Intismeran Plus Pembrolizumab Reduces Recurrence Risk in Resected Melanoma

Adjuvant intismeran autogene (intismeran; V940/mRNA-4157) in combination with pembrolizumab (Keytruda) significantly reduced the risk of recurrence or death by 42% compared with pembrolizumab alone in patients with completely resected stage IIB to IV melanoma, according to detailed results from the phase 3 INTerpath-001 trial (NCT05933577) announced by Merck and Moderna.¹

The late-breaking data will be presented for the first time during Presidential Symposium I at the European Society for Medical Oncology (ESMO) Congress 2026 on Saturday, October 24 (Presentation LBA1), and were selected for an official ESMO press briefing. The findings have also been accepted for publication in The New England Journal of Medicine.¹ Additional updates are expected following the presentation.

At the primary prespecified intention-to-treat (ITT) analysis, after a median follow-up of 24.6 months, the hazard ratio (HR) for recurrence-free survival (RFS) was 0.58 (95% CI, 0.45-0.75; 2-sided P<.001) with intismeran plus pembrolizumab vs pembrolizumab alone. The combination also reduced the risk of distant metastasis or death by 38% (HR, 0.62; 95% CI, 0.45-0.85; 2-sided P = .002). Improvements in RFS and distant metastasis-free survival (DMFS) were generally consistent across prespecified patient subgroups.

The 2-year RFS rate was 82.2% (95% CI, 79.3%-84.8%) in the combination arm compared with 70.0% (95% CI, 65.0%-74.5%) in the pembrolizumab arm, and the 2-year DMFS rates were 88.5% (95% CI, 86.0%-90.6%) and 80.2% (95% CI, 75.6%-84.0%), respectively. Median RFS and DMFS were not reached in either arm. Overall survival (OS) data are not yet mature, although investigators have observed a favorable OS trend with the combination. The study remains ongoing to further evaluate OS and other key end points.

The benefit of the combination became more pronounced after the intismeran immunization regimen was completed. During the first 6 months, efficacy was comparable between the 2 arms for both RFS (HR, 0.99; 95% CI, 0.66-1.49) and DMFS (HR, 1.01; 95% CI, 0.58-1.79). Beyond 6 months, a prespecified sensitivity analysis showed that intismeran plus pembrolizumab reduced the risk of recurrence or death by 58% (piecewise HR, 0.42; 95% CI, 0.30-0.58) and halved the risk of distant metastasis or death (HR, 0.50; 95% CI, 0.34-0.73). In a separate prespecified sensitivity analysis of the modified ITT population, which excluded patients who did not receive at least 1 dose of intismeran or placebo as planned, the HRs were 0.51 (95% CI, 0.39-0.67) for RFS and 0.55 (95% CI, 0.40-0.77) for DMFS.

Regarding safety, treatment-related adverse events (TRAEs) occurred in 95.8% (n = 723/755) of patients who received the combination and 90.0% (n = 342/380) of those who received pembrolizumab alone. Grade 3 to 5 TRAEs occurred in 14.2% (n = 107) and 13.4% (n = 51) of patients, respectively. The most common AEs in the combination arm were pyrexia (52.2%), injection site pain (51.0%), and fatigue (38.5%). The safety profile was generally consistent with previous studies of the combination, and no new safety signals were observed. Based on these data, the companies are engaging with regulatory authorities.

“The transformative INTerpath-001 results have the potential to make a foundational shift in how we treat patients with earlier-stage melanoma in the adjuvant setting,” Georgina Long, MD, PhD, the study’s principal investigator, medical director of Melanoma Institute Australia, and chair of Melanoma Medical Oncology and Translational Research at the University of Sydney, said in the news release.¹ “The INTerpath-001 findings support a fundamentally new and individualized approach to treating resected melanoma in the adjuvant setting, one that tailors treatment to the unique mutational signature of a patient’s tumor to enhance an anti-tumor immune response.”¹

The detailed findings follow a topline announcement on August 19, 2026, which reported that INTerpath-001 met its primary end point of RFS and key secondary end point of DMFS at a prespecified interim analysis.² At that time, the companies described intismeran plus pembrolizumab as the first and only combination regimen to demonstrate statistically significant and clinically meaningful improvements in RFS and DMFS compared with pembrolizumab alone in the adjuvant melanoma setting, and stated plans to present the data at an upcoming international medical meeting.

INTerpath-001 is a randomized, double-blind, placebo- and active comparator–controlled global trial that enrolled 1137 patients with high-risk, completely resected stage IIB, IIC, III, or IV cutaneous melanoma who had not received prior systemic therapy.^1,2 Patients were randomly assigned 2:1 to receive intismeran 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 placebo plus pembrolizumab, for approximately 1 year or until disease recurrence or unacceptable toxicity.

The primary end point is RFS, defined as the time from randomization to any disease recurrence including local, locoregional, regional, or distant as assessed by the investigator, or death from any cause. Key secondary end points include DMFS, OS, safety, tolerability, and quality of life.

Intismeran is an investigational, mRNA-based individualized neoantigen therapy designed using each patient’s tumor sample to identify the unique mutational signature of their cancer. Each therapy consists of a synthetic mRNA coding for up to 34 neoantigens that, once translated in the body, are presented to the immune system to generate specific T-cell responses against cancer cells.¹ The INTerpath-001 results build on previously reported data from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial (NCT03897881), including 5-year follow-up data presented at the 2026 American Society of Clinical Oncology Annual Meeting.¹

“INTerpath-001 is the first [phase 3] study to demonstrate a clinically meaningful improvement in RFS and DMFS over standard-of-care [pembrolizumab] in patients with resected melanoma, setting a new benchmark in the adjuvant setting and representing one of the most significant advances in melanoma treatment since the advent of immunotherapy,” Dean Y. Li, MD, PhD, president of Merck Research Laboratories, said in the release.¹

Merck and Moderna are evaluating intismeran across 9 phase 2 and phase 3 trials in the INTerpath program, including 3 ongoing phase 3 trials in non–small cell lung cancer.¹

References

1. Merck and Moderna will present results from landmark phase 3 INTerpath-001 trial for intismeran autogene plus Keytruda (pembrolizumab) at ESMO 2026 Presidential Symposium. News release. Merck. October 22, 2026. Accessed October 22, 2026. https://tinyurl.com/5btbzfhp
2. 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 October 22, 2026. https://tinyurl.com/77htwprv