Merck and Moderna, Inc. have announced positive topline results from the phase III INTerpath-001 trial (ClinicalTrials.gov identifier NCT05933577) evaluating adjuvant treatment with intismeran autogene (intismeran; V940 or mRNA-4157), a novel investigational mRNA-based individualized neoantigen therapy, in combination with the anti–PD-1 therapy pembrolizumab, in patients with completely resected stage IIB to IV melanoma.
Intismeran is designed and produced using a patient's tumor sample to identify the unique mutational signature of their cancer and generate an antitumor immune response. Each therapy consists of a synthetic mRNA coding for up to 34 neoantigens and is tailored to the unique biology of an individual patient's tumor. Upon administration, the RNA-encoded neoantigen sequences are translated in the body and presented to the immune system, a key step in generating specific T-cell responses against cancer cells. Individualized neoantigen therapies are designed to train and activate an antitumor immune response based on the unique mutational signature of a patient's tumor.
Trial Design
INTerpath-001 is a randomized, double-blind, placebo- and active comparator–controlled global phase III trial evaluating the safety and efficacy of intismeran in combination with pembrolizumab compared to pembrolizumab alone in patients with high-risk (stage IIB–IV) resected cutaneous melanoma. The trial enrolled 1,137 patients who, following complete surgical resection, were randomly assigned 2:1 to receive intismeran at 1 mg every 3 weeks for up to 9 doses and pembrolizumab at 400 mg every 6 weeks for up to 9 cycles (for approximately 1 year) vs pembrolizumab alone for approximately 1 year until disease recurrence or unacceptable toxicity, or for a total treatment duration of up to approximately 56 weeks, whichever was sooner.
The primary endpoint was recurrence-free survival, defined as the time from random assignment to any disease recurrence (local, locoregional, regional, or distant) as assessed by the investigator, or death due to any cause. Key secondary endpoints include distant metastasis–free survival, overall survival, safety, tolerability, and quality of life.
Endpoints Met
The trial met its primary endpoint of recurrence-free survival and a key secondary endpoint of distant metastasis–free survival. The phase III readout builds on previously reported phase IIb results for intismeran in combination with pembrolizumab from the KEYNOTE-942/mRNA-4157-P201 trial, including the 5-year follow-up data presented at the 2026 ASCO Annual Meeting, in which the combination demonstrated a 49% reduction in the risk of recurrence or death (hazard ratio [HR] = 0.51, 95% confidence interval [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 pembrolizumab alone.
This represents the first positive phase III readout for an individualized neoantigen therapy and for an mRNA-based cancer therapy, as well as the first phase III study to demonstrate a clinically meaningful improvement over pembrolizumab alone, a standard-of-care immunotherapy, in the adjuvant setting for patients with resected melanoma.
At a prespecified interim analysis, intismeran in combination with pembrolizumab as adjuvant therapy demonstrated statistically significant and clinically meaningful improvements in recurrence-free survival and distant metastasis–free survival compared to pembrolizumab alone for patients with completely resected stage IIB, IIC, III, or IV cutaneous melanoma who had not undergone prior treatment with systemic therapy. In accordance with the trial protocol, the study will continue in order to evaluate other key secondary endpoints, including overall survival.
The safety profiles of intismeran and pembrolizumab in this trial were consistent with those observed in previously reported studies for the combination, with no new safety signals observed.
These data will be presented at an upcoming international medical meeting and shared with regulatory authorities.
“Today’s results represent a landmark moment for adjuvant melanoma treatment. This is the first phase III 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 pembrolizumab alone,” said Georgina V. Long, PhD, MBBS, FRACP, 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. “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.”
Merck and Moderna are advancing the INTerpath clinical development program evaluating the safety and efficacy of intismeran in combination with pembrolizumab and other anticancer therapies, and as a monotherapy. The INTerpath program currently consists of nine total phase II and phase III clinical trials across multiple tumor types and stages of disease, including melanoma, non–small cell lung cancer (NSCLC), bladder cancer, and renal cell carcinoma. Additional clinical studies include the phase IIb KEYNOTE-942/mRNA-4157-P201 trial (NCT03897881) in adjuvant melanoma, and a phase I study exploring adjuvant pancreatic ductal adenocarcinoma, perioperative gastric carcinoma, and perioperative NSCLC.
