Personalized mRNA Vaccine Plus Keytruda Cuts Melanoma Recurrence Risk by 49% at Five Years
KEYNOTE-942 five-year data: intismeran autogene plus Keytruda reduced melanoma recurrence risk by 49% and kept 68.8% of patients cancer-free versus 49.1% with Keytruda alone. Distant metastasis or death risk fell 59%.
Five-year data from the phase 2b KEYNOTE-942 trial show that the personalized mRNA cancer vaccine intismeran autogene (mRNA-4157/V940) in combination with the immunotherapy drug Keytruda (pembrolizumab) reduced the risk of melanoma recurrence or death by 49% compared with pembrolizumab alone in patients with resected high-risk stage III/IV melanoma. At a median follow-up of 60.3 months, 68.8% of patients in the combination arm remained cancer-free versus 49.1% of patients receiving Keytruda alone.
The results were presented at the 2026 American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago and simultaneously published in the Journal of Clinical Oncology. The 49% reduction is identical to the three-year result reported in 2024, suggesting that the immune system changes induced by the treatment are durable and potentially permanent.
The trial enrolled 157 patients across Australia and the US between 2019 and 2021. All had undergone surgery for advanced skin cancer that had spread to lymph nodes or beyond. Of these, 107 received intismeran plus pembrolizumab and 50 received pembrolizumab alone. The risk of distant metastasis or death was reduced by 59% in the vaccine group. In an exploratory overall survival analysis, the combination produced a 53% improvement in overall survival. Overall survival was 92.2% for the combination group against 71.3% for those who received only immunotherapy. Seven patients died in each group during follow-up, mostly from cancer.
Intismeran autogene is a personalized mRNA vaccine developed by Moderna in collaboration with Merck. After surgical removal of a melanoma tumor, the tumor's DNA is sequenced and bioinformatics algorithms identify up to 34 neoantigens — protein fragments on the tumor's surface that mark it as foreign to the immune system. Those neoantigen sequences are encoded into a synthetic mRNA strand and manufactured as an injectable vaccine customized for that patient. The vaccine trains the immune system to recognize those specific neoantigens, while pembrolizumab, a PD-1 checkpoint inhibitor, releases the immune system's natural brakes, allowing trained T cells to attack any remaining microscopic melanoma cells.
According to the researchers, intismeran is 'well-tolerated' with a 'manageable' safety profile. The most commonly cited side effects of the personalized mRNA vaccine plus Keytruda were fatigue, injection-site pain, chills, fever and headache. The researchers reported no new long-term safety concerns and no severe vaccine-related adverse events.
The combination therapy is currently being evaluated in a phase 3 study, the final confirmation stage. Moderna and Merck now have eight Phase 2 and Phase 3 clinical trials underway across multiple tumor types — including melanoma (Phase 3 pivotal trial now enrolling), non-small cell lung cancer, bladder cancer, renal cell carcinoma, and cutaneous squamous cell carcinoma. The pivotal Phase 3 melanoma trial results are expected in 2026–2027 and will determine whether intismeran receives FDA approval, potentially entering the market in 2027.
Researchers noted that mRNA vaccines have so far been well tolerated, with manageable and transient toxicities, and no evidence of insertional mutagenesis.