Merck and Moderna Report Positive Phase 3 INTerpath-001 Results for Intismeran Autogene Plus KEYTRUDA in Resected Melanoma
Merck, known as MSD outside the United States and Canada, and Moderna, Inc. (NASDAQ: MRNA) have announced detailed positive results from the Phase 3 INTerpath-001 clinical trial evaluating intismeran autogene (intismeran; V940 or mRNA-4157) in combination with KEYTRUDA® (pembrolizumab) as adjuvant treatment for patients with completely resected stage IIB-IV melanoma. The findings demonstrate significant improvements in recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) compared with KEYTRUDA alone, supporting the potential of individualized mRNA-based cancer immunotherapy in the adjuvant setting.
Intismeran autogene is an investigational individualized neoantigen therapy (INT) based on messenger RNA (mRNA) technology. The treatment is being jointly developed by Merck and Moderna to stimulate an immune response directed against tumor-specific mutations. KEYTRUDA, Merck’s anti-PD-1 immunotherapy, works by blocking the programmed death receptor-1 (PD-1) pathway, helping the immune system recognize and attack cancer cells.
The latest INTerpath-001 findings will be presented for the first time during Presidential Symposium I at the European Society for Medical Oncology (ESMO) Congress 2026 as a late-breaking abstract, Presentation #LBA1. The results have also been selected for an official ESMO press briefing and accepted for publication in The New England Journal of Medicine.
Based on the findings, the companies are engaging with regulatory authorities to discuss the results and potential next steps for the investigational combination.
Phase 3 trial demonstrates significant improvements in survival outcomes
At the primary prespecified analysis of the intention-to-treat (ITT) population, with a median follow-up of 24.6 months, intismeran autogene combined with KEYTRUDA significantly reduced the risk of disease recurrence or death compared with KEYTRUDA alone.
The combination reduced the risk of recurrence or death by 42%, with a hazard ratio (HR) of 0.58 (95% confidence interval [CI], 0.45–0.75; two-sided p-value below 0.001). The study also demonstrated a statistically significant improvement in distant metastasis-free survival, with the combination reducing the risk of distant metastasis or death by 38% (HR=0.62; 95% CI, 0.45–0.85; two-sided p=0.002).
These results indicate that adding the individualized mRNA-based therapy to pembrolizumab may provide additional protection against melanoma returning or spreading to distant parts of the body following complete surgical removal of the tumor.
The benefits observed for both RFS and DMFS were generally consistent across the prespecified patient subgroups, suggesting that the treatment effect was not limited to a single subgroup within the study population.
Overall survival (OS) data remain immature. However, the researchers have observed a favorable trend in OS among patients receiving intismeran plus KEYTRUDA compared with those treated with KEYTRUDA alone. The trial is continuing to evaluate overall survival and other important clinical endpoints.
RFS was the primary endpoint of the study, while DMFS and OS were among the key secondary endpoints. These measures are particularly important in high-risk melanoma because patients may remain vulnerable to recurrence or distant disease progression even after the primary tumor has been surgically removed.
Treatment benefit following completion of the initial immunization regimen
Additional analyses examined the timing of treatment benefit during the study. During the first six months, the efficacy of intismeran plus KEYTRUDA was comparable to that of KEYTRUDA alone for both recurrence-free survival and distant metastasis-free survival.
During this initial period, the hazard ratio for recurrence or death was 0.99 (95% CI, 0.66–1.49), while the hazard ratio for distant metastasis or death was 1.01 (95% CI, 0.58–1.79).
At the six-month point, following the intismeran immunization regimen, a prespecified sensitivity analysis of the primary endpoint demonstrated a greater separation between the treatment groups.
The addition of intismeran to KEYTRUDA was associated with a 58% reduction in the risk of recurrence or death, corresponding to a hazard ratio of 0.42 (95% CI, 0.30–0.58). The combination also reduced the risk of distant metastasis or death by 50%, with a hazard ratio of 0.50 (95% CI, 0.34–0.73), compared with KEYTRUDA alone.
These findings provide further insight into the treatment’s efficacy over time and the potential contribution of the individualized immunization regimen to the observed clinical outcomes.
A separate prespecified sensitivity analysis evaluated the modified intention-to-treat (mITT) population, excluding participants who did not receive at least one dose of intismeran or placebo as planned. In this population, the combination reduced the risk of recurrence or death by 49% (HR=0.51; 95% CI, 0.39–0.67) and the risk of distant metastasis or death by 45% (HR=0.55; 95% CI, 0.40–0.77), compared with KEYTRUDA alone.
The consistency of the results across the ITT and mITT analyses strengthens the evidence supporting the combination’s potential benefit in patients with resected high-risk melanoma.
Clinical leaders highlight the potential of individualized cancer immunotherapy
Professor Georgina Long, principal investigator of INTerpath-001 and medical director of Melanoma Institute Australia, as well as Chair of Melanoma Medical Oncology and Translational Research at the University of Sydney, emphasized the potential significance of the results for adjuvant melanoma treatment.
According to Long, the findings could represent a fundamental shift in the management of patients with earlier-stage melanoma following surgery. She highlighted how cancer treatment has traditionally been organized around the organ or tissue in which a tumor originates, whereas individualized neoantigen therapies offer an approach tailored to the unique mutational characteristics of each patient’s cancer.
The INTerpath-001 findings support further investigation of this personalized strategy, which aims to enhance the immune system’s ability to recognize and attack tumor cells based on their specific mutations.
Long also noted that although the current results concern patients with completely resected stage IIB-IV melanoma, the findings may provide valuable insights for ongoing research into intismeran across additional tumor types and treatment settings.
Dr. Dean Y. Li, president of Merck Research Laboratories, described INTerpath-001 as the first Phase 3 study to demonstrate a clinically meaningful improvement in both RFS and DMFS over standard-of-care KEYTRUDA in patients with resected melanoma.
Li said the results establish an important benchmark for adjuvant treatment and represent a significant advance in melanoma care since the introduction of immunotherapy. He also highlighted that the findings build on evidence from the earlier Phase 2b program and strengthen the companies’ confidence in the potential of intismeran autogene when administered with KEYTRUDA.
The results further support the hypothesis that intervening earlier in the course of cancer, after the tumor has been removed but before recurrence occurs, could improve long-term disease control.
Stéphane Bancel, chief executive officer of Moderna, emphasized the role of mRNA technology in developing treatments tailored to individual patients. He noted that the companies’ original vision was to use mRNA to create cancer therapies matched to the unique characteristics of each patient’s tumor.
According to Bancel, the INTerpath-001 findings represent a significant milestone for that approach and reinforce the potential of mRNA technology to change how cancer is treated.
INTerpath-001 study design and patient population
INTerpath-001 is a global, randomized, double-blind, placebo- and active-comparator-controlled Phase 3 clinical trial registered on ClinicalTrials.gov under identifier NCT05933577.
The study was designed to assess the safety and efficacy of intismeran autogene in combination with KEYTRUDA compared with placebo plus KEYTRUDA in patients with high-risk, stage IIB-IV cutaneous melanoma that had been completely resected through surgery.
The trial enrolled 1,137 patients, who were randomized in a 2:1 ratio following complete surgical resection.
Patients assigned to the investigational combination received intismeran at a dose of 1 mg every three weeks for up to nine doses, alongside KEYTRUDA at a dose of 400 mg every six weeks for up to nine cycles, corresponding to approximately one year of treatment.
The control group received placebo plus KEYTRUDA for approximately one year. Treatment continued until disease recurrence, unacceptable toxicity or completion of the planned treatment period, with a maximum duration of approximately 56 weeks.
The primary endpoint was RFS, defined as the time from randomization to disease recurrence, including local, locoregional, regional or distant recurrence, as assessed by the investigator, or death from any cause.
Key secondary endpoints included DMFS, OS, safety, tolerability and quality of life.
The study’s design enables investigators to evaluate whether adding a personalized immunotherapy to an established checkpoint inhibitor can improve outcomes after surgery in patients at substantial risk of melanoma recurrence.
Two-year recurrence-free and distant metastasis-free survival rates
The primary analysis showed improvements in the two-year RFS and DMFS rates among patients receiving intismeran plus KEYTRUDA.
In the ITT population, the two-year RFS rate was 82.2% (95% CI, 79.3%–84.8%) in the combination group, compared with 70.0% (95% CI, 65.0%–74.5%) in the KEYTRUDA-alone group.
This represents an absolute difference of 12.2 percentage points in favor of the investigational combination.
Median RFS was not reached in either treatment group at the time of analysis, indicating that the median time to recurrence or death had not yet been observed within the available follow-up period.
The two-year DMFS rate was also higher among patients treated with the combination. The rate reached 88.5% (95% CI, 86.0%–90.6%) with intismeran plus KEYTRUDA, compared with 80.2% (95% CI, 75.6%–84.0%) with KEYTRUDA alone.
This corresponds to an absolute difference of 8.3 percentage points. Median DMFS was likewise not reached in either group.
Together, these findings suggest that the investigational combination may help more patients remain free from disease recurrence and distant metastasis during the first two years following treatment initiation.
Longer follow-up will be important to determine whether these benefits are sustained and whether the improvements in recurrence-related outcomes ultimately translate into an overall survival benefit.
Safety profile remains consistent with previous studies
The safety results from INTerpath-001 were generally consistent with previously reported studies of intismeran combined with KEYTRUDA. No new safety signals were identified in the latest analysis.
Treatment-related adverse events (TRAEs) were reported in 95.8% of patients receiving intismeran plus KEYTRUDA, representing 723 of 755 patients. In comparison, treatment-related adverse events occurred in 90.0% of patients receiving KEYTRUDA alone, or 342 of 380 patients.
Grade 3–5 treatment-related adverse events were reported in 14.2% of patients in the combination group, corresponding to 107 patients, compared with 13.4%, or 51 patients, in the KEYTRUDA-alone group.
The most frequently reported adverse events in the combination group were pyrexia, or fever, occurring in 52.2% of patients; injection-site pain, reported in 51.0%; and fatigue, affecting 38.5%.
Although treatment-related adverse events were common in both groups, the incidence of grade 3–5 events was relatively similar between the treatment arms. The overall findings support the previously characterized safety profile of the combination, while continued follow-up will help further define its long-term safety and tolerability.
Broader INTerpath clinical development program
Merck and Moderna are continuing to advance the INTerpath clinical development program, which is evaluating intismeran in combination with KEYTRUDA and other anticancer therapies, as well as investigating its potential as a monotherapy.
The program currently comprises nine Phase 2 and Phase 3 clinical trials spanning multiple tumor types and stages of disease. Three ongoing Phase 3 studies are evaluating the investigational therapy in non-small cell lung cancer (NSCLC).
Additional research includes the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial in the adjuvant melanoma setting and a Phase 1 study exploring the therapy in other cancers and treatment settings. These investigations include adjuvant pancreatic ductal adenocarcinoma, for which findings were associated with Abstract #3151P, as well as perioperative gastric carcinoma and perioperative NSCLC.
The broader program reflects the companies’ strategy to assess whether individualized neoantigen therapy can be applied to different cancers by targeting mutations specific to each patient’s tumor.
The latest Phase 3 findings also build on earlier evidence from the KEYNOTE-942/mRNA-4157-P201 Phase 2b trial. Five-year follow-up data from that study were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, extending the evidence base for intismeran in combination with KEYTRUDA among patients with high-risk stage III-IV melanoma following complete resection.
Advancing personalized treatment after melanoma surgery
The positive INTerpath-001 results represent an important clinical milestone for Merck and Moderna as they continue to investigate individualized mRNA-based immunotherapy in cancer care.
The significant improvements in recurrence-free and distant metastasis-free survival demonstrate the potential value of combining a tumor-specific neoantigen approach with an established immune checkpoint inhibitor in patients with resected high-risk melanoma.
While overall survival data remain immature and further follow-up is required, the findings provide encouraging evidence that personalized immunotherapy could help reduce the risk of melanoma returning or spreading after surgery.
The companies are engaging with regulatory authorities based on the results, while the ongoing clinical development program will continue to assess the treatment’s potential in melanoma and other tumor types.
If further research confirms the durability of the observed benefits and establishes the long-term clinical impact, intismeran autogene could become an important addition to the evolving landscape of personalized cancer immunotherapy. For now, the treatment remains investigational, and its potential role in routine clinical practice will depend on further evaluation and regulatory review.
About intismeran autogene
Intismeran autogene (intismeran; V940 or mRNA-4157) is a novel, potential first-in-class investigational messenger RNA (mRNA)-based individualized neoantigen therapy (INT) jointly developed by Merck and Moderna. Intismeran is designed and produced using a patient’s tumor sample to identify the unique mutational signature of their cancer and generate an anti-tumor immune response. Information derived from the patient’s tumor and normal DNA is used to create an individualized treatment design, or “blueprint,” informed by selected neoantigens unique to that patient’s cancer.
Each therapy consists of a synthetic mRNA coding for up to 34 neoantigens. 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 anti-tumor immune response based on the unique mutational signature of a patient’s tumor.
About melanoma
Melanoma, one of the deadliest forms of skin cancer, is characterized by the uncontrolled growth of pigment-producing cells. The rates of melanoma have been rising over the past few decades, with more than 338,000 new cases diagnosed worldwide in 2024. In the U.S., skin cancer is one of the most common types of cancer diagnosed, and melanoma accounts for a large majority of skin cancer deaths. It is estimated there will be about 112,000 new cases of melanoma diagnosed and over 8,500 deaths resulting from the disease in the U.S. in 2026 alone. Despite advances in treatment, patients with resected melanoma remain at risk of disease recurrence, which most often occurs within the first two years following surgery.
Disease recurrence can be metastatic as well as localized, with more than half of patients who experience recurrence developing one or more distant metastases. Distant metastases can spread to critical organs, including the lung, liver and brain, and are associated with substantially worse outcomes, underscoring the continued need for treatment approaches that can help reduce the risk of recurrence and the risk of local and distant metastasis.
About Merck’s research in melanoma
Merck is committed to delivering meaningful advances for patients with melanoma and to continuing research in skin cancers through a broad clinical development program across investigational and approved medicines. KEYTRUDA has been established as an important treatment option for the adjuvant treatment of patients with resected Stage IIB, IIC, or III melanoma based on results of KEYNOTE-054 and KEYNOTE-716.
KEYTRUDA is also approved worldwide for the treatment of patients with unresectable or metastatic melanoma. Leveraging a decade of melanoma clinical trials, Merck continues to explore both innovative treatment approaches, including investigational individualized neoantigen therapies, and novel KEYTRUDA combinations with the goal of further improving long‑term outcomes for people living with melanoma.
About Merck’s early-stage cancer clinical program
Finding cancer at an earlier stage may give patients a greater chance of long-term survival. Many cancers are considered most treatable and potentially curable in their earliest stage of disease. Building on the strong understanding of the role of KEYTRUDA in later-stage cancers, Merck is evaluating our portfolio of medicines and pipeline candidates in earlier disease states, with more than 30 ongoing registrational studies across multiple types of cancer.
About KEYTRUDA® (pembrolizumab) injection for intravenous use, 100 mg
KEYTRUDA is an anti-programmed death receptor-1 (PD-1) therapy that works by increasing the ability of the body’s immune system to help detect and fight tumor cells. KEYTRUDA is a humanized monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2, thereby activating T lymphocytes which may affect both tumor cells and healthy cells.
Merck has the industry’s largest immuno-oncology clinical research program. There are currently more than 2,800 trials studying KEYTRUDA across a wide variety of cancers and treatment settings. The KEYTRUDA clinical program seeks to understand the role of KEYTRUDA across cancers and the factors that may predict a patient’s likelihood of benefitting from treatment with KEYTRUDA, including exploring several different biomarkers.