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Merck and Moderna Report Positive Phase 3 Results for Personalized Melanoma Therapy

Merck and Moderna have announced positive topline results from the Phase 3 INTerpath-001 trial evaluating intismeran autogene in combination with pembrolizumab as adjuvant treatment for patients with completely resected stage IIB to IV melanoma.

The investigational regimen met the study’s primary endpoint of recurrence-free survival and a key secondary endpoint measuring the time patients remained free from distant metastases.

The companies said the combination produced statistically significant and clinically meaningful improvements compared with pembrolizumab alone.

Trial Shows Benefit After Melanoma Surgery

INTerpath-001 evaluated patients with completely removed stage IIB, IIC, III, or IV cutaneous melanoma who had not previously received systemic treatment.

At a planned interim analysis, patients receiving intismeran autogene with pembrolizumab experienced better recurrence-free survival than those treated with pembrolizumab alone. The combination also improved distant metastasis-free survival.

The trial enrolled 1,137 patients, according to reports on the study. Detailed numerical efficacy data have not yet been released. The study will continue so researchers can assess additional outcomes, including overall survival.

First Positive Phase 3 Readout for Individualized Neoantigen Therapy

The companies said the results represent the first positive Phase 3 readout for an individualized neoantigen therapy and the first positive late-stage result for an mRNA-based cancer treatment.

Intismeran autogene is also known as intismeran, V940, or mRNA-4157. It is designed individually for each patient by using the specific mutations found in that patient’s tumor.

The treatment is intended to train the immune system to identify and attack cancer cells carrying those tumor-specific mutations.

When combined with pembrolizumab, the approach is designed to pair personalized immune activation with PD-1 pathway inhibition.

Regulatory Submissions Planned

Merck and Moderna said they will discuss the Phase 3 results with regulators and prepare filing submissions for intismeran autogene in combination with pembrolizumab.

The product remains investigational and has not been approved for the treatment of melanoma or any other cancer indication.

The companies are jointly developing the therapy as part of the broader INTerpath clinical program, which includes nine Phase 2 and Phase 3 studies across melanoma, non-small cell lung cancer, bladder cancer, and renal cell carcinoma.

Additional studies are evaluating the therapy in different settings, including adjuvant pancreatic ductal adenocarcinoma, perioperative gastric cancer, and perioperative non-small cell lung cancer.

Earlier Melanoma Data Supported Development

The Phase 3 results build on earlier findings from the Phase 2b KEYNOTE-942 and mRNA-4157-P201 study.

Five-year follow-up results presented at the 2026 American Society of Clinical Oncology Annual Meeting showed that intismeran autogene combined with pembrolizumab reduced the risk of recurrence or death by 49% compared with pembrolizumab alone. The combination also reduced the risk of distant metastasis or death by 59% in that study.

The earlier findings helped support continued development of the personalized mRNA therapy, but the Phase 3 INTerpath-001 results will require full data review and regulatory assessment.

Potential Shift in Adjuvant Melanoma Care

Pembrolizumab is an established immunotherapy option in the adjuvant treatment of resected melanoma. The INTerpath-001 results suggest that adding a patient-specific neoantigen therapy may improve protection against recurrence and distant spread.

Moderna and Merck report 5‑year follow‑up for intismeran autogene plus pembrolizumab in resected high‑risk melanoma

Moderna and Merck have released updated results from the phase 2b KEYNOTE‑942/mRNA‑4157‑P201 trial, providing the first median five‑year follow‑up for the personalised mRNA neoantigen therapy intismeran autogene given with pembrolizumab in patients with completely resected stage III/IV melanoma at high risk of relapse.

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The adjuvant combination continued to deliver a sustained and clinically meaningful improvement in recurrence‑free survival compared with pembrolizumab alone, reinforcing the potential of this strategy in the post‑surgical setting.

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In this pre‑specified analysis, adjuvant treatment with intismeran autogene plus pembrolizumab was associated with a 49% relative reduction in the risk of recurrence or death versus pembrolizumab monotherapy.

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Expanding late‑stage development across tumour types

The long‑term KEYNOTE‑942 results support a broad development programme for intismeran autogene in partnership with Merck, spanning melanoma, lung, bladder and kidney cancers. A pivotal phase 3 trial in the adjuvant melanoma setting (INTerpath‑001; NCT05933577) evaluating intismeran autogene plus pembrolizumab versus pembrolizumab alone following complete resection is fully enrolled.

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Two phase 3 studies in non‑small cell lung cancer are ongoing: one in patients with completely resected disease receiving adjuvant therapy, and another in patients with resectable disease who receive neoadjuvant pembrolizumab plus platinum‑based chemotherapy followed by postsurgical treatment. A randomized phase 2 trial testing adjuvant intismeran autogene plus pembrolizumab in renal cell carcinoma has completed enrolment, while separate phase 2 randomized studies in resected muscle‑invasive and resected non‑muscle‑invasive bladder cancer continue to enrol patients. In addition, phase 2 trials are underway assessing the combination as first‑line systemic treatment for metastatic melanoma and for metastatic squamous non‑small cell lung cancer.

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Intismeran autogene: individualized mRNA neoantigen therapy

Intismeran autogene is an investigational individualized neoantigen therapy built on messenger RNA technology. For each patient, tumour DNA is sequenced to identify tumour‑specific mutations, and a bespoke synthetic mRNA is designed to encode up to 34 predicted neoantigens arising from that mutational profile. Once administered, the mRNA is translated inside the body to produce the encoded neoantigen peptides, which are processed and presented by antigen‑presenting cells, a critical step in initiating adaptive immune responses.

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The goal of this individualized approach is to prime and expand tumour‑specific T‑cell populations capable of recognising and attacking cancer cells that carry the same neoantigens, thereby enhancing antitumour immunity when combined with checkpoint blockade. By tailoring the encoded antigens to each patient’s tumour, intismeran autogene aims to generate a focused immune response against malignant cells while sparing normal tissues.

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Overview of the KEYNOTE‑942/mRNA‑4157‑P201 study

KEYNOTE‑942 is an ongoing, randomized, open‑label phase 2b study that enrolled 157 patients with high‑risk stage III or IV cutaneous melanoma who had undergone complete surgical resection. Participants were stratified by disease stage and assigned in a 2:1 ratio to receive intismeran autogene plus pembrolizumab or pembrolizumab alone as adjuvant therapy until recurrence, unacceptable toxicity, or completion of the planned treatment course.

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In the combination arm, patients received intramuscular intismeran autogene at a dose of 1 mg every three weeks for up to nine doses, together with intravenous pembrolizumab 200 mg every three weeks for up to 18 cycles, corresponding to approximately one year of treatment. Patients in the control arm were treated with pembrolizumab alone on the same schedule for about one year, in line with standard adjuvant practice in this setting.

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The primary endpoint of the trial is recurrence‑free survival, defined as the time from the first pembrolizumab dose to locoregional or distant melanoma recurrence, emergence of a new primary melanoma, or death from any cause in the intention‑to‑treat population. Key secondary endpoints include distant metastasis‑free survival and safety, while exploratory analyses are evaluating factors such as tumour mutational burden and their relationship to clinical outcomes.

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