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

Background 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. Methods 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. Findings 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 center dot 561 [95% CI 0 center dot 309-1 center dot 017]; two-sided p=0 center dot 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 center dot 0-85 center dot 6) versus 62% (46 center dot 9-74 center dot 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 mRNA4157-related grade 4-5 events. Immune -mediated adverse event frequency was similar for the combination (37 [36%]) and monotherapy (18 [36%]) groups. Interpretation 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.