Compared with pembrolizumab alone, the combination treatment showed stronger recurrence-free survival and distant metastasis-free survival in patients with resected high-risk stage III or IV melanoma.
According to results from the phase 2b clinical trial KEYNOTE-942 (NCT03897881, also referred to as KEYNOTE-942/mRNA-4157-P201), the investigational individualized neoantigen therapy (INT), mRNA-4157 (V940; Moderna), in combination with pembrolizumab (Keytruda; Merck), demonstrated a clinically meaningful and durable improvement in recurrence-free survival (RFS) in patients with resected high-risk stage III or IV melanoma following complete resection. The analysis results were presented at the 2024 American Society of Clinical Oncology (ASCO) Annual Meeting, taking place in Chicago, Illinois from May 31 to June 4. Prior findings were presented at the American Association for Cancer Research (AACR) Annual Meeting in April 2023, as well as the ASCO Annual Meeting in June 2023.1-3
mRNA-4157 is a novel investigational mRNA-based INT that is made up of a synthetic mRNA coding for up to 34 neoantigens and is designed and produced based on the individual DNA sequence of a patient’s tumor. When administered, the RNA-encoded neoantigen sequences are internally translated and undergo a significant step in adaptive immunity, natural cellular antigen processing and presentation. INTs are intended to train and activate an anti-tumor immune response by generating specific T-cell responses based on the individual patient’s tumor mutation signature.1
Pembrolizumab is an anti-programmed death receptor-1 (PD-1) therapy that increases the ability of a patient’s immune system to help detect and fight tumor cells. It also blocks the interaction between PD-1 as well as its ligands—PD-L1 and PD-L2—and activates T lymphocytes which can affect both tumor cells and healthy cells. Researchers speculated that mRNA-4157 in combination with pembrolizumab may provide benefit to patients with high-risk stage III or IV melanoma over pembrolizumab alone.1
Trial Name: An Efficacy Study of Adjuvant Treatment With the Personalized Cancer Vaccine mRNA-4157 and Pembrolizumab in Participants With High-Risk Melanoma (KEYNOTE-942)
ClinicalTrials.gov ID: NCT03897881
Sponsor: ModernaTX, Inc.
Completion Date (Estimated): September 9, 2029
KEYNOTE-942 is an ongoing randomized, open-label phase 2b trial investigating a combination of mRNA-4157 patients with high-risk stage III or IV melanoma. A total of 157 patients were enrolled, all of whom had completed surgical resection. Patients were randomly assigned to receive up to 9 1-mg doses of mRNA-4157 every 21 days plus 200 mg of intravenous pembrolizumab every 21 days (up to 18 total cycles or approximately 1 year of treatment), or pembrolizumab alone (same dosage and administration method) for about 1 year or until disease recurrence or unacceptable toxicity.1,4
The trial’s primary end point is a new primary melanoma, RFS up to 5 years (defined as the time from first pembrolizumab dose until the date of first recurrence, either local, regional, or distant metastasis), or death from any cause in the intention-to-treat population. Secondary end points include distant metastasis-free survival and safety, with exploratory end points include the distribution of tumor mutational burden (TMB) expression in baseline tumor samples across all study arms, as well as their association with the primary RFS end point.1,4
According to the analysis findings, patients who received treatment with mRNA-4157 with pembrolizumab had reduced risk of recurrence or death by approximately 49% (HR [95% CI], 0.510 [0.288–0.906]; 2-sided nominal p-value 0.019) compared with those who received pembrolizumab alone at a 34.9 month follow-up. Additionally, the combination treatment had also demonstrated a meaningful improvement in distant metastasis-free survival (DMFS) and reduced the risk of death or the development of distant metastasis by approximately 62% (HR [95% CI], 0.384 [0.172–0.858], 2-sided nominal p-value 0.015).1
“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 [pembrolizumab] 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, MD, senior vice president and head of Development, Therapeutics and Oncology, Moderna, in the news release. “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.”1
Additionally, the RFS benefit of mRNA-4157 plus pembrolizumab compared with pembrolizumab on its own 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 negative (0.207 [0.091–0.470]) subpopulations. Further, overall survival (OS) was better in the combination treatment group (96.0%) than in the pembrolizumab alone group (90.2%) at 2.5 years (HR [95% CI], 0.425 [0.114–1.584]).1
In KEYNOTE-942, the safety profile of mRNA-4157 remains consistent with what was demonstrated in the primary analysis. The most common adverse events (AEs) reported by patients receiving the combination treatment includes fatigue (60.6%), injection site pain (56.7%), and chills (49.0%). Additionally, most AEs resulting from mRNA-4157 treatment were grades 1 and 2 in severity, with fatigue being the most common grade 3 AE. There were no AEs that were grades 4 or 5 in severity reported by participants. Immune-related AEs were reported by approximately 37.5% of patients who received the combination treatment, and 36% of those who received pembrolizumab alone.1
In earlier reports of the KEYNOTE-942 trial, AEs were consistent with those that were observed in the phase 1 clinical trial, and the safety profile of pembrolizumab was consistent with previous studies’ findings. Between the 2 treatment arms, the number of patients who reported grade 3 or higher AEs were similar (mRNA-4157 plus pembrolizumab: 25%; pembrolizumab alone: 18%). Additionally, the most common AEs of any grade—resulting from either mRNA-4157 or the combination treatment—were fatigue (60.6%), injection site pain (55.8%), and chills (50.0%).2,3
“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 [pembrolizumab] to help patients with resected high-risk melanoma,” said Marjorie Green, MD, senior vice president and head of oncology, global clinical development, Merck Research Laboratories, in the news release. “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.”1
According to the investigators, the following randomized clinical trials evaluating mRNA-4157 with pembrolizumab are currently ongoing:1
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