Merck, Moderna Cancer Vaccine Cuts Melanoma Recurrence Risk by 42%

Adding the investigational individualized neoantigen therapy intismeran autogene (intismeran; V940 or mRNA-4157) to pembrolizumab (Keytruda; Merck) reduced the risk of recurrence or death by 42% vs pembrolizumab alone in patients with completely resected stage IIB-IV melanoma, according to detailed phase 3 INTerpath-001 (NCT05933577) results.¹

“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,” said Professor Georgina Long, 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 statement. “For decades, cancer treatment has largely been defined by where a tumor originates in the body. 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. While these results are in patients with completely resected stage IIB-IV melanoma, they provide valuable insights and will help inform our understanding of intismeran as clinical research continues into other tumor types and across settings.”

The data will be presented during Presidential Symposium I at the European Society for Medical Oncology (ESMO) Congress 2026 and have been accepted for publication in The New England Journal of Medicine. They follow the companies' August announcement that the trial met its primary end point of recurrence-free survival (RFS) and key secondary end point of distant metastasis-free survival (DMFS).²

42% Lower Risk of Recurrence or Death

After a median follow-up of 24.6 months, intismeran plus pembrolizumab lowered the risk of recurrence or death (HR, 0.58; 95% CI, 0.45-0.75; P < .001) and reduced the risk of distant metastasis or death by 38% (HR, 0.62; 95% CI, 0.45-0.85; P = .002) vs pembrolizumab alone.¹ The 2-year RFS rate was 82.2% with the combination vs 70.0% with pembrolizumab alone, and 2-year DMFS rates were 88.5% and 80.2%, respectively. Median RFS and DMFS were not reached in either arm, and improvements were generally consistent across prespecified subgroups.

The trial randomly assigned 1137 patients 2:1 after complete surgical resection to intismeran 1 mg every 3 weeks for up to 9 doses plus pembrolizumab 400 mg every 6 weeks for up to 9 cycles, or to placebo plus pembrolizumab, for approximately 1 year. Intismeran is produced from each patient's tumor sample and consists of synthetic mRNA coding for up to 34 neoantigens unique to that patient's cancer.

Benefit Emerged After 6-Month Immunization Regimen

During the first 6 months, efficacy was comparable between arms for recurrence or death (HR, 0.99; 95% CI, 0.66-1.49) and distant metastasis or death (HR, 1.01; 95% CI, 0.58-1.79). After 6 months, following completion of the intismeran regimen, a prespecified sensitivity analysis showed a 58% reduction in the risk of recurrence or death (HR, 0.42; 95% CI, 0.30-0.58) and a 50% reduction in the risk of distant metastasis or death (HR, 0.50; 95% CI, 0.34-0.73).

In a modified intention-to-treat analysis that excluded participants who did not receive at least 1 dose of intismeran or placebo as planned, the reductions were 49% (HR, 0.51; 95% CI, 0.39-0.67) and 45% (HR, 0.55; 95% CI, 0.40-0.77), respectively.

Overall survival data are not yet mature, although the companies reported a favorable trend. Treatment-related adverse events (TRAEs) occurred in 95.8% of patients receiving the combination and 90.0% receiving pembrolizumab alone; grade 3-5 TRAEs occurred in 14.2% and 13.4%, respectively. The most common adverse events with the combination were pyrexia (52.2%), injection site pain (51.0%), and fatigue (38.5%). No new safety signals were observed, and the companies said they are engaging with regulatory authorities.

Results Land at Low End of Investor Expectations

The data leaked online the morning before the companies released them, and the primary RFS result fell at the low end of investor expectations, BioSpace reported.³ Investors had anchored on the earlier phase 2b KEYNOTE-942 study, in which the combination produced an HR of 0.51 for recurrence or death, according to RBC Capital Markets. Moderna shares fell 21% after the release. RBC called the data clinically meaningful and likely approvable but questioned the therapy's value relative to neoadjuvant immunotherapy, which may deliver similar efficacy at lower cost, and BMO Capital Markets cautioned against extrapolating the findings to other tumor types. BioSpace also reported 8 deaths in the combination arm; 5 occurred before patients received intismeran, and the other 3 were not attributed to the therapy.

Merck and Moderna are evaluating intismeran in 9 phase 2 and phase 3 trials across multiple tumor types, including 3 ongoing phase 3 trials in non-small cell lung cancer.¹

“From the beginning, we believed mRNA technology could make it possible to develop cancer treatments uniquely matched to each patient’s tumor. The INTerpath-001 results mark a defining moment for that vision and show what’s possible when we rethink how medicines are made,” said Stéphane Bancel, chief executive officer of Moderna, in a statement. “These results reinforce our conviction that mRNA has the potential to fundamentally change how we treat cancer.”

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://www.merck.com/news/merck-and-moderna-will-present-results-from-landmark-phase-3-interpath-001-trial-for-intismeran-autogene-plus-keytruda-pembrolizumab-at-esmo-2026-presidential-symposium/
2. Steinzor P. Moderna, Merck mRNA cancer vaccine succeeds in late-stage trial. AJMC. August 19, 2026. Accessed October 22, 2026. https://www.ajmc.com/view/moderna-merck-mrna-cancer-vaccine-succeeds-in-late-stage-trial
3. Armstrong A. ESMO 2026: Merck, Moderna shares fall as cancer vaccine disappoints after data leak. BioSpace. October 22, 2026. Accessed October 22, 2026. https://www.biospace.com/drug-development/esmo-2026-merck-moderna-shares-fall-as-cancer-vaccine-disappoints-after-data-leak