Messenger ribonucleic acid (mRNA)-4157 is an innovative approach to personalized neoantigen therapy. It utilizes mRNA to enhance the body’s natural immune response against tumor cells by targeting specific mutations unique to each patient.
Key findings from the phase 2 mRNA-4157-P201 (KEYNOTE-942) trial, with a median planned follow-up of 23 months, revealed that patients with completely resected high-risk stage IIIB–IV cutaneous melanoma who received a combination of mRNA-4157 and pembrolizumab experienced significantly prolonged recurrence-free survival (RFS) and distant metastasis-free survival (DMFS) compared to those who received pembrolizumab alone.
The study design involved patients being allocated in a 2:1 ratio to receive mRNA-4157 (1 mg intramuscularly, maximum of 9 doses) in combination with pembrolizumab (200 mg intravenously, maximum of 18 cycles) or pembrolizumab alone. The primary end point of this study was the investigator’s assessment of RFS, and secondary end points included DMFS and safety. This planned analysis was conducted when the last randomly assigned patient had a follow-up of ≥2 years.
Additionally, translational subgroup analyses were performed, where human leukocyte antigens (HLA) genotypes were examined through exome sequencing of DNA obtained from peripheral blood mononuclear cells. Formal testing was not conducted for RFS and DMFS; the reported P values are descriptive and nominal.
Following an additional year of observation (data cutoff, November 3, 2023; median [range], 34.9 [25.1–51.0] months) after the primary analysis, there were minimal new occurrences. The benefit of RFS in the combination treatment compared to pembrolizumab alone was sustained, showing a 49% risk reduction in recurrence and/or death (hazard ratio [HR], 95% CI, 0.510 [0.288-0.906]; 2-sided nominal P value, .019).
The 2.5-year RFS rate for the combination treatment versus pembrolizumab alone was 74.8% versus 55.6%. Additionally, the combination treatment also demonstrated a clinically significant and lasting improvement in DMFS compared to pembrolizumab alone (HR [95% CI], 0.384 [0.172-0.858], 2-sided nominal P value, .0154).
Overall survival (OS) favored the combination treatment over pembrolizumab alone, with a 2.5-year OS rate of 96.0% versus 90.2% (HR [95% CI], 0.425 [0.114-1.584]). The benefit of combination therapy compared to pembrolizumab alone in terms of RFS was consistent across various subgroups, including those with high tumor mutational burden (TMB), non-high TMB, programmed death ligand 1 (PD-L1)-positive, PD-L1–negative, and circulating tumor DNA (ctDNA)-negative.
However, the HR for the ctDNA-positive subgroup could not be estimated. No significant correlations were found between specific HLA alleles and RFS in either treatment arm. Interestingly, having maximal heterozygosity at HLA class I genotype loci (A, B, C) was associated with improved RFS compared to homozygosity for ≥1 locus in the pembrolizumab arm but not in the combination therapy arm.
The investigational mRNA-4157 was well tolerated, and the safety profile of combination therapy was consistent with previous findings, showing no increased risk of immune-related adverse events.
This analysis, which included a median follow-up of around 3 years, revealed enduring and substantial long-term advantages in RFS and DMFS when using mRNA-4157 combined with pembrolizumab instead of pembrolizumab alone.
Furthermore, the combined treatment was indicated to potentially improve OS. Findings from HLA and translational subgroup assessments suggest that mRNA-4157 plus pembrolizumab might benefit a broader range of patients than pembrolizumab alone.
Weber JS, Khattak MA, Carlino MS, et al. Individualized neoantigen therapy mRNA-4157 (V940) plus pembrolizumab in resected melanoma: 3-year update from the mRNA-4157-P201 (KEYNOTE-942) trial. Chicago, IL, & online: presented at 2024 ASCO Annual Meeting; June 3, 2024: abstract LBA9512.
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