, Sajeve, Buchbinder, Elizabeth I, Healy, Jane A, Huang, Mo, Morrissey, Manju, Feldman, Igor, Sehgal, Vasudha, Robert-Tissot, Celine, Hou, Peijie, Zhu, Lili, Brown, Michelle, Aanur, Praveen, Meehan, Robert S, Zaks, Tal
• Format: Article
• Language: English
• Subjects: Adverse events; Antigens; Automation; Bioinformatics; Biomarkers; Cancer therapies; Combination therapy; COVID-19 vaccines; Disease transmission; Hematology; Immune checkpoint inhibitors; Immunotherapy; Labels; Leukocytes; Manufacturing; Melanoma; Metastases; Metastasis; Monoclonal antibodies; Mortality; mRNA; Mutation; Neoantigens; Oncology; Patients; Pembrolizumab; Peptides; Risk; Safety management; Survival; Targeted cancer therapy; Therapy; Toxicity
• ISSN: 0140-6736; 1474-547X; 1474-547X
• DOI: 10.1016/S0140-6736(23)02268-7

Checkpoint 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. We 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. From 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. Adjuvant 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. Moderna in collaboration with Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA.