These study results are the first to demonstrate randomized evidence that a personalized neoantigen approach could be beneficial for patients with cancer.
The combination of the personalized mRNA vaccine mRNA-4157 with pembrolizumab (Keytruda; Merck & Co) as an adjuvant therapy for patients with resected high-risk melanoma was shown to significantly prolong recurrence free survival (RFS) compared to pembrolizumab alone, according to researchers at the Perlmutter Cancer Center at NYU Langone Health in a presentation at the AACR Annual Meeting 2023.1
Additionally, the randomized, open-label phase 2 mRNA-4157-P201/Keynote-942 trial (NCT03897881) showed that the combination therapy reduced the risk of death by 44% when compared to pembrolizumab alone without increasing clinically meaningful adverse events (AEs).1
“Our phase 2b study shows that a neoantigen mRNA vaccine, when used in combination with pembrolizumab, resulted in prolonged time without recurrence or death compared with pembrolizumab alone,” said study senior investigator Jeffrey Weber, MD, PhD, the deputy director of the Perlmutter Cancer Center, in a press release.2
Prior research has shown that targeting mutation-derived epitopes (neoantigens) by T cells can drive anti-tumor immune responses. The mRNA-4157 vaccine used in the Keynote-942 trial is a novel personalized cancer vaccine that can encode up to 34 patient-specific tumor neoantigens.1
These study results are the first to demonstrate randomized evidence that a personalized neoantigen approach could be beneficial for patients with cancer. Additionally, the combination therapy is the first to show RFS improvement over adjuvant standard of care in resected high-risk melanoma. Based on these results, the investigators noted that a phase 3 study will be initiated in patients with melanoma.1
During the trial, eligibility for patient enrollment was based on whether they had completely resected, high-risk cutaneous melanoma. Recruited patients were then stratified by stage and randomly assigned 2:1 to receive mRNA-4157 in combination with pembrolizumab or pembrolizumab alone.1
The mRNA-4157 vaccine at 1 mg dose was administered intramuscularly every 3 weeks for a total of 9 doses, and pembrolizumab at 200 mg was administered intravenously every 3 weeks for up to 18 cycles. Additionally, safety was a secondary endpoint in the trial, with RFS in the overall intention-to-treat population the primary endpoint.
The primary analysis for RFS occurred following patients completing a minimum of 12 months in the trial, with at least 40 RFS events observed. Further, the study was designed with 80% power to detect a hazard ratio (HR) of 0.5 with an overall 1-sided type I error of 0.1 when a total of 40 RFS events were observed by the investigators.1
In the combination treatment arm, 107 patients received the combination therapy, while 50 patients were treated in the pembrolizumab monotherapy treatment arm. At a median follow-up point of 101 and 105 weeks, recurrence or death was reported in 24 of 107 patients (22.4%) in the combination arm, while in the monotherapy arm, it was 20 of 50 patients (40%). The RFS rates (95% CI) at 18 months were 78.6% (69.0%, 85.6%) in the combination arm vs 62.2% (46.9%, 74.3%) in the monotherapy arm. The combination therapy showed a reduction in the risk of recurrence or death by 44% (HR = 0.561; 95% CI: (0.309, 1.017), with a stratified log-rank test 1-sided p-value of 0.0266.1
The majority of treatment related AEs (TRAEs) reported were grade 1/2, with the number of patients reporting TRAEs of grade 3 or more at generally a similar rate between each arm (25% vs 18%, respectively). Related to mRNA-4157, the most common grade 3 event was fatigue, while no grade 4 or 5 events were reported. Additionally, there were no potentiation of immune-mediated AEs observed with the addition of mRNA-4157 to pembrolizumab.1