Intismeran Autogene Plus Pembrolizumab Meets RFS and DMFS End Points in Resected Stage IIB-IV Melanoma

Adjuvant treatment with the combination of intismeran autogene (V940; mRNA-4157) and pembrolizumab (Keytruda) led to a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS) and distant metastasis–free survival (DMFS) compared with pembrolizumab alone in patients with completely resected stage IIB to IV cutaneous melanoma, meeting the primary end point of RFS and the key secondary end point of DMFS at a prespecified interim analysis of the phase 3 INTerpath-001 trial (NCT05933577).¹

The trial met both end points at the prespecified interim analysis, according to a news release from Merck and Moderna. Overall survival (OS), an additional secondary end point, was not yet mature at the time of the analysis, and the study is continuing to evaluate OS along with other secondary end points.

The companies characterized the readout as the first positive phase 3 readout for an individualized neoantigen therapy and for an mRNA-based cancer therapy.

The safety profiles of intismeran and pembrolizumab in the trial were consistent with those observed in previously reported studies of the combination, with no new safety signals identified.

Full results from INTerpath-001 will be presented at an upcoming international medical meeting, and the companies plan to share the data with regulatory authorities to support potential filing submissions for intismeran autogene in combination with pembrolizumab.

“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-IV melanoma compared to KEYTRUDA alone,” Georgina Long, MD, PhD, medical director of Melanoma Institute Australia and chair of melanoma medical oncology and translational research at the University of Sydney in Australia, stated in a news release. “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.”

What was the design of INTerpath-001?

INTerpath-001 was a phase 3, randomized, double-blind, placebo- and active-comparator–controlled study that enrolled 1,137 patients with surgically resected stage IIB, IIC, III, or IV cutaneous melanoma who were disease free and had received no prior systemic therapy.^1,2 Patients were required to have undergone complete resection within 13 weeks of randomization, and those with ocular or mucosal melanoma or unresectable metastatic disease were excluded.²

Patients were randomly assigned 2:1 to receive intismeran autogene at 1 mg intramuscularly every 3 weeks for up to 9 doses plus pembrolizumab at 400 mg intravenously every 6 weeks for up to 9 cycles, or placebo plus pembrolizumab on the same schedule.¹

The primary end point was RFS; secondary end points included DMFS, OS, safety and tolerability, and quality of life.²

“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,” Dean Y. Li, MD, PhD, president of Merck Research Laboratories, added in a news release. “We believe individualized neoantigen therapies have the potential to redefine how patients with completely resected stage IIB-IV melanoma are treated.”

What data have previously been reported for intismeran autogene plus pembrolizumab in resected melanoma?

Five-year follow-up data from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial (NCT03897881) presented at the 2026 ASCO Annual Meeting showed that the combination reduced the risk of recurrence or death by 49% (HR, 0.51; 95% CI, 0.294-0.887) and risk of distant metastasis or death by 59% (HR, 0.411; 95% CI, 0.200-0.843) compared with pembrolizumab alone.^1,3

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. August 19, 2026. Accessed August 19, 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. A phase 3, randomized, double-blind, placebo- and active-comparator-controlled clinical study of adjuvant V940 (mRNA-4157) plus pembrolizumab versus adjuvant placebo plus pembrolizumab in participants with high-risk stage II-IV melanoma (INTerpath-001). ClinicalTrials.gov. Updated September 24, 2025. Accessed August 19, 2026. https://clinicaltrials.gov/study/NCT05933577
3. Carlino MS, Khattak A, Meniawy T, et al. Individualized neoantigen therapy intismeran autogene (intismeran) plus pembrolizumab (pembro) in resected melanoma: 5-year update of the KEYNOTE-942 study. J Clin Oncol. 2026;44(suppl 16):9500. doi:10.1200/JCO.2026.44.16_suppl.9500