mRNA-4157 (V940) Personalized Cancer Vaccine: 79% RFS at 18 Months

mRNA-4157, also designated V940, is an individualized neoantigen therapy (INT) developed jointly by Moderna and Merck. It is designed to encode up to 34 patient-specific neoantigen peptides on a single mRNA construct, delivered in a lipid nanoparticle. The program is the first randomized Phase 2 readout of an individualized mRNA neoantigen vaccine in a solid-tumor adjuvant setting, and the efficacy signal in high-risk resected melanoma is the strongest to date in this modality [1].

The December 2023 presentation at the Society for Melanoma Research and subsequent ASCO updates established the KEYNOTE-942 data as a benchmark for personalized cancer vaccine research. The confirmatory Phase 3 INTerpath-001 trial began enrolling in 2023 and is a pivotal program for Moderna outside the infectious-disease franchise.

KEYNOTE-942 (also designated mRNA-4157-P201) is a randomized, open-label Phase 2b trial conducted across sites in the United States and Australia. It enrolled 157 patients with completely resected, high-risk cutaneous melanoma (AJCC 8th edition stage IIIB, IIIC, IIID, or IV). Patients were randomized 2:1 to receive mRNA-4157 plus pembrolizumab versus pembrolizumab alone [2].

• Population: resected high-risk melanoma (stage IIIB-IV)
• Randomization: 2:1 combination vs pembrolizumab monotherapy
• mRNA-4157 dose: 1 mg IM every 3 weeks, up to 9 doses
• Pembrolizumab: 200 mg IV every 3 weeks, up to 18 cycles
• Primary endpoint: recurrence-free survival (RFS)
• Secondary endpoints: distant metastasis-free survival (DMFS), overall survival, safety

Individualized neoantigen selection was performed by Modernas internal bioinformatics pipeline using patient-specific tumor and germline sequencing to identify up to 34 mutation-derived neoantigens predicted to bind the patients HLA class I and class II alleles.

The RFS hazard ratio of 0.56 translates to a 44% relative reduction in the risk of recurrence or death for the combination arm. The distant metastasis-free survival signal was numerically stronger (HR 0.35), suggesting the vaccine may particularly affect systemic dissemination [3]. At longer follow-up updates presented in 2024 and 2025, the RFS separation was maintained.

mRNA-4157 is a single mRNA construct that encodes a concatenated string of up to 34 patient-specific neoantigen peptide sequences. After intramuscular injection, the lipid nanoparticle delivers the mRNA to local antigen-presenting cells, which translate the construct, process the resulting polyprotein through the proteasome, and present the neoantigen-derived peptides on HLA class I and II molecules to CD8+ and CD4+ T cells [4].

The platform relies on three linked steps: (1) whole-exome and transcriptome sequencing of the patients tumor and matched normal tissue to identify somatic mutations, (2) in silico prediction of which mutated peptides will bind the patients specific HLA alleles and be presented at the cell surface, and (3) GMP synthesis and release of the individualized mRNA drug product.

Pembrolizumab is a humanized anti-PD-1 monoclonal antibody approved as adjuvant therapy after resection of high-risk melanoma. Blocking the PD-1 / PD-L1 axis lifts the brake on T-cell responses, but checkpoint blockade alone cannot create antigen-specific T-cell clones that do not already exist at useful frequency [5].

The mechanistic rationale for combining mRNA-4157 with pembrolizumab is complementary: the mRNA vaccine primes and expands neoantigen-specific T-cell clones, and pembrolizumab prevents those T cells from being functionally exhausted in the tumor microenvironment. The KEYNOTE-942 hazard ratio is consistent with this synergy hypothesis.

Each mRNA-4157 drug product is manufactured for a single patient. Moderna has reported a target turnaround time of approximately 6 to 8 weeks from tumor sample receipt to first dose, encompassing sequencing, neoantigen prediction, mRNA synthesis, lipid nanoparticle formulation, fill-finish, and quality release. This represents a significant operational departure from conventional biologic manufacturing [6].

Manufacturing scalability is one of the central open questions for the modality. Individualized mRNA production is well-suited to high-value oncology indications but presents a different cost and logistics profile than the off-the-shelf antigen products used in most peptide-vaccine development programs.

INTerpath-001 (NCT05933577) is the randomized Phase 3 confirmatory trial of mRNA-4157 plus pembrolizumab versus pembrolizumab alone in resected stage IIB, IIC, III, and IV cutaneous melanoma. Enrollment began in 2023. The trial expanded beyond KEYNOTE-942s stage IIIB-IV population to include earlier-stage IIB/IIC disease, reflecting a broader adjuvant opportunity. Primary endpoint is RFS; key secondary endpoints include DMFS and overall survival [7].

• FDA Breakthrough Therapy Designation: granted February 2023
• EMA PRIME designation: granted
• Phase 3 INTerpath-001: enrolling
• Additional Phase 3 programs: non-small cell lung cancer (INTerpath-009), renal cell carcinoma, bladder cancer
• Potential accelerated approval pathway depending on Phase 3 interim readouts

A firm approval date has not been publicly disclosed. Timing depends on Phase 3 event accrual and regulatory dialogue on whether Phase 2b data combined with Phase 3 interim results could support an accelerated submission in the melanoma indication.

The KEYNOTE-942 readout is the strongest randomized evidence to date that an individualized antigen-specific approach can improve outcomes on top of checkpoint blockade in a solid tumor. It validates the broader neoantigen concept that underpins both mRNA and peptide-based personalized cancer vaccine programs — and it raises the evidentiary bar against which competing platforms (long synthetic peptide vaccines, peptide-pulsed dendritic cells, shared-antigen vaccines) will be evaluated [8].