First and only combination regimen to demonstrate statistically significant and clinically meaningful improvements in RFS and DMFS compared to KEYTRUDA alone for these patients in the adjuvant melanoma setting
The Companies plan to present data at an upcoming international medical meeting and will engage with regulators on filing submissions for intismeran autogene in combination with KEYTRUDA
Intismeran autogene is an mRNA-based individualized neoantigen therapy (INT) designed specifically for each patient based on the unique set of mutations within their tumor to train and activate the immune system to recognize and fight cancer
RAHWAY, N.J. & CAMBRIDGE, Mass.–(BUSINESS WIRE)–Merck (NYSE: MRK), known as MSD outside of the United States and Canada, and Moderna, Inc. (NASDAQ: MRNA) today announced positive topline results from the Phase 3 INTerpath-001 trial evaluating adjuvant treatment with intismeran autogene (intismeran; V940 or mRNA-4157), a novel investigational mRNA-based individualized neoantigen therapy (INT) being jointly developed by Merck and Moderna, in combination with KEYTRUDA® (pembrolizumab), Merck’s anti-PD-1 therapy, in patients with completely resected stage IIB-IV melanoma. The trial met its primary endpoint of recurrence-free survival (RFS) and a key secondary endpoint of distant metastasis-free survival (DMFS). This represents the first positive Phase 3 readout for an individualized neoantigen therapy (INT) and for an mRNA-based cancer therapy, as well as the first Phase 3 study to demonstrate a clinically meaningful improvement over KEYTRUDA alone, a standard-of-care immunotherapy, in the adjuvant setting for patients with resected melanoma.
At a pre-specified interim analysis, intismeran in combination with KEYTRUDA as adjuvant therapy demonstrated statistically significant and clinically meaningful improvements in RFS and DMFS compared to KEYTRUDA alone for patients with completely resected stage IIB, IIC, III or IV cutaneous melanoma who had not undergone prior treatment with systemic therapy. In accordance with the trial protocol, the study will continue in order to evaluate other key secondary endpoints, including overall survival (OS).
The safety profiles of intismeran and KEYTRUDA in this trial were consistent with those observed in previously reported studies for the combination, with no new safety signals observed.
These data will be presented at an upcoming international medical meeting and shared with regulatory authorities.
“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,” said Professor Georgina Long, the study’s principal investigator and medical director of Melanoma Institute Australia, 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.”
“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,” said Dr. Dean Y. Li, president, Merck Research Laboratories. “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.”
“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,” said Stéphane Bancel, CEO of Moderna. “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.”
Merck and Moderna are advancing the robust INTerpath clinical development program evaluating the safety and efficacy of intismeran in combination with KEYTRUDA and other anti-cancer therapies, and as a monotherapy. The INTerpath program currently consists of nine total Phase 2 and Phase 3 clinical trials across multiple tumor types and stages of disease, including melanoma, non-small cell lung cancer (NSCLC), bladder cancer and renal cell carcinoma. Additional clinical studies include the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial in adjuvant melanoma and a Phase 1 study exploring adjuvant pancreatic ductal adenocarcinoma, perioperative gastric carcinoma and perioperative NSCLC.
Today’s Phase 3 readout builds on previously reported Phase 2b results for intismeran in combination with KEYTRUDA from the KEYNOTE-942/mRNA-4157-P201 trial, including the five-year follow-up data presented at the 2026 ASCO Annual Meeting, in which the combination demonstrated a 49% reduction in the risk of recurrence or death (HR=0.51; [95% CI, 0.294-0.887]) and a 59% reduction in the risk of distant metastasis or death (HR=0.411; [95% CI, 0.200-0.843]) compared to KEYTRUDA alone.
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 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. 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.
Selected KEYTRUDA® (pembrolizumab) Indications in the U.S.
Melanoma
KEYTRUDA is indicated for the treatment of patients with unresectable or metastatic melanoma.
KEYTRUDA is indicated for the adjuvant treatment of adult and pediatric (12 years and older) patients with Stage IIB, IIC, or III melanoma following complete resection.
See additional selected KEYTRUDA indications in the U.S. after the Selected Important Safety Information.
Selected Safety Information for KEYTRUDA
Severe and Fatal Immune-Mediated Adverse Reactions
KEYTRUDA is a monoclonal antibody that belongs to a class of drugs that bind to either the programmed death receptor-1 (PD-1) or the programmed death ligand 1 (PD-L1), blocking the PD-1/PD-L1 pathway, thereby removing inhibition of the immune response, potentially breaking peripheral tolerance and inducing immune-mediated adverse reactions. Immune-mediated adverse reactions, which may be severe or fatal, can occur in any organ system or tissue, can affect more than one body system simultaneously, and can occur at any time after starting treatment or after discontinuation of treatment. Important immune-mediated adverse reactions listed here may not include all possible severe and fatal immune-mediated adverse reactions.
Monitor patients closely for symptoms and signs that may be clinical manifestations of underlying immune-mediated adverse reactions. Early identification and management are essential to ensure safe use of anti–PD-1/PD-L1 treatments. Evaluate liver enzymes, creatinine, and thyroid function at baseline and periodically during treatment. For patients with TNBC treated with KEYTRUDA in the neoadjuvant setting, monitor blood cortisol at baseline, prior to surgery, and as clinically indicated. In cases of suspected immune-mediated adverse reactions, initiate appropriate workup to exclude alternative etiologies, including infection. Institute medical management promptly, including specialty consultation as appropriate.
Withhold or permanently discontinue KEYTRUDA depending on severity of the immune-mediated adverse reaction. In general, if KEYTRUDA requires interruption or discontinuation, administer systemic corticosteroid therapy (1 to 2 mg/kg/day prednisone or equivalent) until improvement to Grade 1 or less. Upon improvement to Grade 1 or less, initiate corticosteroid taper and continue to taper over at least 1 month. Consider administration of other systemic immunosuppressants in patients whose adverse reactions are not controlled with corticosteroid therapy.
Immune-Mediated Pneumonitis
KEYTRUDA can cause immune-mediated pneumonitis. The incidence is higher in patients who have received prior thoracic radiation. Immune-mediated pneumonitis occurred in 3.4% (94/2799) of patients receiving KEYTRUDA, including fatal (0.1%), Grade 4 (0.3%), Grade 3 (0.9%), and Grade 2 (1.3%) reactions. Systemic corticosteroids were required in 67% (63/94) of patients. Pneumonitis led to permanent discontinuation of KEYTRUDA in 1.3% (36) and withholding in 0.9% (26) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Pneumonitis resolved in 59% of the 94 patients.
Pneumonitis occurred in 8% (31/389) of adult patients with cHL receiving KEYTRUDA as a single agent, including Grades 3-4 in 2.3% of patients. Patients received high-dose corticosteroids for a median duration of 10 days (range: 2 days to 53 months). Pneumonitis rates were similar in patients with and without prior thoracic radiation. Pneumonitis led to discontinuation of KEYTRUDA in 5.4% (21) of patients. Of the patients who developed pneumonitis, 42% interrupted KEYTRUDA, 68% discontinued KEYTRUDA, and 77% had resolution.
Pneumonitis occurred in 7% (41/580) of adult patients with resected NSCLC who received KEYTRUDA as a single agent for adjuvant treatment of NSCLC, including fatal (0.2%), Grade 4 (0.3%), and Grade 3 (1%) adverse reactions. Patients received high-dose corticosteroids for a median duration of 10 days (range: 1 day to 2.3 months). Pneumonitis led to discontinuation of KEYTRUDA in 26 (4.5%) of patients. Of the patients who developed pneumonitis, 54% interrupted KEYTRUDA, 63% discontinued KEYTRUDA, and 71% had resolution.
Immune-Mediated Colitis
KEYTRUDA can cause immune-mediated colitis, which may present with diarrhea. Cytomegalovirus infection/reactivation has been reported in patients with corticosteroid-refractory immune-mediated colitis. In cases of corticosteroid-refractory colitis, consider repeating infectious workup to exclude alternative etiologies. Immune-mediated colitis occurred in 1.7% (48/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (1.1%), and Grade 2 (0.4%) reactions. Systemic corticosteroids were required in 69% (33/48); additional immunosuppressant therapy was required in 4.2% of patients. Colitis led to permanent discontinuation of KEYTRUDA in 0.5% (15) and withholding in 0.5% (13) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, 23% had recurrence. Colitis resolved in 85% of the 48 patients.
Hepatotoxicity and Immune-Mediated Hepatitis
KEYTRUDA as a Single Agent
KEYTRUDA can cause immune-mediated hepatitis. Immune-mediated hepatitis occurred in 0.7% (19/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.4%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 68% (13/19) of patients; additional immunosuppressant therapy was required in 11% of patients. Hepatitis led to permanent discontinuation of KEYTRUDA in 0.2% (6) and withholding in 0.3% (9) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Hepatitis resolved in 79% of the 19 patients.
KEYTRUDA With Axitinib
KEYTRUDA in combination with axitinib can cause hepatic toxicity. Monitor liver enzymes before initiation of and periodically throughout treatment. Consider monitoring more frequently as compared to when the drugs are administered as single agents. For elevated liver enzymes, interrupt KEYTRUDA and axitinib, and consider administering corticosteroids as needed. With the combination of KEYTRUDA and axitinib, Grades 3 and 4 increased alanine aminotransferase (ALT) (20%) and increased aspartate aminotransferase (AST) (13%) were seen at a higher frequency compared to KEYTRUDA alone. Fifty-nine percent of the patients with increased ALT received systemic corticosteroids. In patients with ALT ≥3 times upper limit of normal (ULN) (Grades 2-4, n=116), ALT resolved to Grades 0-1 in 94%. Among the 92 patients who were rechallenged with either KEYTRUDA (n=3) or axitinib (n=34) administered as a single agent or with both (n=55), recurrence of ALT ≥3 times ULN was observed in 1 patient receiving KEYTRUDA, 16 patients receiving axitinib, and 24 patients receiving both. All patients with a recurrence of ALT ≥3 ULN subsequently recovered from the event.
Immune-Mediated Endocrinopathies
Adrenal Insufficiency
KEYTRUDA can cause primary or secondary adrenal insufficiency. For Grade 2 or higher, initiate symptomatic treatment, including hormone replacement as clinically indicated. Withhold KEYTRUDA depending on severity. Adrenal insufficiency occurred in 0.8% (22/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.3%) reactions. Systemic corticosteroids were required in 77% (17/22) of patients; of these, the majority remained on systemic corticosteroids. Adrenal insufficiency led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.3% (8) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Hypophysitis
KEYTRUDA can cause immune-mediated hypophysitis. Hypophysitis can present with acute symptoms associated with mass effect such as headache, photophobia, or visual field defects. Hypophysitis can cause hypopituitarism. Initiate hormone replacement as indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Hypophysitis occurred in 0.6% (17/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.3%), and Grade 2 (0.2%) reactions. Systemic corticosteroids were required in 94% (16/17) of patients; of these, the majority remained on systemic corticosteroids. Hypophysitis led to permanent discontinuation of KEYTRUDA in 0.1% (4) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Thyroid Disorders
KEYTRUDA can cause immune-mediated thyroid disorders. Thyroiditis can present with or without endocrinopathy. Hypothyroidism can follow hyperthyroidism. Initiate hormone replacement for hypothyroidism or institute medical management of hyperthyroidism as clinically indicated. Withhold or permanently discontinue KEYTRUDA depending on severity. Thyroiditis occurred in 0.6% (16/2799) of patients receiving KEYTRUDA, including Grade 2 (0.3%). None discontinued, but KEYTRUDA was withheld in <0.1% (1) of patients.
Hyperthyroidism occurred in 3.4% (96/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (0.8%). It led to permanent discontinuation of KEYTRUDA in <0.1% (2) and withholding in 0.3% (7) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. Hypothyroidism occurred in 8% (237/2799) of patients receiving KEYTRUDA, including Grade 3 (0.1%) and Grade 2 (6.2%). It led to permanent discontinuation of KEYTRUDA in <0.1% (1) and withholding in 0.5% (14) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement. The majority of patients with hypothyroidism required long-term thyroid hormone replacement. The incidence of new or worsening hypothyroidism was higher in 1185 patients with HNSCC, occurring in 16% of patients receiving KEYTRUDA as a single agent or in combination with platinum and FU, including Grade 3 (0.3%) hypothyroidism. The incidence of new or worsening hypothyroidism was higher in 389 adult patients with cHL (17%) receiving KEYTRUDA as a single agent, including Grade 1 (6.2%) and Grade 2 (10.8%) hypothyroidism. The incidence of new or worsening hyperthyroidism was higher in 580 patients with resected NSCLC, occurring in 11% of patients receiving KEYTRUDA as a single agent as adjuvant treatment, including Grade 3 (0.2%) hyperthyroidism. The incidence of new or worsening hypothyroidism was higher in 580 patients with resected NSCLC, occurring in 22% of patients receiving KEYTRUDA as a single agent as adjuvant treatment (KEYNOTE-091), including Grade 3 (0.3%) hypothyroidism.
Type 1 Diabetes Mellitus (DM), Which Can Present With Diabetic Ketoacidosis
Monitor patients for hyperglycemia or other signs and symptoms of diabetes. Initiate treatment with insulin as clinically indicated. Withhold KEYTRUDA depending on severity. Type 1 DM occurred in 0.2% (6/2799) of patients receiving KEYTRUDA. It led to permanent discontinuation in <0.1% (1) and withholding of KEYTRUDA in <0.1% (1) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement.
Immune-Mediated Nephritis With Renal Dysfunction
KEYTRUDA can cause immune-mediated nephritis. Immune-mediated nephritis occurred in 0.3% (9/2799) of patients receiving KEYTRUDA, including Grade 4 (<0.1%), Grade 3 (0.1%), and Grade 2 (0.1%) reactions. Systemic corticosteroids were required in 89% (8/9) of patients. Nephritis led to permanent discontinuation of KEYTRUDA in 0.1% (3) and withholding in 0.1% (3) of patients. All patients who were withheld reinitiated KEYTRUDA after symptom improvement; of these, none had recurrence. Nephritis resolved in 56% of the 9 patients.
Immune-Mediated Dermatologic Adverse Reactions
KEYTRUDA can cause immune-mediated rash or dermatitis. Exfoliative dermatitis, including Stevens-Johnson syndrome, drug rash with eosinophilia and systemic symptoms, and toxic epidermal necrolysis, has occurred with anti– PD-1/PD-L1 treatments. Topical emollients and/or topical corticosteroids may be adequate to treat mild to moderate nonexfoliative rashes. Withhold or permanently discontinue KEYTRUDA depending on severity. Immune-mediated dermatologic adverse reactions occurred in 1.
Contacts
Merck Media Contacts:
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Moderna Media Contacts:
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