Five years later, personalized mRNA vaccine cuts melanoma recurrence risk by half

A personalized mRNA cancer vaccine continued to reduce the risk of recurrence and distant spread in resected high-risk melanoma at five years of follow-up, according to updated results from a randomized phase 2b trial published recently in the Journal of Clinical Oncology.

The trial, KEYNOTE-942, evaluated the effects of intismeran autogene, which is an investigational neoantigen vaccine formerly known as V940 or mRNA-4157, when added to the PD-1 inhibitor pembrolizumab (Keytruda) in 157 patients with resected stage IIIB-IV melanoma.

At four years, recurrence-free survival (RFS) stood at 72.4% in the combination arm versus 49.1% with pembrolizumab alone. Distant metastasis-free survival (DMFS) was 83.9% versus 65.4%, respectively. The combination reduced the risk of recurrence or death by 49% and the risk of distant metastasis or death by 59%.

Findings were also presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting, held last week in Chicago.

"This study confirms that intismeran plus pembrolizumab demonstrates a durable benefit over pembrolizumab alone in resected high-risk melanoma," Matteo Carlino, M.D., Ph.D., of the University of Sydney and lead author, said during his ASCO presentation.

Overall survival differences did not reach statistical significance, though a favorable trend was observed with four-year rates of 92.2% in the combination arm and 85.6% with pembrolizumab alone. The results were published simultaneously in the Journal of Clinical Oncology.

The vaccine works by encoding up to 34 personalized neoantigens, derived from each patient's own tumor via a tissue sample, within a lipid nanoparticle. The approach aims to reinforce existing T-cell responses and generate new antitumor activity. Translational data presented alongside the clinical results showed that the vaccine produced sustained novel T-cell clones associated with a lower risk of recurrence, suggesting durable immune surveillance.

No new safety signals emerged with longer follow-up. Treatment-related adverse events occurred in all patients in the combination arm and 84% of those receiving pembrolizumab alone. Most were low-grade, including fatigue, injection-site pain, fever, and chills. Grade 3 events attributable to intismeran were reported in 10.6% of patients.

The RFS benefit was consistent across prespecified subgroups, including tumor stage, PD-L1 expression, BRAF mutation status and tumor mutation burden.

ASCO discussant Rodrigo Ramella Munhoz, M.D., Ph.D., of Sírio Libanês Hospital in São Paulo, acknowledged the results while raising questions about how the vaccine would fit into an evolving treatment landscape, in an interview with Medscape. He noted that clinically detectable stage 3 disease is increasingly being managed with neoadjuvant immunotherapy and that no adjuvant therapy has demonstrated an overall survival benefit in a randomized trial since EORTC 18071 approximately a decade ago.

Munhoz said patients who may still benefit from an adjuvant approach include those who do not achieve a complete pathological response after neoadjuvant therapy, as well as those with stage III microscopic disease or high-risk stage II melanoma. He also cautioned that manufacturing complexity, timelines and costs could limit the vaccine's accessibility at scale.

A confirmatory phase 3 trial, INTerpath-001, has fully enrolled. The vaccine is also under evaluation in late-stage lung cancer and in earlier-phase studies across other tumor types.