Merck and Moderna's Intismeran Autogene Plus Pembrolizumab Meets Endpoints in Phase 3 Melanoma Trial

Merck and Moderna announced positive topline results from the phase 3 INTerpath-001 trial evaluating intismeran autogene (V940 or mRNA-4157) plus pembrolizumab (Keytruda), a humanized monoclonal antibody (mAb), as adjuvant therapy in patients with completely resected stage IIB-IV melanoma, the companies said August 19, 2026.¹ The trial met its primary endpoint of recurrence-free survival (RFS) and a key secondary endpoint of distant metastasis-free survival (DMFS), marking the first positive phase 3 readout for an individualized neoantigen therapy and for a messenger RNA (mRNA)-based cancer therapy.¹

"Today's results represent a landmark moment for adjuvant melanoma treatment...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," said Professor Georgina Long, PhD, the study’s principal investigator and medical director of Melanoma Institute Australia, chair of Melanoma Medical Oncology and Translational Research at the University of Sydney, in a company press release.¹

What did the phase 3 trial show?

At a pre-specified interim analysis, intismeran combined with pembrolizumab demonstrated statistically significant and clinically meaningful improvements in RFS and DMFS compared with pembrolizumab alone in patients with completely resected stage IIB, IIC, III, or IV cutaneous melanoma who had not previously received systemic therapy.¹ INTerpath-001 (NCT05933577) enrolled 1137 patients, randomized 2:1 to receive intismeran (1 mg every 3 weeks for up to 9 doses) plus pembrolizumab (400 mg every 6 weeks for up to 9 cycles) or pembrolizumab alone for approximately 1 year.¹ The trial will continue to evaluate other secondary endpoints, including overall survival, and the safety profile was consistent with previously reported studies of the combination, with no new signals.

How does this build on earlier data for the combination?

The result follows 5-year follow-up data from the phase 2b KEYNOTE-942 trial, presented at the 2026 ASCO Annual Meeting, in which intismeran plus pembrolizumab reduced the risk of recurrence or death by 49% (HR=0.51; 95% confidence interval [CI], 0.294-0.887) and the risk of distant metastasis or death by 59% (HR=0.411; 95% CI, 0.200-0.843) compared with pembrolizumab alone.¹^,² In the original phase 2b trial, patients with resected stage IIIB-IV melanoma were randomized 2:1 to intismeran plus pembrolizumab or pembrolizumab monotherapy, establishing the signal the phase 3 program was designed to confirm.³

How does intismeran autogene work?

Intismeran autogene is an mRNA-based individualized neoantigen therapy designed and manufactured for each patient using their own tumor sample to identify its unique mutational signature. Each therapy consists of a synthetic mRNA encoding up to 34 neoantigens tailored to an individual patient's tumor; once administered, the encoded sequences are translated and presented to the immune system to help generate a tumor-specific T-cell response.¹ Merck and Moderna are jointly developing intismeran across the broader INTerpath program, which includes 9 total phase 2 and phase 3 trials spanning melanoma, non-small cell lung cancer, bladder cancer, and renal cell carcinoma.¹

What's next for the combination?

The companies plan to present the INTerpath-001 data at an upcoming international medical meeting and will engage with regulators on filing submissions for intismeran in combination with pembrolizumab. The mAb is already approved for adjuvant treatment of resected stage IIB, IIC, or III melanoma based on the KEYNOTE-054 and KEYNOTE-716 trials, and this result is the first to show a clinically meaningful improvement over pembrolizumab alone in this adjuvant setting, according to the companies.¹

References

1. Moderna. 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. Press release. Published August 19, 2026. Accessed August 19, 2026. https://news.modernatx.com/merck-and-moderna-announce-phase-3-interpath-001-trial-of-intismeran-plus-keytruda-met-endpoints-of-rfs-and-dmfs-in-melanoma
2. Khattak MA, Carlino MS, Meniawy T, et al. Intismeran autogene plus pembrolizumab versus pembrolizumab alone in high-risk resected melanoma: 5-year update of the randomized phase IIb KEYNOTE-942 study. J Clin Oncol. 2026 Jun 1:JCO2600835. doi:10.1200/JCO-26-00835
3. Weber JS, Carlino MS, Khattak A, et al. Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomized, phase 2b study. Lancet. 2024;403(10427):632-644. doi:10.1016/S0140-6736(23)02268-7