Patients with resected stage III/IV melanoma remain at substantial risk for recurrence despite advances in adjuvant immunotherapy. Personalized neoantigen mRNA vaccines represent a next-generation strategy designed to enhance antitumor immune memory when combined with PD-1 blockade.
Study Overview
Updated 5-year follow-up data from the phase 2b KEYNOTE-942 trial (NCT03897881) show that intismeran autogenein combination with pembrolizumab continues to deliver a sustained and clinically meaningful improvement in recurrence-free survival (RFS) compared with pembrolizumab alone in patients with high-risk melanoma, according to a press release from Merck.
At 5 years, treatment with the combination resulted in a 49% reduction in the risk of recurrence or death versus pembrolizumab monotherapy (HR, 0.510; 95% CI, 0.294–0.887; P = .0075), confirming the durability of benefit first observed in earlier analyses.
Earlier Efficacy Signals and Trial Design
Results from the 3-year update, presented at the American Society of Clinical Oncology (ASCO) 2024 Annual Meeting, provided the foundation for the long-term findings. In KEYNOTE-942, patients were randomized 2:1 to receive either the combination (n = 107) or pembrolizumab alone (n = 50).
In the experimental arm, patients received up to 1 year of pembrolizumab plus intramuscular mRNA-4157 administered every 3 weeks for up to 9 doses, alongside standard pembrolizumab dosing every 3 weeks for up to 18 cycles. The control arm received matched pembrolizumab monotherapy.
At the time of the 3-year analysis, median RFS was not evaluable in the combination arm compared with 42.5 months in the monotherapy arm (HR, 0.510; 95% CI, 0.288–0.906; P = .019). RFS rates consistently favored the combination across multiple time points, including 18, 24, and 30 months.
Distant Metastasis-Free Survival and Overall Survival
The combination also demonstrated a significant improvement in distant metastasis–free survival (DMFS), with a 62% reduction in the risk of distant recurrence or death (HR, 0.384; 95% CI, 0.172–0.858; P = .015). Median DMFS was not reached in either arm, but separation of the curves emerged early and was maintained.
Overall survival data remain immature, with median OS not reached in either group. However, the observed trend favored the mRNA-4157/pembrolizumab combination (HR, 0.425; 95% CI, 0.114–1.584).
Importantly, subgroup analyses showed consistent benefit regardless of PD-L1 expression, tumor mutational burden, or circulating tumor DNA status.
Safety and Tolerability
The safety profile of the combination was consistent with expectations for checkpoint inhibition and vaccine-based therapy. Any-grade adverse events occurred in all patients receiving the combination versus 92% in the pembrolizumab-alone arm. Rates of grade ≥3 adverse events were similar between groups (34.6% vs 36.0%).
Common adverse events associated with the mRNA vaccine included fatigue, injection-site pain, chills, pyrexia, and headache. Immune-related adverse events occurred at comparable frequencies in both arms, and no new long-term safety signals emerged with extended follow-up.
Expert Perspective
“For many patients with stage III/IV melanoma, there is a significant risk of recurrence following surgery,”
said Marjorie Green, senior vice president and head of oncology, global clinical development at Merck Research Laboratories.
“As such, demonstrating the longer-term potential of intismeran autogene and pembrolizumab to reduce the risk of recurrence for certain patients with melanoma is a meaningful milestone.”
Commenting on the earlier data, Jeffrey S. Weber noted that
“mRNA-4157 plus pembrolizumab demonstrated a durable clinically significant improvement in RFS and DMFS compared with standard-of-care pembrolizumab in high-risk resected melanoma.”
Clinical Implications
The sustained 5-year RFS benefit reinforces the concept that personalized mRNA cancer vaccines can meaningfully augment PD-1–based immunotherapy in the adjuvant setting. As melanoma management increasingly shifts toward long-term disease control and cure, the mRNA-4157/pembrolizumab combination represents a potential paradigm shift in how postoperative relapse risk is addressed in high-risk patients.
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