Merck and Moderna Report Positive Phase 3 Results for Personalized mRNA Cancer Therapy in Melanoma
Merck, known as MSD outside the United States and Canada, and Moderna, Inc. have announced positive topline results from the Phase 3 INTerpath-001 clinical trial evaluating intismeran autogene, also known as intismeran, V940 or mRNA-4157. The investigational therapy is an individualized neoantigen therapy based on messenger RNA (mRNA) technology and is being jointly developed by Merck and Moderna.
The Phase 3 study evaluated intismeran in combination with KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, as an adjuvant treatment for patients with completely resected stage IIB to IV melanoma.
The results represent an important milestone for personalized cancer treatment. According to the companies, INTerpath-001 is the first Phase 3 trial to report positive results for an individualized neoantigen therapy and the first Phase 3 study to demonstrate a clinically meaningful improvement with an mRNA-based cancer therapy over KEYTRUDA alone in the adjuvant treatment of resected melanoma.
At a prespecified interim analysis, the combination of intismeran and KEYTRUDA demonstrated statistically significant and clinically meaningful improvements in both recurrence-free survival (RFS), the study’s primary endpoint, and distant metastasis-free survival (DMFS), a key secondary endpoint.
The findings were observed in patients with completely resected stage IIB, IIC, III or IV cutaneous melanoma who had not previously received systemic therapy.
Positive Results for Recurrence-Free and Distant Metastasis-Free Survival
The primary objective of INTerpath-001 was to determine whether adding intismeran to KEYTRUDA could improve recurrence-free survival compared with KEYTRUDA alone.
At the interim analysis, the combination achieved a statistically significant improvement in RFS. The treatment also produced a statistically significant improvement in DMFS, indicating a reduced risk of cancer spreading to distant parts of the body or death compared with KEYTRUDA alone.
The results are particularly significant because pembrolizumab is already an established standard-of-care immunotherapy in the adjuvant melanoma setting.
The ability of an individualized neoantigen therapy to improve outcomes when added to an existing immunotherapy could potentially establish a new treatment approach for patients who have undergone surgery to completely remove their melanoma.
The study will continue according to its prespecified protocol so that researchers can evaluate additional endpoints. These include overall survival, which will provide further information about the long-term impact of the treatment combination.
The companies said the safety profiles observed for intismeran and KEYTRUDA were consistent with findings from previous studies of the combination. No new safety signals were identified during the Phase 3 trial.
Detailed findings are expected to be presented at an upcoming international medical meeting and submitted to regulatory authorities for review.
A Personalized Approach to Cancer Treatment
One of the distinguishing features of intismeran is its individualized approach.
Traditional cancer treatments are generally developed to target biological features shared by groups of patients with the same type of cancer. Individualized neoantigen therapies, by contrast, are designed using information about the unique mutations present in an individual patient’s tumor.
Cancer cells can contain mutations that produce abnormal proteins, known as neoantigens. These neoantigens may be recognized by the immune system as being different from normal cells.
The concept behind intismeran is to use mRNA technology to create a personalized therapy based on the specific neoantigens identified in a patient’s tumor.
The treatment is intended to help stimulate an immune response directed against cancer cells carrying those tumor-specific targets.
This approach could potentially allow the immune system to recognize and attack residual cancer cells that may remain in the body after surgery, even when no detectable disease remains.
For patients with melanoma, this is particularly relevant because recurrence can occur following surgical removal of the primary tumor or metastatic lesions.
Adjuvant therapy is administered after surgery with the objective of eliminating microscopic disease and reducing the risk that cancer will return.
Potential New Paradigm in Adjuvant Melanoma
Professor Georgina Long, the principal investigator of INTerpath-001 and medical director of Melanoma Institute Australia, described the findings as a major milestone for adjuvant melanoma treatment.
Long highlighted that intismeran is designed according to the unique mutational profile of each patient’s tumor. When combined with pembrolizumab, the therapy demonstrated an ability to reduce the risk of recurrence or death compared with KEYTRUDA alone in patients with completely resected stage IIB-IV melanoma.
The findings raise the possibility that individualized neoantigen therapies could become an important component of future adjuvant treatment strategies.
For patients whose melanoma has been completely removed through surgery, the objective of adjuvant treatment is to reduce the possibility of recurrence and increase the likelihood of long-term disease control or cure.
The positive Phase 3 results provide further support for evaluating whether personalized immune-based therapies can improve outcomes beyond what is achievable with established checkpoint inhibitor treatments alone.
Building on Earlier Phase 2 Evidence
The INTerpath-001 results build on earlier clinical findings from the Phase 2b KEYNOTE-942/mRNA-4157-P201 study, which also evaluated intismeran in combination with KEYTRUDA in patients with melanoma.
Five-year follow-up results from the Phase 2b study were presented at the 2026 ASCO Annual Meeting.
In those data, the combination demonstrated a 49% reduction in the risk of recurrence or death compared with KEYTRUDA alone, with a hazard ratio of 0.51 and a 95% confidence interval of 0.294 to 0.887.
The combination also demonstrated a 59% reduction in the risk of distant metastasis or death, with a hazard ratio of 0.411 and a 95% confidence interval of 0.200 to 0.843.
The longer-term Phase 2b results helped establish the rationale for continuing development into a larger Phase 3 program.
The positive INTerpath-001 readout now provides Phase 3 evidence supporting the potential of the individualized neoantigen approach in the adjuvant melanoma setting.
Merck and Moderna Expand Development Program
The companies are developing intismeran through a broader clinical development program known as INTerpath.
The program is evaluating the investigational therapy both in combination with KEYTRUDA and other anticancer treatments and as a potential monotherapy.
According to Merck and Moderna, the INTerpath program currently includes nine Phase 2 and Phase 3 clinical trials covering multiple tumor types and stages of cancer.
In addition to melanoma, the development program includes studies in non-small cell lung cancer, bladder cancer, and renal cell carcinoma.
The companies are also conducting additional studies to determine whether individualized neoantigen therapy could provide benefits in other cancers and different stages of treatment.
These include the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial in the adjuvant melanoma setting, as well as a Phase 1 study investigating the technology in adjuvant pancreatic ductal adenocarcinoma, perioperative gastric carcinoma, and perioperative non-small cell lung cancer.
The broad development strategy reflects the companies’ interest in determining whether the personalized mRNA platform can be applied across multiple cancer types.
Earlier Intervention May Improve Outcomes
Dean Y. Li, president of Merck Research Laboratories, emphasized the importance of treating cancer earlier in its course.
Adjuvant treatment is designed to intervene after surgery, when the visible tumor has been removed but microscopic cancer cells may still remain.
The goal is to prevent those cells from developing into recurrent disease and, ultimately, to increase the possibility of long-term remission or cure.
The positive Phase 3 findings provide support for the concept that a personalized approach could complement established immunotherapy at this earlier point in the cancer treatment journey.
Merck believes individualized neoantigen therapies could potentially change how patients with completely resected melanoma are treated.
The company is working with Moderna to further analyze the INTerpath-001 results and prepare the data for presentation at a future medical meeting and discussions with regulatory authorities.
Advancing mRNA Technology Beyond Infectious Diseases
The findings also represent a major development for the application of mRNA technology in oncology.
mRNA technology became widely recognized through the development of vaccines, but researchers have increasingly investigated its potential for therapeutic applications beyond infectious diseases.
Cancer is one of the areas where mRNA technology could offer significant advantages because it can potentially be programmed to encode multiple tumor-specific targets.
For individualized neoantigen therapy, information from an individual patient’s tumor can be used to identify relevant mutations and create a customized treatment designed around those targets.
The ability to produce such therapies using an mRNA platform could potentially enable a more flexible approach to personalized medicine.
Stéphane Bancel, CEO of Moderna, said the Phase 3 findings represent an important moment for cancer research and demonstrate progress toward making individualized mRNA cancer treatments a clinical reality.
Bancel also acknowledged the contributions of patients, investigators, and clinical research teams involved in the development program.
While the positive topline results represent an important milestone, additional data from INTerpath-001 will be needed to fully characterize the benefit-risk profile of intismeran in combination with KEYTRUDA.
The ongoing study will continue evaluating other important endpoints, including overall survival. Detailed efficacy and safety data are expected to be presented at an international medical meeting.
Regulatory discussions will also determine the next steps for the therapy’s development and potential future approval.
For Merck and Moderna, the Phase 3 results provide important validation of their strategy to combine checkpoint inhibition with individualized neoantigen therapy.
For the broader oncology field, the findings could mark a significant step toward increasingly personalized cancer treatment.
Melanoma remains an important area for innovation because even patients who undergo complete surgical resection can face a risk of recurrence. Existing immunotherapies have improved outcomes, but additional treatment strategies are still needed to further reduce recurrence and metastatic disease.
If subsequent analyses confirm the topline findings, intismeran could potentially become an important addition to the adjuvant treatment landscape.
The broader INTerpath program will help determine whether the approach can be extended beyond melanoma to other tumor types.
Overall, the positive Phase 3 INTerpath-001 results represent a significant advancement in the development of individualized neoantigen therapies. By combining a treatment tailored to the molecular characteristics of each patient’s tumor with KEYTRUDA, Merck and Moderna are pursuing a highly personalized approach to cancer immunotherapy.
The next stages of clinical development, long-term follow-up, regulatory evaluation, and additional trials across different cancers will determine the ultimate role of intismeran. For now, the Phase 3 findings provide encouraging evidence that personalized mRNA-based cancer therapy may have the potential to improve outcomes for patients following surgical treatment of melanoma and could help shape the future direction of precision oncology.
About INTerpath-001
INTerpath-001 is a randomized, double-blind, placebo- and active-comparator-controlled global Phase 3 trial (ClinicalTrials.gov, NCT05933577 ) evaluating the safety and efficacy of intismeran in combination with KEYTRUDA compared to KEYTRUDA alone in patients with high-risk (stage IIB-IV) resected cutaneous melanoma.
The trial enrolled 1,137 patients who, following complete surgical resection, were randomized 2:1 to receive intismeran (1 mg every three weeks for up to nine doses) and KEYTRUDA (400 mg every six weeks up to nine cycles [for approximately one year]) versus KEYTRUDA alone for approximately one 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 is RFS, defined as the time from randomization to any disease recurrence (local, locoregional, regional or distant) as assessed by the investigator, or death due to any cause. Key secondary endpoints include DMFS, OS, safety, tolerability and quality of life.
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, or “fingerprint,” of their cancer and generate an anti-tumor 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 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 330,000 new cases diagnosed worldwide in 2022. In the US, 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 US 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. The majority of recurrences are metastatic rather than localized, highlighting the ongoing need for treatment approaches that may help reduce the risk of recurrence and improve long-term outcomes.
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.