A Phase 2b clinical trial has found that a personalized mRNA cancer vaccine developed by Moderna, when combined with the immunotherapy drug pembrolizumab, substantially lowered the risk of recurrence in patients with high-risk melanoma. The trial, known as KEYNOTE-942, enrolled 157 patients who had undergone surgery to remove stage III or IV melanoma. Participants were randomly assigned to receive either the vaccine plus pembrolizumab or pembrolizumab alone.
The vaccine, designated mRNA-4157 (V940), is tailored to each patient. Researchers sequence the patient's tumor to identify up to 34 neoantigens — mutated proteins unique to that cancer — and encode them into a single mRNA vaccine. The goal is to train the immune system to recognize and attack any remaining cancer cells bearing those specific mutations.
After a median follow-up of approximately three years, the combination therapy reduced the risk of recurrence or death by 49% compared to pembrolizumab alone. The three-year recurrence-free survival rate was 74.8% in the combination arm versus 55.6% in the control arm. Distant metastasis-free survival also improved, with a 62% reduction in the risk of distant spread or death.
Serious treatment-related adverse events occurred in 25% of patients receiving the combination, compared to 20% in the pembrolizumab-only group. The most common side effects were fatigue and injection-site reactions. No new safety signals were identified beyond the known profiles of the individual treatments.
Based on these results, Moderna and Merck are advancing the program to a Phase 3 trial, KEYNOTE-A942, which aims to enroll more than 1,000 patients globally. The Phase 3 study will further evaluate efficacy and safety in a broader population and is a necessary step toward potential regulatory approval.
The trial represents a proof of concept for the personalized mRNA vaccine approach in solid tumors. Because the platform can be adapted to target different neoantigens, researchers are investigating its use in other cancers, including non-small cell lung cancer and bladder cancer. Manufacturing each bespoke vaccine currently takes several weeks, a timeline the companies are working to shorten.
Experts caution that longer follow-up is needed to confirm durable overall survival benefits and to understand which patients benefit most. The Phase 2b trial was not powered to show a statistically significant improvement in overall survival, though a favorable trend was observed. Regulatory decisions will depend on the Phase 3 outcomes.
If successful in Phase 3, this would mark the first approved personalized mRNA cancer vaccine, demonstrating that the technology used for COVID-19 vaccines can be redirected to treat established cancer. The approach exemplifies a shift toward therapies customized to an individual's tumor genetics.
Moderna cancer vaccine stops melanoma returning: what’s next for personalized treatments?
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