Personalized mRNA-Based Melanoma Vaccine Meets Primary Endpoints in Landmark Phase 3 Trial

This week, Merck and Moderna announced positive topline results from the phase 3 INTerpath-001 trial (NCT05933577) evaluating intismeran autogene (intismeran; V940 or mRNA-4157) in combination with pembrolizumab (KEYTRUDA) as adjuvant treatment for patients with completely resected stage IIB-IV cutaneous melanoma.¹ The trial met its primary endpoint of recurrence-free survival (RFS) and a key secondary endpoint of distant metastasis-free survival (DMFS).

Breakthrough Phase 3 Milestones

At a prespecified interim analysis, the combination demonstrated statistically significant and clinically meaningful improvements in both RFS and DMFS compared with pembrolizumab alone. According to the companies, INTerpath-001 represents the first positive phase 3 readout for an individualized neoantigen therapy and an mRNA-based cancer therapy, as well as the first phase 3 study to demonstrate a clinically meaningful improvement over pembrolizumab alone in the adjuvant melanoma setting.

“By intervening earlier in the course of disease, when many cancers are considered most treatable, the goal of adjuvant therapy given after surgery is to increase the possibility of cure for more patients,” said Dean Y. Li, MD, PhD, president of Merck Research Laboratories. “These first phase 3 findings for intismeran in combination with KEYTRUDA as adjuvant therapy reinforce the promise of a more personalized approach to cancer treatment. We believe individualized neoantigen therapies have the potential to redefine how patients with completely resected stage IIB-IV melanoma are treated.”¹

Study Design and Outcomes

The randomized, double-blind, placebo- and active-comparator-controlled global trial enrolled 1,137 patients with high-risk, completely resected stage IIB, IIC, III, or IV cutaneous melanoma who had not previously received systemic therapy. Patients were randomized 2:1 to receive either intismeran plus pembrolizumab or pembrolizumab alone. Intismeran was administered at a dose of 1 mg every 3 weeks for up to 9 doses, while pembrolizumab was administered at 400 mg every 6 weeks for up to 9 cycles, for approximately 1 year.

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RFS was the primary endpoint and was defined as the time from randomization to any local, locoregional, regional, or distant recurrence, or death from any cause. Key secondary endpoints included DMFS, overall survival (OS), safety, tolerability, and quality of life. Although RFS and DMFS were positive, the study will continue to evaluate other key secondary endpoints, including OS. The press release did not provide numerical hazard ratios or other detailed efficacy data from the phase 3 trial. The safety profiles of intismeran and pembrolizumab were consistent with previously reported studies of the combination, and no new safety signals were identified.

“The news of positive results from the phase 3 trials of Moderna’s and Merck’s neoadjuvant mRNA-based melanoma therapy represents one of the most monumental advancements for the field of dermatology ever, and demonstrates that personalized approaches to melanoma and cancer treatment overall are entering a new era. We all eagerly await full release of the phase 3 data. Conversations with melanoma patients are about to change drastically, and for the better,” said Christopher Bunick, MD, PhD, associate professor of dermatology at Yale School of Medicine and editor in chief of Dermatology Times, in an exclusive statement.

Intismeran’s Mechanism of Action

Intismeran is an investigational mRNA-based individualized neoantigen therapy designed using a tumor sample from each patient. The approach identifies the unique mutational signature of an individual’s tumor, or mutational “fingerprint,” as Professor Georgina Long AO, BSc, PhD, and the companies call it, and generates a synthetic mRNA encoding up to 34 neoantigens. After administration, the RNA-encoded neoantigen sequences are translated in the body and presented to the immune system, with the goal of generating tumor-specific T-cell responses.

“Today’s results represent a landmark moment for adjuvant melanoma treatment,” Long, the study’s principal investigator, said. “Intismeran in combination with pembrolizumab has the potential to establish a new treatment paradigm in the adjuvant melanoma setting, helping patients remain cancer-free for longer.”¹ Long is also the medical director of Melanoma Institute Australia and the chair of melanoma medical oncology and translational research at the University of Sydney.

Looking Ahead

The phase 3 findings build on results from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial. Five-year follow-up data presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting showed that intismeran plus pembrolizumab reduced the risk of recurrence or death by 49% compared with pembrolizumab alone (HR, 0.51; 95% CI, 0.294-0.887).² The combination also reduced the risk of distant metastasis or death by 59% (HR, 0.411; 95% CI, 0.200-0.843) in that study.

The companies said they plan to present detailed INTerpath-001 data at an upcoming international medical meeting and engage with regulatory authorities regarding filing submissions for intismeran in combination with pembrolizumab. The broader INTerpath development program currently includes 9 phase 2 and phase 3 trials evaluating intismeran with pembrolizumab and other anticancer therapies, as well as monotherapy, across melanoma, non-small cell lung cancer, bladder cancer, and renal cell carcinoma.

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. Published August 19, 2026. Accessed August 20, 2026. https://www.merck.com/news/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-patient/

2. Moderna and Merck Present 5-Year Data for Intismeran Autogene in Combination With KEYTRUDA® (pembrolizumab) in Patients With High-Risk Stage III/IV Melanoma Following Complete Resection at the 2026 ASCO Annual Meeting. News release. Merck, Published June 1, 2026. Accessed August 20, 2026. https://www.merck.com/news/moderna-and-merck-present-5-year-data-for-intismeran-autogene-in-combination-with-keytruda-pembrolizumab-in-patients-with-high-risk-stage-iii-iv-melanoma-following-complete-resection-at-the-20/