Merck and Moderna report Phase 3 results showing 42% lower recurrence risk with intismeran plus Keytruda in resected melanoma. Overall survival remains immature.
Written By: Anshu Gupta, PharmD
Reviewed By: Pharmacally Editorial Team
Merck and Moderna have reported detailed results from the Phase 3 INTerpath-001 trial, in which intismeran autogene (intismeran; V940 or mRNA-4157) combined with pembrolizumab (Keytruda) significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) in patients with completely resected stage IIB–IV melanoma.
At the prespecified primary analysis, after a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% compared with pembrolizumab alone (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.45–0.75; p<0.001). The risk of distant metastasis or death decreased by 38% (HR, 0.62; 95% CI, 0.45–0.85; p=0.002).
At 24 months, RFS was 82.2% with the combination versus 70.0% with pembrolizumab alone, an absolute difference of 12.2 percentage points. DMFS was 88.5% versus 80.2%, respectively, a difference of 8.3 percentage points. Improvements were generally consistent across prespecified patient subgroups.
The findings were announced on October 22, 2026, ahead of their presentation at the European Society for Medical Oncology (ESMO) Congress 2026 Presidential Symposium I (abstract LBA1). The results have also been accepted for publication in The New England Journal of Medicine.
Individualized mRNA Therapy and Immune Checkpoint Inhibition
Intismeran is an investigational messenger RNA (mRNA)-based individualized neoantigen therapy jointly developed by Merck and Moderna. It is designed using mutations identified in an individual patient’s tumour and encodes up to 34 selected neoantigens intended to stimulate tumour-directed T-cell responses.
Pembrolizumab is a programmed death receptor-1 (PD-1) inhibitor that enhances antitumour immune activity by blocking PD-1 signalling. The combination aims to complement checkpoint inhibition with an immune response directed against tumour-specific neoantigens.
INTerpath-001 enrolled 1,137 patients following complete surgical resection. Participants were randomized in a 2:1 ratio to receive intismeran 1 mg every three weeks for up to nine doses plus pembrolizumab 400 mg every six weeks for up to nine cycles, or placebo plus pembrolizumab. Pembrolizumab treatment continued for approximately one year, subject to recurrence or unacceptable toxicity.
Treatment Effect in the Six-Month Sensitivity Analysis
During the first six months, efficacy was comparable between groups for RFS (HR, 0.99; 95% CI, 0.66–1.49) and DMFS (HR, 1.01; 95% CI, 0.58–1.79).
In a prespecified sensitivity analysis examining outcomes after six months, the combination reduced the risk of recurrence or death by 58% (HR, 0.42; 95% CI, 0.30–0.58) and the risk of distant metastasis or death by 50% (HR, 0.50; 95% CI, 0.34–0.73).
These findings suggest that the observed treatment effect varied over time. However, the analysis does not establish that the therapy begins working only after six months, and the estimates should be interpreted alongside the overall trial results.
Safety and Overall Survival
The safety profile was generally consistent with previous studies of the combination, with no new safety signals reported. Grade 3 or higher adverse events occurred in 23.6% of patients receiving intismeran plus pembrolizumab and 20.3% receiving placebo plus pembrolizumab. Treatment-related Grade 3–5 adverse events occurred in 14.2% and 13.4%, respectively.
The most common adverse events in the combination group included fever (52.2%), injection-site pain (51.0%) and fatigue (38.5%). Overall survival (OS) data remain immature, although the companies reported a favourable trend. The trial is continuing to evaluate OS and other key endpoints.
Merck and Moderna are engaging with regulatory authorities based on the findings. Intismeran remains investigational, and regulatory approval has not been established.
Clinical Interpretation
INTerpath-001 provides Phase 3 evidence that adding individualized neoantigen therapy to pembrolizumab can improve recurrence-related outcomes after surgery for high-risk melanoma. The 12.2-percentage-point difference in 24-month RFS indicates a clinically relevant separation between treatment groups during the reported follow-up.
However, improvements in RFS and DMFS do not yet establish an overall survival benefit. Longer follow-up will be important to determine whether the reduction in recurrence and distant metastasis translates into improved long-term survival and to further characterize the durability of benefit and safety of the combination.
References
Merck. Merck and Moderna Will Present Results from Landmark Phase 3 INTerpath-001 Trial for Intismeran Autogene Plus KEYTRUDA (pembrolizumab) at ESMO 2026 Presidential Symposium. October 22, 2026.
A Clinical Study of Intismeran Autogene (V940) Plus Pembrolizumab in People with High-Risk Melanoma (V940-001), ClinicalTrials.gov ID NCT05933577
About the Writer
Anshu Gupta (LinkedIn) is a PharmD professional and healthcare writer with interests in clinical research, pharmacovigilance, regulatory affairs, and medical writing. She has presented research at academic conferences and completed certifications in Good Clinical Practice (GCP), ICH-GCP, and drug safety. Passionate about clinical trials and evidence-based medicine, she is committed to translating scientific evidence into accurate, reliable, and accessible healthcare content.