Moderna, Inc. (Nasdaq: MRNA) and Merck (MRK) announced the first presentation of detailed results from the Phase 2b KEYNOTE-942/mRNA-4157-P201 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). In the overall intention-to-treat population, adjuvant treatment with mRNA-4157 (V940) in combination with KEYTRUDA demonstrated a statistically significant and clinically meaningful improvement in recurrence-free survival (RFS), and reduced the risk of recurrence or death by 44% (HR=0.56 [95% CI, 0.309-1.017]; one-sided p value=0.0266) compared with KEYTRUDA alone.
These findings will be presented during the American Association for Cancer Research (AACR) Annual Meeting 2023 plenary session and press conference (Abstract #CT001). Data from a subgroup analysis of KEYNOTE-942/mRNA-4157-P201 (Abstract #CT224) evaluating mRNA-4157 (V940) in combination with KEYTRUDA among patients based on tumor mutational burden (TMB) status will also be presented.
“Today’s results provide further encouragement for the potential of mRNA as an individualized neoantigen therapy to positively impact patients with high-risk resected melanoma,” said Dr. Kyle Holen, M.D. Moderna’s Senior Vice President and Head of Development, Therapeutics and Oncology. “The profound observed reduction in the risk of recurrence-free survival suggests this combination may be a novel means of potentially extending the lives of patients with high-risk melanoma. We look forward to starting the Phase 3 melanoma trial soon and expanding testing to lung cancer and beyond.”
“Data from KEYNOTE-942 provide evidence for the potential of mRNA-4157 (V940) in combination with KEYTRUDA to improve recurrence-free survival when given to patients with resected high-risk melanoma,” said Dr. Eliav Barr, senior vice president, head of global clinical development and chief medical officer, Merck Research Laboratories. “These data support the potential of mRNA-4157 (V940) in combination with KEYTRUDA to help fight melanoma earlier and warrant investigation of the combination in a larger Phase 3 trial. We also look forward to studying mRNA-4157 (V940) and KEYTRUDA in a variety of other early-stage cancers.”
Based on data from KEYNOTE-942/mRNA-4157-P201, the U.S. Food and Drug Administration and European Medicines Agency granted Breakthrough Therapy Designation and the PRIME scheme, respectively, for mRNA-4157 (V940) in combination with KEYTRUDA for the adjuvant treatment of patients with high-risk melanoma following complete resection. Additional data from KEYNOTE-942/mRNA-4157-P201 will be shared at an upcoming medical meeting and published in a peer-reviewed publication. The companies previously announced positive data from this study in December 2022.
Additional efficacy and safety data from KEYNOTE-942/mRNA-4157-P201 (Abstract #CT001)
In KEYNOTE-942/mRNA-4157-P201, 107 patients received mRNA-4157 (V940) in combination with KEYTRUDA and 50 patients were treated with KEYTRUDA alone. Recurrence or death was reported in 22.4% of patients (n=24/107) in the combination arm compared with 40% of patients (n=20/50) who received KEYTRUDA alone with a median follow-up of 23 and 24 months, respectively. The 12-month RFS rate was 83.4% (95% CI, 74.7-89.3) and 77.1% (95% CI, 62.5-86.6) in the combination and control arms, respectively. The 18-month RFS rate was 78.6% (95% CI, 69.0-85.6) and 62.2% (95% CI, 46.9-74.3) in the combination and control arms, respectively.
Adverse events reported with mRNA-4157 (V940) in KEYNOTE-942 were consistent with those previously observed in a Phase 1 clinical trial. The safety profile of KEYTRUDA was consistent with findings from previous studies. The number of patients reporting treatment related Grade ≥ 3 adverse events were similar between the arms (25% vs 18%, respectively). The most common adverse events of any grade attributed to either mRNA-4157 (V940) or the combination of mRNA-4157 (V940) and KEYTRUDA were fatigue (60.6%), injection site pain (55.8%) and chills (50.0%).
TMB subgroup analysis from KEYNOTE-942/mRNA-4157-P201 (#CT224)
Data from an exploratory subgroup analysis of KEYNOTE-942/mRNA-4157-P201 showed that improvement in RFS was observed with mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone regardless of TMB status. TMB was assessed using tumor biopsies analyzed by whole exome sequencing (WES) and whole transcriptome sequencing. According to the established WES genomic score for KEYTRUDA, TMB high was defined as ≥10 mut/Mb (175 mut/exome) assessed using the FoundationOne CDx assay.
The RFS benefit of mRNA-4157 (V940) in combination with KEYTRUDA compared to KEYTRUDA alone observed in the intention-to-treat population was maintained across both TMB high (HR=0.65; 95% CI: 0.284-1.494) and TMB non-high (HR=0.59; 95% CI: 0.243-1.425) subpopulations. The association between TMB and mRNA-4157 (V940) treatment effect will be further explored in upcoming planned studies.
About mRNA-4157 (V940)
mRNA-4157 (V940) is a novel investigational messenger ribonucleic acid (mRNA)-based individualized neoantigen therapy1 consisting of a single 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 prime the immune system so that a patient can generate a tailored antitumor response specific to their tumor mutation signature. mRNA-4157 (V940) is designed to stimulate an 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. Based on early clinical studies, combining mRNA-4157 (V940) with KEYTRUDA may potentially provide an additive benefit and enhance T cell-mediated destruction of tumor cells.
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 randomized 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.
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.
