Moderna (MRNA) Study update summary

Study Overview and Rationale

• Intismeran is a personalized mRNA-based neoantigen therapy designed to activate patient-specific T cell responses against cancer by targeting individual tumor mutations.

• The therapy uses next-generation sequencing, bioinformatics, and small-scale manufacturing to encode up to 34 unique neoantigens per patient.

• Prior individualized vaccines showed T cell induction but lacked efficacy in randomized trials; intismeran is the first to demonstrate efficacy in this setting.

• The adjuvant setting was chosen to maximize T cell fitness and minimize tumor heterogeneity, addressing unmet needs in high-risk cancers.

• The approach is being expanded to IO-sensitive and less IO-sensitive tumors, with ongoing trials in melanoma, lung, bladder, gastric, pancreatic, and renal cell cancers.

Study Design and Patient Eligibility

• KEYNOTE-942 is a randomized, open-label Phase 2b trial enrolling 157 high-risk stage III/IV melanoma patients post-resection, randomized 2:1 to combination or pembrolizumab alone.

• Primary endpoint is recurrence-free survival; secondary endpoints include distant metastasis-free survival and safety.

• Key eligibility: resectable cutaneous melanoma, complete resection within 13 weeks, disease-free at entry, ECOG 0 or 1, and suitable tumor sample for sequencing.

Five-Year Efficacy Results

• At median 5-year follow-up, intismeran plus pembrolizumab reduced risk of recurrence or death by 49% and distant metastasis or death by 59% compared to pembrolizumab alone.

• Durable improvements in recurrence-free and distant metastasis-free survival were observed, with hazard ratios of 0.51 for RFS and 0.41 for DMFS.

• Subgroup analyses confirmed consistent recurrence-free survival benefit across age, sex, disease stage, PD-L1 status, BRAF status, TMB, and ctDNA status.

• Overall survival showed a hazard ratio of 0.47, with trends favoring intismeran, though data remain immature.

• The absolute benefit in relapse-free survival was 23%, with efficacy maintained over five years.