Moderna (MRNA) Study update summary

Trial design and delivery

• Double-blind phase 3 INTerpath-001 randomized 1,137 patients with resected stage IIB–IV melanoma 2:1 to intismeran plus pembrolizumab or placebo plus pembrolizumab; median follow-up was 24.6 months.

• Pembrolizumab began at randomization and intismeran when available; investigator-assessed RFS was the primary endpoint and DMFS the key secondary endpoint.

• More than 99% of 757 patients assigned intismeran had successful manufacturing; 91% had 34 neoantigens identified, median time to first dose was 64 days and median doses received was 9.

Efficacy results

• RFS events were 18.0% vs 29.2%; HR 0.58 (95% CI 0.45–0.75), p<0.001. Estimated 2-year RFS was 82.2% vs 70.0%.

• RFS HR was 0.99 in months 0–6 and 0.42 thereafter; modified intent-to-treat RFS HR was 0.51.

• DMFS events were 11.8% vs 18.7%; HR 0.62 (95% CI 0.45–0.85), p=0.002; estimated DMFS was 88.5% vs 80.2%.

• DMFS HR was 1.01 during the first 6 months and 0.50 thereafter; modified intent-to-treat HR was 0.55.

• RFS and DMFS benefits favored combination treatment in most prespecified subgroups. OS remained immature (HR 0.77, 95% CI 0.45–1.31, p=0.33); follow-up is ongoing.

Safety and mechanism

• Grade 3–5 and serious adverse events were broadly similar; treatment-related adverse events and discontinuations were higher with combination treatment, with no apparent potentiation of pembrolizumab toxicities.

• Intismeran-related events were mainly transient grade 1–2 injection-site pain or reaction, chills and fever.

• Tumor sequencing and algorithms select up to 34 personalized neoantigens for delivery as mRNA in a lipid nanoparticle; the standardized tissue-to-dose workflow takes 6–8 weeks.

• Phase 2 analyses linked novel T-cell clonotype expansion with clinical benefit; in seven patients, an average of one in three cassette neoantigens induced a specific CD4 or CD8 T-cell response.