Moderna and Merck Report Strong 3-Year Data for mRNA-4157 in Combination With KEYTRUDA

At a median planned follow-up of the Phase 2b study at 34.9 months, mRNA-4157 (V940) in combination with KEYTRUDA reduced the risk of recurrence or death by 49% and the risk of distant metastasis or death by 62% compared to KEYTRUDA alone in these patients

The 2.5-year recurrence-free survival rate of mRNA-4157 (V940) in combination with KEYTRUDA was 74.8% as compared to 55.6% for KEYTRUDA alone, with the benefit observed across exploratory subgroups

The companies have initiated Phase 3 studies in patients with high-risk melanoma and non-small cell lung cancer, in addition to Phase 2 studies in patients with renal cell carcinoma and urothelial carcinoma and a Phase 2/3 study for cutaneous squamous cell carcinoma

Moderna , Inc. (NASDAQ:MRNA) and Merck (MRK), known as MSD outside of the United States and Canada, today announced the first presentation of results from a planned analysis from the Phase 2b randomized KEYNOTE-942/mRNA-4157-P201 study, a clinical trial evaluating mRNA-4157 (V940), an investigational individualized neoantigen therapy (INT), in combination with KEYTRUDA, Merck's anti-PD-1 therapy, in patients with resected high-risk melanoma (stage III/IV) following complete resection (n=157). With a median follow-up of approximately three years (34.9 months), adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA continued to demonstrate a clinically meaningful and durable improvement in recurrence-free survival (RFS), the primary endpoint of the study, reducing the risk of recurrence or death by 49% (HR [95% CI], 0.510 [0.288-0.906]; two-sided nominal p-value 0.019) compared with KEYTRUDA alone. mRNA-4157 (V940) in combination with KEYTRUDA also continued to demonstrate a meaningful improvement in distant metastasis-free survival (DMFS), a key secondary endpoint of the study, compared with KEYTRUDA alone, reducing the risk of developing distant metastasis or death by 62% (HR [95% CI], 0.384 [0.172-0.858], two-sided nominal p-value 0.015).

These data are being presented today during a rapid oral abstract session at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting (abstract #LBA9512). With an additional year of planned follow-up, these data build on the earlier analysis of the primary and key secondary endpoints of the study, presented in 2023. The 2.5-year recurrence-free survival rate of mRNA-4157 (V940) in combination with KEYTRUDA was 74.8%, as compared to 55.6% for KEYTRUDA alone, with the benefit observed across exploratory subgroups.

"We are encouraged by the latest results from the KEYNOTE-942/mRNA-4157-P201 study. These data highlight the sustained benefit in RFS and DMFS of mRNA-4157 (V940) as adjuvant treatment in combination with KEYTRUDA in people with resected high-risk melanoma. Importantly, this benefit was observed across various patient exploratory subgroups, reflecting the potential of mRNA-4157 (V940) for a broad range of these patients," said Kyle Holen, M.D., Moderna's Senior Vice President and Head of Development, Therapeutics and Oncology. "These findings reinforce our commitment to advancing this innovative treatment in collaboration with Merck, and we are dedicated to harnessing mRNA technology to potentially transform cancer therapy and improve patient outcomes."

"The sustained improvements in recurrence-free survival and distant metastasis-free survival observed at approximately three years in the KEYNOTE-942/mRNA-4157-P201 study provide further support of the potential of mRNA-4157 (V940) in combination with KEYTRUDA to help patients with resected high-risk melanoma," said Dr. Marjorie Green, senior vice president and head of oncology, global clinical development, Merck Research Laboratories. "We look forward to building on our legacy of turning breakthrough science into medicines that may have a meaningful impact on patients' lives as we continue advancing our broad clinical development program evaluating this novel approach with Moderna."

Additional efficacy and subgroup data

Data from an exploratory subgroup analysis of the Phase 2b KEYNOTE-942/mRNA-4157-P201 study in patients with resected high-risk melanoma (stage III/IV) following complete resection showed that improvement in RFS was observed with mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone regardless of tumor mutational burden (TMB) or programmed death-ligand 1 (PD-L1) status.

The RFS benefit of mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone was maintained across both TMB high (HR [95% CI], 0.564 [0.253-1.258]), TMB non-high (0.571 [0.245-1.331]), PD-L1 positive (0.471 [0.226-0.979]), PD-L1 negative (0.147 [0.034-0.630]), and circulating tumor DNA (ctDNA) negative (0.207 [0.091-0.470]) subpopulations. ctDNA positive HR was not estimable due to the small sample size. There were no significant associations between individual human leukocyte antigen (HLA) alleles and RFS observed for mRNA-4157 (V940) in combination with KEYTRUDA.

The exploratory endpoint of overall survival (OS) favored mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone, with a 2.5-year OS rate of 96.0% vs. 90.2%, respectively (HR [95% CI], 0.425 [0.114-1.584]).

The safety profile with mRNA-4157 (V940) in combination with KEYTRUDA in KEYNOTE-942/mRNA-4157-P201 remains consistent with the primary analysis. The most common adverse events attributed to mRNA-4157 (V940) in combination with KEYTRUDA were fatigue (60.6%), injection site pain (56.7%), and chills (49.0%). The majority of the adverse events attributed to mRNA-4157 (V940) were Grade 1-2, with fatigue being the most common Grade 3 event and no Grade 4-5 events. Immune-related adverse events occurred in 37.5% of patients receiving the combination and 36% receiving KEYTRUDA alone.

Ongoing clinical development programs

Merck and Moderna have initiated Phase 3 randomized clinical trials evaluating mRNA-4157 (V940) in combination with KEYTRUDA as an adjuvant treatment in patients with resected high-risk (Stage IIB-IV) melanoma (INTerpath-001, NCT05933577) and non-small cell lung cancer (INTerpath-002, NCT06077760). Both trials are actively enrolling.

In 2024, Merck and Moderna also initiated a two-part Phase 2/3 randomized clinical trial evaluating mRNA-4157 (V940)in combination with KEYTRUDA as neoadjuvant and adjuvant treatment in patients with resectable locally advanced Stage II-IV (M0) cutaneous squamous cell carcinoma (INTerpath-007, NCT06295809), a Phase 2 randomized clinical trial evaluating mRNA-4157 (V940) in combination with KEYTRUDA as adjuvant treatment in patients with intermediate-high-risk, high-risk, or M1 no evidence of disease renal cell carcinoma (INTerpath-004, NCT06307431), and a Phase 2 randomized clinical trial evaluating mRNA-4157 (V940) in combination with KEYTRUDA as adjuvant treatment in patients with high-risk muscle-invasive urothelial carcinoma post-radical resection (INTerpath-005, NCT06305767).

About mRNA-4157 (V940)

mRNA-4157 (V940) is a novel investigational messenger RNA (mRNA)-based individualized neoantigen therapy (INT) consisting of a synthetic mRNA coding for up to 34 neoantigens that is designed and produced based on the unique mutational signature of the DNA sequence of the patient's tumor. Upon administration into the body, the algorithmically derived and RNA-encoded neoantigen sequences are endogenously translated and undergo natural cellular antigen processing and presentation, a key step in adaptive immunity.

Individualized neoantigen therapies are designed to train and activate an antitumor immune response by generating specific T-cell responses based on the unique mutational signature of a patient's tumor. KEYTRUDA is an immunotherapy that works by increasing the ability of the body's immune system to help detect and fight tumor cells. As previously announced from the Phase 2b KEYNOTE-942/mRNA-4157-P201 trial evaluating patients with high-risk stage III/IV melanoma, combining mRNA-4157 (V940) with KEYTRUDA may provide a meaningful benefit over KEYTRUDA alone.

About KEYNOTE-942/mRNA-4157-P201 (NCT03897881)

KEYNOTE-942 is an ongoing randomized, open-label Phase 2b trial that enrolled 157 patients with high-risk stage III/IV melanoma. Following complete surgical resection, patients were assigned 2:1 (stratified by stage) to receive mRNA-4157 (V940) (1 mg every three weeks for nine doses) and KEYTRUDA (200 mg every three weeks up to 18 cycles [for approximately one year]) versus KEYTRUDA alone for approximately one year until disease recurrence or unacceptable toxicity. The primary endpoint is RFS, defined as the time from first dose of KEYTRUDA until the date of first recurrence (local, regional, or distant metastasis), a new primary melanoma, or death from any cause in the intention-to-treat population. Secondary endpoints include distant metastasis-free survival and safety, and exploratory endpoints include distribution of TMB expression in baseline tumor samples across study arms and their association with the primary RFS endpoint. The KEYNOTE-942 trial is ongoing to collect additional translational data, and an additional 100 patients are currently being enrolled.

Key eligibility criteria for the trial included: patients with resectable cutaneous melanoma metastatic to a lymph node and at high risk of recurrence, patients with complete resection within 13 weeks prior to the first dose of KEYTRUDA, patients were disease free at study entry (after surgery) with no loco-regional relapse or distant metastasis and no clinical evidence of brain metastases, patients had a formalin fixed paraffin embedded (FFPE) tumor sample available suitable for sequencing, Eastern Cooperative Oncology Group (ECOG) Performance Status 0 or 1 and patients with normal organ and marrow function reported at screening.

About Melanoma

Melanoma, the most serious form 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 more than 100,000 new cases of melanoma diagnosed and more than 8,000 deaths resulting from the disease in the U.S. in 2024.

About KEYTRUDA^� (pembrolizumab) injection, 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 1,600 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.