Merck and Moderna, Inc. have jointly announced that the phase III INTerpath-001 trial met its primary endpoint and a key secondary endpoint in evaluating the novel, investigational messenger RNA (mRNA)–based individualized neoantigen therapy intismeran autogene (intismeran; V940 or mRNA-4157) in combination with pembrolizumab in patients with completely resected stage IIB to IV melanoma.  

The study is the first phase III trial to show positive results with an individualized neoantigen therapy and an mRNA-based cancer therapy.  

At a prespecified interim analysis, the combination regimen demonstrated statistically significant and clinically meaningful improvements in recurrence-free survival, the study’s primary endpoint, and distant metastasis–free survival, a key secondary endpoint, compared with pembrolizumab monotherapy.  

Findings from the study are expected to be presented at an upcoming international medical meeting and submitted to 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 KEYTRUDA alone,” stated principal study investigator Georgina V. Long, BSc, PhD, MBBS, FRACP, FAHMS, AAHMS, FAA, FASCO, 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.” 

AI-Based Vaccine Design

The phase III findings build upon results from the phase IIb KEYNOTE-942 trial evaluating intismeran autogene in combination with pembrolizumab in patients with high-risk resected melanoma. Updated 5-year results, presented at the 2026 ASCO Annual Meeting and published in the Journal of Clinical Oncology, showed significant improvements in both recurrence-free survival and distant metastasis–free survival compared with pembrolizumab alone after a median follow-up of 60.3 months.  

The report notes that a “deterministic machine learning bioinformatic algorithm” was used for the design of the individualized neoantigen therapy to identify patient-specific somatic neoantigens for targeting.  

However, the new press release does not mention the proprietary AI, instead explaining that the therapy is designed using a patient’s tumor sample to “identify the unique mutational signature, or ‘fingerprint,’ of their cancer and generate an anti-tumor immune response.” 

A recent paper published to provide further details on the generation and delivery of intismeran autogene explained that the patient’s tumor undergoes next-generation sequencing, after which the neoantigen selection algorithm evaluates candidate mutations and selects those for inclusion in the therapy.  

Additionally, in a Moderna blog, Kyle Holen, Head of Development, Oncology & Therapeutics, described the combination of intismeran autogene and pembrolizumab as both a technological advancement and a medical breakthrough. He explained that AI helps simplify some of the complexities associated with designing and manufacturing an individualized therapy for each patient within the required timeframe.  

“On the design end, a series of fully integrated AI algorithms takes next-generation sequencing data from tumor and blood samples, reviews their genetic mutations, and predicts up to 34 of those neoantigens that are most likely to elicit an immune response. This algorithm has the potential to learn over time, through pairing clinical and immunogenicity data, and will hopefully become better at selecting the most clinically active neoantigens,” he wrote.  

Mainstream media outlets have also reported on the use of AI to select neoantigens for the individualized vaccine.  

Merck and Moderna are continuing to jointly develop the INTerpath program evaluating intismeran autogene with or without pembrolizumab across multiple tumor types, including non–small cell lung cancer, bladder cancer, renal cell carcinoma, pancreatic ductal adenocarcinoma, and gastric carcinoma. 

Study Design and Safety Findings

The randomized, double-blind, placebo- and active-comparator–controlled global phase III INTerpath-001 trial enrolled 1,137 patients with high-risk stage IIB to IV cutaneous melanoma following complete surgical resection. Patients were randomly assigned 2:1 to receive intismeran autogene at 1 mg every 3 weeks for up to nine doses plus pembrolizumab at 400 mg every 6 weeks for up to nine cycles, or pembrolizumab alone. Treatment continued for approximately 1 year or until disease recurrence or unacceptable toxicity.  

The study’s primary endpoint was recurrence-free survival, and key secondary endpoints included distant metastasis–free survival, overall survival, safety, tolerability, and quality of life.  

The safety profile of intismeran autogene plus pembrolizumab was consistent with that observed in prior studies of the regimen, with no new safety signals identified.  

In accordance with trial protocol, INTerpath-001 will continue to evaluate other key secondary endpoints. 

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