mRNA Vaccine Plus Pembrolizumab Yields RFS, DMFS Benefit in Resectable Melanoma

Intismeran autogene (intismeran; V940; mRNA-4157) in combination with pembrolizumab (Keytruda) met the primary end point of recurrence-free survival (RFS) and the key secondary end point of distant metastasis-free survival (DMFS) compared with pembrolizumab alone in patients with completely resected stage IIB to IV melanoma, according to topline results from the phase 3 INTerpath-001 trial (NCT05933577).¹

At a prespecified interim analysis, the addition of the mRNA-based neoantigen therapy resulted in showed statistically significant and clinically meaningful improvements in RFS and DMFS in patients with completely resected cutaneous melanoma who had not received prior systemic therapy. Per the trial protocol, the study will continue to evaluate additional secondary end points, including overall survival (OS). A news release from the sponsor characterized this as the first positive phase 3 readout for an individualized neoantigen therapy (INT) and for an mRNA-based cancer therapy, and the first phase 3 study to show a clinically meaningful improvement over pembrolizumab alone in the adjuvant setting for resected melanoma.

“Today's results represent a landmark moment for adjuvant melanoma treatment. This is the first phase 3 study to show that intismeran, a treatment designed based on the unique mutational 'fingerprint' of a patient's own tumor, given in combination with pembrolizumab can reduce the risk of recurrence or death in patients with completely resected stage IIB [to] IV melanoma compared [with pembrolizumab] alone,” Georgina Long, MD, PhD, the trial’s principal investigator, medical director of Melanoma Institute Australia, and chair of melanoma medical oncology and translational research at the University of Sydney, stated in a news release.

Background and Trial Design

The phase 3 readout builds on previously reported phase 2b results for intismeran plus pembrolizumab from the KEYNOTE-942/mRNA-4157-P201 trial (NCT03897881), including 5-year follow-up data presented at the 2026 ASCO Annual Meeting. In that trial of 157 patients with stage IIIB to IV resected melanoma, the combination was associated with a 49% reduction in the risk of recurrence or death (HR, 0.51; 95% CI, 0.294-0.887) and a 59% reduction in the risk of distant metastasis or death (HR, 0.411; 95% CI, 0.200-0.843) compared with pembrolizumab alone.²

INTerpath-001 is a randomized, double-blind, placebo- and active comparator-controlled global trial that enrolled 1137 patients with high-risk cutaneous melanoma following complete surgical resection. Patients were randomly assigned on a 2:1 basis to receive intismeran autogene at 1 mg every 3 weeks for up to 9 doses plus pembrolizumab at 400 mg every 6 weeks for up to 9 cycles or pembrolizumab alone. Pembrolizumab was continued until disease recurrence, unacceptable toxicity, or a maximum treatment duration of approximately 56 weeks, whichever occurred first. The primary end point is RFS, defined as time from randomization to any disease recurrence (local, locoregional, regional, or distant) per investigator assessment, or death from any cause. Key secondary end points include DMFS, OS, safety, tolerability, and quality of life.

Safety Findings

The safety profiles of intismeran and pembrolizumab in INTerpath-001 were reported to be consistent with those observed in previously reported studies of the combination, with no new safety signals identified, according to the release. In the KEYNOTE-942 trial, adverse events (AEs) associated with intismeran included injection site reaction, fatigue, and chills, but were primarily grade 1 or 2, and no grade 4 or 5 adverse events (AEs) were associated with intismeran. Grade 3 immune-related AEs occurred at a rate of 10.6% in patients receiving intismeran plus pembrolizumab vs 12% in those receiving pembrolizumab alone.

Regulatory and Development Plans

Merck and Moderna plan to present the INTerpath-001 data at an upcoming international medical meeting and to engage with regulatory authorities on filing submissions for intismeran in combination with pembrolizumab. The companies are jointly advancing the broader INTerpath clinical development program; 9 phase 2 and phase 3 trials are evaluating intismeran in combination with pembrolizumab and other anticancer therapies, as well as monotherapy, across advanced melanoma (INTerpath-012; NCT06961006), non–small cell lung cancer (INTerpath-002; NCT06077760), bladder cancer (INTerpath-011; NCT06833073), and renal cell carcinoma (INTerpath-004; NCT06307431). Additional studies include a phase 1 study in adjuvant pancreatic ductal adenocarcinoma, perioperative gastric carcinoma, and perioperative non–small cell lung cancer.

REFERENCES

1. Merck and Moderna Announce Phase 3 INTerpath-001 Trial of Intismeran Autogene Plus KEYTRUDA® Met Endpoints of Recurrence-Free Survival (RFS) and Distant Metastasis-Free Survival (DMFS) in Patients With Completely Resected Stage IIB-IV Melanoma. News release. Merck & Co, Inc; Moderna, Inc. August 19, 2026. Accessed August 19, 2026. https://tinyurl.com/y6j7txe4

2. Carlino, MS. Individualized neoantigen therapy intismeran autogene (intismeran) plus pembrolizumab (pembro) in resected melanoma: 5-year update of the KEYNOTE-942 study. Presented at: 2026 ASCO Annual Meeting; May 29–June 2, 2026; Chicago Illinois. Abstract 9500.