Merck and Moderna announced positive topline results from the Phase 3 INTerpath-001 trial evaluating intismeran autogene in combination with KEYTRUDA (pembrolizumab) as an adjuvant treatment for patients with completely resected Stage IIB-IV melanoma.
The trial met its primary endpoint of recurrence-free survival and a key secondary endpoint of distant metastasis-free survival. The companies said the combination produced statistically significant and clinically meaningful improvements in both measures compared with KEYTRUDA alone at a pre-specified interim analysis.
The results represent the first positive Phase 3 readout for an individualized neoantigen therapy and the first positive Phase 3 readout for an mRNA-based cancer therapy. Merck and Moderna also said INTerpath-001 is the first Phase 3 study to demonstrate a clinically meaningful improvement over KEYTRUDA alone in the adjuvant setting for patients with resected melanoma.
INTerpath-001 evaluated patients with completely resected Stage IIB, IIC, III or IV cutaneous melanoma who had not previously received systemic therapy. Although the study has met its recurrence-free survival and distant metastasis-free survival objectives, it will continue to evaluate additional key secondary endpoints, including overall survival. The companies said the safety profiles observed for intismeran and KEYTRUDA were consistent with previously reported studies of the combination, with no new safety signals identified.
Merck and Moderna plan to present the detailed Phase 3 results at an upcoming international medical meeting and share the findings with regulatory authorities. The companies also plan to engage regulators regarding potential filing submissions for intismeran in combination with KEYTRUDA.
INTerpath-001 is a randomized, double-blind, placebo- and active-comparator-controlled global Phase 3 study involving 1,137 patients with high-risk resected cutaneous melanoma. Following complete surgical resection, participants were randomized 2:1 to receive intismeran at 1 mg every three weeks for up to nine doses in combination with KEYTRUDA at 400 mg every six weeks for up to nine cycles, or KEYTRUDA alone. Treatment continued for approximately one year, until disease recurrence or unacceptable toxicity, or for a maximum treatment duration of approximately 56 weeks.
Intismeran, also known as V940 or mRNA-4157, is an investigational individualized neoantigen therapy jointly developed by Merck and Moderna. The therapy is produced using a sample from an individual patient’s tumor to identify the unique mutations associated with that cancer. A personalized treatment is then designed to train and activate the patient’s immune system to recognize and attack cancer cells carrying those mutations.
Each individualized therapy consists of synthetic mRNA encoding up to 34 neoantigens selected based on the unique biology of the patient’s tumor. Once administered, those RNA-encoded sequences are translated in the body and presented to the immune system with the goal of generating tumor-specific T-cell responses.
KEYTRUDA is Merck’s anti-PD-1 therapy. The drug works by blocking the interaction between the PD-1 receptor and its ligands PD-L1 and PD-L2, helping activate T lymphocytes and increase the immune system’s ability to detect and fight tumor cells. KEYTRUDA is already used as an adjuvant treatment for certain patients with resected melanoma.
The Phase 3 results build on earlier findings from the Phase 2b KEYNOTE-942/mRNA-4157-P201 study. Five-year follow-up data presented at the 2026 ASCO Annual Meeting showed that intismeran plus KEYTRUDA reduced the risk of recurrence or death by 49% and reduced the risk of distant metastasis or death by 59% compared with KEYTRUDA alone.
Merck and Moderna are also evaluating intismeran through the broader INTerpath clinical development program. The program currently includes nine Phase 2 and Phase 3 studies across multiple cancer types and stages, including melanoma, non-small cell lung cancer, bladder cancer and renal cell carcinoma. Other studies are examining the technology in pancreatic ductal adenocarcinoma, gastric carcinoma and additional non-small cell lung cancer settings.
Melanoma remains one of the deadliest forms of skin cancer. More than 330,000 new cases were diagnosed worldwide in 2022, and approximately 112,000 new U.S. melanoma cases and more than 8,500 deaths are estimated for 2026. Even after complete surgical removal, patients with melanoma can remain at risk for recurrence, with many recurrences occurring within the first two years.
KEY QUOTES:
“Today’s results represent a landmark moment for adjuvant melanoma treatment. This is the first Phase 3 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. 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.”
Professor Georgina Long, Principal Investigator of INTerpath-001, Medical Director of Melanoma Institute Australia, and Chair of Melanoma Medical Oncology and Translational Research at the University of Sydney
“By intervening earlier in the course of disease, when many cancers are considered most treatable, the goal of adjuvant therapy given after surgery is to increase the possibility of cure for more patients. These first Phase 3 findings for intismeran in combination with KEYTRUDA as adjuvant therapy reinforce the promise of a more personalized approach to cancer treatment. We believe individualized neoantigen therapies have the potential to redefine how patients with completely resected stage IIB-IV melanoma are treated. Together with Moderna, we look forward to presenting data from INTerpath-001 at an international medical meeting and sharing with regulatory authorities.”
Dr. Dean Y. Li, President of Merck Research Laboratories
“These Phase 3 findings represent a pivotal moment for the field of cancer research. For many years, the idea of creating an mRNA treatment designed specifically for an individual patient’s cancer was aspirational. We are now helping turn that vision into a reality. Together with Merck, we have started to demonstrate the transformative potential of this technology to address critical unmet needs in the adjuvant melanoma setting. We are deeply grateful to the patients, investigators and study teams whose contributions make this progress possible.”
Stéphane Bancel, CEO of Moderna
