Intismeran Plus Pembrolizumab Improves RFS in Melanoma

Merck and Moderna announced positive phase 3 results demonstrating that intismeran autogene (V940/mRNA-4157), an investigational individualized mRNA-based neoantigen therapy, in combination with pembrolizumab (Keytruda), significantly improved recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) compared with pembrolizumab alone in patients with completely resected stage IIB-IV melanoma.

The findings from the phase 3 INTerpath-001 trial will be presented during a Presidential Symposium at the European Society for Medical Oncology (ESMO) Congress 2026 and have been accepted for publication in The New England Journal of Medicine.

At a median follow-up of 24.6 months, the combination reduced the risk of recurrence or death by 42% compared with pembrolizumab alone (HR, 0.58; 95% CI, 0.45-0.75; P < .001). The combination also reduced the risk of distant metastasis or death by 38% (HR, 0.62; 95% CI, 0.45-0.85; P = .002).

The 2-year RFS rate was 82.2% (95% CI, 79.3%-84.8%) among patients receiving intismeran plus pembrolizumab compared with 70.0% (95% CI, 65.0%-74.5%) with pembrolizumab alone. Two-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 had not been reached in either treatment arm.

Benefit Emerges Following Intismeran Immunization

A prespecified sensitivity analysis suggested the magnitude of benefit increased following completion of the intismeran immunization regimen.

During the first 6 months, efficacy with intismeran plus pembrolizumab was comparable with pembrolizumab alone for recurrence or death (HR, 0.99; 95% CI, 0.66-1.49). After 6 months, however, the combination reduced the risk of recurrence or death by 58% (HR, 0.42; 95% CI, 0.30-0.58) compared with pembrolizumab alone.

The risk of distant metastasis or death was similarly reduced by 50% after 6 months (HR, 0.50; 95% CI, 0.34-0.73).

In a modified intention-to-treat analysis excluding participants who did not receive at least 1 planned dose of intismeran or placebo, the combination reduced the risk of recurrence or death by 49% (HR, 0.51; 95% CI, 0.39-0.67) and the risk of distant metastasis or death by 45% (HR, 0.55; 95% CI, 0.40-0.77).

Overall survival data remain immature, although investigators reported a favorable trend with the combination. The trial is continuing to evaluate overall survival and other secondary end points.

Phase 3 Trial Enrolls More Than 1100 Patients

INTerpath-001 is a randomized, double-blind, placebo- and active-comparator-controlled global phase 3 trial evaluating intismeran plus pembrolizumab in patients with high-risk resected cutaneous melanoma.

The trial enrolled 1137 patients with completely resected stage IIB-IV disease. Participants were 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 placebo plus pembrolizumab. Treatment continued for approximately 1 year or until disease recurrence, unacceptable toxicity, or a maximum treatment duration of approximately 56 weeks.

RFS served as the trial's primary end point, with key secondary end points including DMFS, overall survival, safety, tolerability, and quality of life.

Treatment-related adverse events occurred in 95.8% of patients receiving intismeran plus pembrolizumab and 90.0% of those receiving pembrolizumab alone. Grade 3 to 5 treatment-related adverse events occurred in 14.2% and 13.4% of patients, respectively.

The most common adverse events reported with the combination were pyrexia (52.2%), injection-site pain (51.0%), and fatigue (38.5%). Investigators reported no new safety signals.

Individualized mRNA Approach to Melanoma

Intismeran is an investigational individualized neoantigen therapy jointly developed by Merck and Moderna. The treatment is designed using tumor and normal DNA from an individual patient to identify mutations unique to that patient's cancer.

Each individualized therapy contains synthetic mRNA encoding up to 34 selected neoantigens. Once administered, the encoded neoantigens are expressed and presented to the immune system with the goal of generating tumor-specific T-cell responses.

The phase 3 findings build on results from the phase 2b KEYNOTE-942/mRNA-4157-P201 trial. At 5 years of follow-up, intismeran plus pembrolizumab reduced the risk of recurrence or death by 49% and the risk of distant metastasis or death by 59% compared with pembrolizumab alone in patients with high-risk stage III/IV melanoma following complete resection.

Merck and Moderna stated that they are engaging with regulatory authorities based on the phase 3 findings. The broader INTerpath clinical development program currently includes 9 phase 2 and phase 3 trials evaluating the individualized therapy across multiple tumor types and disease settings.

References

1. Merck. Merck and Moderna announce phase 3 INTerpath-001 trial of intismeran autogene plus KEYTRUDA met endpoints of recurrence-free survival and distant metastasis-free survival in patients with completely resected stage IIB-IV melanoma. Published August 19, 2026. Merck.com
   Merck phase 3 INTerpath-001 announcement
2. ClinicalTrials.gov. A clinical study of intismeran autogene (V940) plus pembrolizumab in people with high-risk melanoma (V940-001). ClinicalTrials.gov identifier: NCT05933577. ClinicalTrials.gov
   INTerpath-001 ClinicalTrials.gov record
3. Merck. Moderna & Merck announce 5-year data for intismeran autogene in combination with KEYTRUDA (pembrolizumab) demonstrated sustained improvement in recurrence-free survival in patients with high-risk stage III/IV melanoma following complete resection. Published January 20, 2026. Merck.com