A Phase 2, Randomized, Double-Blind, Placebo- and Active-Comparator-Controlled Clinical Study of V940 (mRNA-4157) Plus Pembrolizumab Versus Placebo Plus Pembrolizumab in Participants With First-Line Advanced Melanoma (INTerpath-012)

Overview

V940 (mRNA-4157) is an individualized, lipid‑nanoparticle–formulated mRNA cancer vaccine designed to be custom‑manufactured for each patient and given with pembrolizumab in the adjuvant setting after tumor resection. The most mature data are in resected high‑risk melanoma from the randomized phase 2b KEYNOTE‑942 trial, with additional phase 3 programs underway in melanoma and non‑small cell lung cancer (NSCLC). (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Tumor and normal DNA/RNA are sequenced to identify patient‑specific neoantigens; a computational pipeline selects up to 34 neoantigen sequences that are encoded on a single mRNA construct and delivered intramuscularly in lipid nanoparticles. The goal is to prime de novo, tumor‑specific T‑cell responses that synergize with PD‑1 blockade. (springermedicine.com)

Efficacy

Resected high‑risk melanoma (stage IIIB–IV), KEYNOTE‑942 (phase 2b; mRNA‑4157 + pembrolizumab vs pembrolizumab alone; n=157)

• Primary analysis (Lancet 2024): Recurrence‑free survival (RFS) favored the combination (HR for recurrence or death 0.561; 95% CI 0.309–1.017). Eighteen‑month RFS was 79% with the combination vs 62% with pembrolizumab alone; events 22% vs 40%. Distant metastasis‑free survival (DMFS) was also improved. (hmsom.elsevierpure.com)
• Planned 3‑year update (ASCO 2024): With median follow‑up ~34.9 months, the combination reduced risk of recurrence or death by 49% (HR 0.51; 95% CI 0.288–0.906) and reduced risk of distant metastasis or death by 62% (HR 0.384; 95% CI 0.172–0.858). The 2.5‑year RFS rate was 74.8% vs 55.6%. (ascopubs.org)

Ongoing pivotal trials

• Melanoma (adjuvant), INTerpath‑001 (phase 3): Pembrolizumab + V940 vs pembrolizumab + placebo; primary endpoint RFS; target n≈1089; enrollment ongoing (NCT05933577). (ascopubs.org)
• NSCLC (adjuvant), INTerpath‑002 (phase 3): Completely resected stage II–IIIB (N2) NSCLC after adjuvant chemotherapy; V940 + pembrolizumab vs placebo + pembrolizumab; primary endpoint DFS; enrollment ongoing (NCT06077760). (aacrjournals.org)

Additional development

• Renal cell carcinoma (adjuvant), INTerpath‑004 (phase 2; design/TPs): Randomized, double‑blind V940 + pembrolizumab vs placebo + pembrolizumab; recruitment ongoing (NCT06307431). (ascopubs.org)

Safety

• In KEYNOTE‑942 (Lancet 2024), most treatment‑related adverse events (AEs) were grade 1–2. Grade ≥3 treatment‑related AEs occurred in 25% with the combination vs 18% with pembrolizumab alone; immune‑mediated AE frequency was similar (36% in each arm). No V940‑related grade 4–5 events were reported. Common V940‑related AEs included fatigue, injection‑site pain, and chills. (hmsom.elsevierpure.com)
• At the 3‑year update, the safety profile remained consistent with earlier analyses. (newswire.com)

Further reading

• Lancet primary report of KEYNOTE‑942 (phase 2b): Weber JS et al., 2024. https://pubmed.ncbi.nlm.nih.gov/38246194/ (pubmed.ncbi.nlm.nih.gov)
• ASCO 2024 late‑breaking abstract (3‑year update) for KEYNOTE‑942: https://ascopubs.org/doi/10.1200/JCO.2024.42.17_suppl.LBA9512 (ascopubs.org)
• ASCO 2024 melanoma phase 3 design (INTerpath‑001): https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.TPS9616 (ascopubs.org)
• AACR/Cancer Research abstract of NSCLC phase 3 design (INTerpath‑002): https://aacrjournals.org/cancerres/article/84/7_Supplement/CT281/742595 (aacrjournals.org)
• JCO abstract of NSCLC phase 3 design (INTerpath‑002): https://ascopubs.org/doi/abs/10.1200/JCO.2024.42.16_suppl.TPS8116 (ascopubs.org)
• JCO abstract of RCC phase 2 design (INTerpath‑004): https://ascopubs.org/doi/10.1200/JCO.2025.43.5_suppl.TPS610 (ascopubs.org)
• AACR news release (trial presentation overview; background on neoantigen approach): https://www.aacr.org/about-the-aacr/newsroom/news-releases/adding-a-personalized-mrna-cancer-vaccine-to-immunotherapy-may-prolong-recurrence-free-survival-in-patients-with-high-risk-melanoma/ (aacr.org)

Notes - V940 remains investigational; no regulatory approvals as of October 7, 2025. Evidence of benefit comes from a randomized phase 2b melanoma study with ongoing confirmatory phase 3 trials. (pubmed.ncbi.nlm.nih.gov)

Last updated: Oct 2025

Inclusion Criteria:

The main inclusion criteria include but are not limited to the following:

* Has unresectable and histologically confirmed Stage III or IV cutaneous melanoma per American Joint Committee on Cancer (AJCC) Eighth Edition guidelines.

* Has been untreated for melanoma except if participant received prior adjuvant or neoadjuvant therapy with targeted therapy or immunotherapy (such as anti-cytotoxic T-lymphocyte-associated protein \[CTLA-4\], anti-programmed cell death 1 protein \[PD-1\] therapy or interferon), and only if relapse did not occur within 12 months after treatment discontinuation.

* Have documentation of serine/threonine-protein kinase B-raf (BRAF) V600-activating mutation status or had BRAF V600 mutation testing per local institutional standards during the screening period (participants with BRAF mutation positive melanoma as well as BRAF wild-type or unknown are eligible).

* Have the presence of at least 1 measurable lesion by computed tomography (CT) or magnetic resonance imaging (MRI) per Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1) as determined by the local site investigator/radiology assessment.

* Provides tumor tissue (preferably from a metastatic site and, if not available, from the primary tumor) that is suitable for next generation sequencing and biomarker analysis as required for this study.

* Participants with human immunodeficiency virus (HIV) must have well controlled HIV on antiretroviral therapy (ART).

* Participants who are hepatitis B surface antigen (HBsAg) positive are eligible if they have received hepatitis B virus (HBV) antiviral therapy for at least 4 weeks, and have undetectable HBV viral load prior to randomization.

* Participants with history of hepatitis C virus (HCV) infection are eligible if HCV viral load is undetectable at screening.

Exclusion Criteria:

The main exclusion criteria include but are not limited to the following:

* Has clinically significant heart failure, defined as New York Heart Association class III or IV, within the past 6 months, unless the disease is well controlled in the opinion of the investigator.

* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease.

* Has ocular or mucosal melanoma.

* Received transfusion of blood products (including platelets or red blood cells) or administration of colony-stimulating factors (including granulocyte colony-stimulating factor, granulocyte macrophage colony-stimulating factor, or recombinant erythropoietin) within 2 weeks of the Screening blood sample (including the blood sample for V940 generation).

* Received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent, or with an agent directed to another stimulatory or coinhibitory T-cell receptor (eg, CTLA-4, lymphocyte activation gene 3 \[LAG-3\], tumor necrosis factor receptors \[OX-40 or CD137\]), with some exceptions.

* Received prior systemic anticancer therapy for melanoma before randomization, with some exceptions.

* Received prior radiotherapy within 2 weeks of start of study intervention or has ongoing radiation related toxicities.

* Received a live or live-attenuated vaccine within 30 days before the first dose of study intervention.

* Received prior treatment with another universal or personalized cancer vaccine.