{"entity":{"id":"paper-keynote-942-lancet-2024","kind":"paper","name":"KEYNOTE-942: a personalised mRNA cancer vaccine plus pembrolizumab after melanoma surgery","aka":[],"tldr":"A vaccine custom-made from each patient's own tumour mutations, given with pembrolizumab after surgery for high-risk melanoma, reduced recurrence by about 44% compared with pembrolizumab alone in a mid-sized randomised trial, the first sign that personalised cancer vaccines can work.","summary":"Open-label randomised phase 2b trial of 157 patients with completely resected stage IIIB-IV melanoma randomised 2:1 to mRNA-4157 (V940, intismeran autogene, encoding up to 34 patient-specific neoantigens) plus pembrolizumab or pembrolizumab alone for about a year. Primary endpoint was recurrence-free survival.\n\nRecurrence-free survival HR was 0.56 (18-month RFS 78.6% vs 62.2%) and distant metastasis-free survival HR 0.35, with benefit regardless of tumour mutational burden or PD-L1. Toxicity was mainly injection-site reactions and flu-like symptoms. It triggered the phase 3 INTerpath-001 trial and a wave of investment in individualised neoantigen vaccines.","asOf":"2026-09-08","links":[{"label":"PubMed search: KEYNOTE-942 mRNA-4157 Lancet 2024","url":"https://pubmed.ncbi.nlm.nih.gov/?term=mRNA-4157+V940+pembrolizumab+melanoma+KEYNOTE-942+Lancet"},{"label":"ClinicalTrials.gov NCT03897881","url":"https://clinicaltrials.gov/study/NCT03897881"}],"tags":[],"related":[],"cancers":["melanoma"],"sections":[],"technologies":["neoantigen-mrna-vaccine","checkpoint-inhibitor","wes-wgs"],"targets":["pd1"],"drugs":["intismeran-autogene","pembrolizumab"],"companies":["moderna","merck"],"institutions":[],"pathways":[],"terms":["neoantigen","tmb","neoadjuvant-adjuvant"],"trials":["interpath-001"],"people":["ryan-sullivan"],"bottlenecks":["b-immunotherapy-response","b-manufacturing-cell-therapy","b-trial-design"],"keyPapers":[],"journals":["lancet"],"dependsOn":[],"notes":[],"journal":"The Lancet","year":2024,"doi":"10.1016/S0140-6736(23)02268-7","pmid":"38246194","authors":"Weber JS, Carlino MS, Khattak A, et al.","paperType":"rct","findings":["Recurrence-free survival HR 0.561 (95% CI 0.309-1.017); 18-month RFS 78.6% vs 62.2%.","Distant metastasis-free survival HR 0.347 (95% CI 0.145-0.828).","Benefit was seen in both high and low tumour mutational burden and in PD-L1-negative tumours.","Three-year update: RFS HR 0.51, with the curves continuing to separate.","Grade 3 or higher treatment-related adverse events 25% vs 18%; vaccine-related events were mostly grade 1-2 fatigue, injection-site pain and chills.","Manufacturing took about six to eight weeks per patient from biopsy sequencing to first dose."],"whatItMeans":"For the first time a randomised trial suggests that a vaccine tailored to an individual's tumour can reduce relapse when combined with immunotherapy, which is a proof of concept for a field that had failed for decades. Nothing changes for patients yet: the trial was small, the confidence interval crossed one, and the phase 3 trial in melanoma (and parallel trials in lung and other cancers) must confirm it. If it does, personalised mRNA vaccines could become a routine adjunct to checkpoint inhibitors after surgery.","caveats":["Phase 2b with 157 patients and an upper confidence limit above 1.0; the prespecified one-sided p-value was met but the result needs confirmation.","Open-label; recurrence assessments were investigator-based.","Individualised manufacturing is slow and expensive and has never been scaled to thousands of patients.","No biomarker predicts who benefits, and the mechanism (neoantigen-specific T-cell expansion) has been shown in only a subset."],"changedPractice":false,"participants":157},"route":"/key-papers/paper-keynote-942-lancet-2024/","neighbours":{"cancer":[{"id":"melanoma","kind":"cancer","name":"Melanoma","route":"/cancers/melanoma/"}],"technology":[{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"neoantigen-mrna-vaccine","kind":"technology","name":"Personalised neoantigen (mRNA) vaccines","route":"/technologies/neoantigen-mrna-vaccine/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"pd1","kind":"target","name":"PD-1","route":"/targets/pd1/"}],"drug":[{"id":"intismeran-autogene","kind":"drug","name":"Intismeran autogene","route":"/drugs/intismeran-autogene/"},{"id":"pembrolizumab","kind":"drug","name":"Pembrolizumab","route":"/drugs/pembrolizumab/"}],"company":[{"id":"merck","kind":"company","name":"Merck & Co. (MSD)","route":"/companies/merck/"},{"id":"moderna","kind":"company","name":"Moderna","route":"/companies/moderna/"}],"term":[{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/"},{"id":"neoantigen","kind":"term","name":"Neoantigen","route":"/terms/neoantigen/"},{"id":"tmb","kind":"term","name":"Tumour mutational burden (TMB)","route":"/terms/tmb/"}],"trial":[{"id":"nct03897881","kind":"trial","name":"An Efficacy Study of Adjuvant Treatment With the Personalized Cancer Vaccine mRNA-4157 and Pembrolizumab in Participants With High-Risk Melanoma (KEYN","route":"/trials/nct03897881/"},{"id":"interpath-001","kind":"trial","name":"INTerpath-001 (V940-001)","route":"/trials/interpath-001/"}],"person":[{"id":"jeffrey-weber","kind":"person","name":"Jeffrey S. Weber","route":"/people/jeffrey-weber/"},{"id":"ryan-sullivan","kind":"person","name":"Ryan J. Sullivan","route":"/people/ryan-sullivan/"}],"bottleneck":[{"id":"b-manufacturing-cell-therapy","kind":"bottleneck","name":"Manufacturing cost and time for living and radioactive medicines","route":"/bottlenecks/b-manufacturing-cell-therapy/"},{"id":"b-immunotherapy-response","kind":"bottleneck","name":"No one can predict who responds to immunotherapy","route":"/bottlenecks/b-immunotherapy-response/"},{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"}],"journal":[{"id":"lancet","kind":"journal","name":"The Lancet","route":"/journals/lancet/"}]}}