Merck and Moderna have announced positive topline results from the Phase 3 INTerpath-001 trial, demonstrating that intismeran autogene (intismeran; V940 or mRNA-4157) in combination with KEYTRUDA® (pembrolizumab) significantly improved both recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) compared to KEYTRUDA alone in patients with completely resected stage IIB–IV cutaneous melanoma. This marks the first positive Phase 3 readout for an individualized neoantigen therapy (INT) and for any mRNA-based cancer therapeutic.

Clinical Takeaway

The Phase 3 INTerpath-001 trial is the first Phase 3 study to demonstrate a clinically meaningful improvement over KEYTRUDA alone in the adjuvant setting for resected melanoma. The combination of intismeran autogene plus pembrolizumab met its primary endpoint of RFS and a key secondary endpoint of DMFS with statistically significant and clinically meaningful results at a pre-specified interim analysis. These findings build on Phase 2b data and represent a potential new treatment paradigm for patients with high-risk resected melanoma.

Drug Profile & Mechanism

  • Intismeran autogene (V940 / mRNA-4157) is an investigational mRNA-based individualized neoantigen therapy (INT) co-developed by Merck and Moderna.
  • The therapy is uniquely designed for each patient based on the specific mutational “fingerprint” identified within their tumor, enabling a truly personalized oncology approach.
  • By encoding up to 34 tumor-specific neoantigens selected from an individual patient’s tumor, intismeran is designed to train and activate the patient’s immune system to recognize and attack cancer cells.
  • It is administered in combination with pembrolizumab, an anti-PD-1 checkpoint inhibitor, leveraging complementary immunologic mechanisms to enhance antitumor responses.

Target Population

  • Disease: Completely resected cutaneous melanoma
  • Stage: Stage IIB, IIC, III, or IV
  • Prior therapy: No prior systemic therapy
  • Setting: Adjuvant (post-surgical)

Study Design

  • Trial name: Phase 3 INTerpath-001 (NCT05933577)
  • Design: Randomized, double-blind, placebo- and active-comparator-controlled global Phase 3 trial enrolling 1,137 patients
  • Randomization: 2:1 to intismeran autogene + KEYTRUDA versus KEYTRUDA alone
  • Experimental arm: Intismeran autogene 1 mg every 3 weeks for up to 9 doses + KEYTRUDA 400 mg every 6 weeks for up to 9 cycles
  • Control arm: KEYTRUDA (pembrolizumab) alone for approximately 1 year
  • Treatment duration: Until disease recurrence, unacceptable toxicity, or up to approximately 56 weeks, whichever occurred first
  • Analysis trigger: Pre-specified interim analysis
  • Ongoing assessments: The study will continue to evaluate additional key secondary endpoints, including overall survival (OS), per protocol.

Endpoints

  • Primary endpoint: Recurrence-free survival (RFS)
  • Key secondary endpoint: Distant metastasis-free survival (DMFS)
  • Additional secondary endpoints: Overall survival (OS), safety, tolerability, and quality of life

Efficacy Outcomes

  • At a pre-specified interim analysis, intismeran + KEYTRUDA demonstrated statistically significant and clinically meaningful improvements in both RFS and DMFS versus KEYTRUDA alone.
  • This is the first Phase 3 study to show a clinically meaningful benefit over pembrolizumab monotherapy in the adjuvant melanoma setting.
  • Results build on Phase 2b data from the KEYNOTE-942/mRNA-4157-P201 trial, including five-year follow-up data presented at the 2026 ASCO Annual Meeting, which demonstrated a 49% reduction in the risk of recurrence or death (HR=0.51; 95% CI, 0.294–0.887) and a 59% reduction in the risk of distant metastasis or death (HR=0.411; 95% CI, 0.200–0.843) compared to KEYTRUDA alone.
  • Full data from INTerpath-001 are planned to be presented at an upcoming international medical meeting and shared with regulatory authorities.

Safety

  • The safety profiles of intismeran autogene and KEYTRUDA in INTerpath-001 were consistent with those observed in previously reported studies for this combination.
  • No new safety signals were identified in this Phase 3 trial.

Broader Clinical Development Program

Merck and Moderna are advancing the INTerpath clinical development program, which currently encompasses nine Phase 2 and Phase 3 trials evaluating intismeran in combination with KEYTRUDA, other anti-cancer therapies, and as monotherapy across multiple tumor types and disease stages, including:

  • Melanoma (adjuvant setting)
  • Non-small cell lung cancer (NSCLC)
  • Bladder cancer
  • Renal cell carcinoma
  • Additional Phase 1 investigations in pancreatic ductal adenocarcinoma, perioperative gastric carcinoma, and perioperative NSCLC

Key Clinical Implications

✔ Intismeran autogene + pembrolizumab is the first combination regimen to demonstrate statistically significant and clinically meaningful improvements in both RFS and DMFS over pembrolizumab alone in the adjuvant melanoma setting, representing a potential new treatment option for patients with completely resected stage IIB–IV disease.

✔ This is the first positive Phase 3 readout for an individualized neoantigen therapy and an mRNA-based cancer therapy, providing Phase 3 evidence supporting the clinical potential of individualized mRNA-based cancer therapy.

✔ The individualized nature of intismeran means each patient’s treatment is constructed based on the unique mutational profile of their tumor, underscoring a shift toward truly personalized oncology that goes beyond biomarker-selected subgroups.

✔ The safety profiles of intismeran and pembrolizumab were consistent with previously reported studies of the combination, with no new safety signals observed, supporting continued development in the adjuvant setting.

✔ Oncology clinicians managing resected high-risk melanoma should watch for presentation of the full INTerpath-001 data and subsequent regulatory filings, as Merck and Moderna plan to engage with regulatory authorities regarding submissions for the combination.

Bottom Line

The Phase 3 INTerpath-001 trial represents a landmark achievement in both melanoma treatment and the broader field of personalized cancer immunotherapy. Intismeran autogene plus pembrolizumab demonstrated statistically significant and clinically meaningful improvements in RFS and DMFS compared with pembrolizumab alone in patients with completely resected stage IIB–IV cutaneous melanoma. With no new safety signals reported and a robust Phase 2 foundation—including five-year KEYNOTE-942 data—these findings support the potential of individualized mRNA-based neoantigen therapy as a new adjuvant treatment approach. Full INTerpath-001 data are expected at an upcoming international medical meeting, and Merck and Moderna plan to engage regulatory authorities regarding filing submissions.

Sources:

  • Merck & Co., Inc.; Moderna, Inc. 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. Published August 19, 2026. Merck press release