mRNA-4157/V940 in combination with pembrolizumab improved recurrence-free survival in patients with high-risk melanoma.
In the adjuvant setting for high-risk melanoma, findings from the phase 2b mRNA-4157-P201/KEYNOTE-942 trial (NCT03897881) that evaluated mRNA-4157/V940 in combination with pembrolizumab (Keytruda) showed improved recurrence-free survival (RFS) compared with pembrolizumab alone.1
The findings, which were presented during the American Association for Cancer Research Annual Meeting 2023, showed that the overall 18-month RFS rate was 78.6% (95% CI, 69.0%-85.6%) with the combination vs 62.2% (95% CI, 46.9%-74.3%) with pembrolizumab alone, leading to a 44% reduction in the risk of disease recurrence or death (HR, 0.561; 95% CI, 0.309-1.017; 1-sided P = .0266).
These data, which were presented by senior author Jeffrey S. Weber, MD, PhD, were found to be statistically significant and clinically meaningful.
“For the first time in a randomized study with a control arm, the addition of an mRNA neoantigen vaccine appeared to augment the benefit of PD-1 blockade without adding significant high-grade toxicity,” Weber said in a press release.2 Weber is deputy director of the New York University (NYU) Langone’s Perlmutter Cancer Center and Laura and Isaac Perlmutter Professor of Oncology at NYU Grossman School of Medicine, both in New York, New York. “This study is extraordinarily important because it gives hope that this novel strategy will provide clinical benefit.”
In February 2023, the FDA granted a breakthrough therapy designation to mRNA-4157/ V940 in combination with pembrolizumab for the adjuvant treatment of patients with high-risk melanoma following complete resection.3 As part of the trial, patients’ normal tissue and tumor tissue samples were extracted and analyzed, followed by sequencing to identify mutations in protein neoantigen. The vaccine is designed to target a patient’s unique tumor mutations, with individualized mRNA encoding for up to 34 neoantigens.
In the mRNA-4157-P201/KEYNOTE-942 study, patients were randomly assigned 2:1 to receive mRNA-4157 at 1 mg intramuscularly every 3 weeks for up to 9 doses plus pembrolizumab at 200 mg intravenously every 3 weeks for up to 18 cycles (n = 107) or pembrolizumab alone (n = 50). Patients were stratified by disease stage.
The primary end point was RFS, with secondary end points of safety, tolerability, and distant metastasis–free survival. Follow-up for RFS was up to 3 years following the first pembrolizumab dose.
The study had 80% power to detect an HR of 0.5, with at least 40 RFS events and a 1-sided α of 0.1. The median follow-up was 23 months and 24 months for the combination and pembrolizumab-alone arms, respectively.
To be eligible for enrollment, patients had to have stage IIIB, IIIC, IIID, or IV cutaneous melanoma and have undergone complete surgical resection within 13 weeks before the first pembrolizumab dose. Patients must have been disease free at study entry, had an ECOG performance status of 0 or 1, and had tissue available for next-generation sequencing.
Additional findings showed that the 12-month RFS rate was 83.4% with the combination and 77.1% with single-agent pembrolizumab. Disease recurrence or death occurred in 22.4% of patients on the combination regimen and 40% of those on the monotherapy arm at a median follow-up of 101 and 105 weeks, respectively.
Regarding safety, the combination was found to be well tolerated and consistent with the safety profiles of each agent alone. Treatment-related adverse effects (AEs) that were grade 3 or higher occurred in 25% of patients on mRNA-4157/pembrolizumab vs 18% of those on pembrolizumab monotherapy; serious AEs occurred in 14.4% and 10% of patients, respectively.
Grade 3 or higher immune-mediated AEs were reported in 10.6% and 14% of patients on the combination and pembrolizumab alone, respectively.
Grade 3 or higher mRNA-4157–related AEs that occurred in more than 20% of patients were fatigue (4.8%), pyrexia (1%), and myalgia (1%). Grade 3 or higher pembrolizumab-related AEs in more than 20% of patients were fatigue (5.8%) and diarrhea (1.9%).
Tumor mutational burden (TMB), tumor inflammation score (TIS), and PD-L1 expression were measured at baseline. The TMB threshold that was used was 175 mutations per exome (10 muts/Mb per FoundationOne CDx).
For TIS, RNA sequencing was performed to identify tumor transcriptome, and the TIS computed weighted average was 18 genes used in the gene expression profile score. The cutoff for TIS was based on median values across the entire study population.
FFPE biopsy results were stained for PD-L1, and the combined positivity score (CPS) across tumor and infiltrating cells was used. A CPS of 1 or more was identified as a positive result.
It was noted that patients randomly assigned to the combination at baseline were more likely to have higher TMB vs those who were on the PD-1 inhibitor alone. No difference in PD-L1 expression or TIS was observed in the 2 groups.
The RFS benefit with the combination vs single-agent pembrolizumab was observed in TIS-high tumors (HR, 0.576; 95% CI, 0.209-1.591) and TIS-nonhigh tumors (HR, 0.528; 95% CI, 0.253-1.101). In PD-L1–positive tumors, the HR was 0.485 (95% CI, 0.226-1.039) and 0.162 (95% CI, 0.038-0.685) in PD-L1–negative tumors.
Limitations of the study were that KEYNOTE-942 was a phase 2b trial with “modest statistical power” and that the neoantigen vaccine is based on DNA and RNA sequencing of tissue.
Because of this, it may not be an optimal therapy for those with earlier-stage disease, because there may be a lack of tissue available for patients with tumors smaller in size. A phase 3 trial of the combination in this patient population is planned.