KEYNOTE-942: a personalised mRNA cancer vaccine plus pembrolizumab after melanoma surgery
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.
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.
Recurrence-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.
- 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.
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.
- 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.
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not linked directly; found by shared links- Key paperRojas 2023: a personalised mRNA vaccine trained T cells against each patient's pancreatic cancer, and those who responded stayed cancer-free longer
Shares INTerpath-001 (V940-001), Intismeran autogene, Tumour mutational burden (TMB), Neoantigen.
- IdeaPersonalised cancer vaccines at commodity cost through fully automated manufacturing
Shares Moderna, Intismeran autogene, Neoantigen, Personalised neoantigen (mRNA) vaccines.
- PairingPersonalised neoantigen vaccine + PD-1 blockade
Shares INTerpath-001 (V940-001), Intismeran autogene, Personalised neoantigen (mRNA) vaccines, Pembrolizumab.
- IdeaVaccines aimed only at mutations shared by every tumour cell
Shares INTerpath-001 (V940-001), Moderna, Neoantigen, Personalised neoantigen (mRNA) vaccines.
- IdeaPersonalised vaccines given only when the blood test turns positive
Shares Moderna, Intismeran autogene, Neoantigen, Personalised neoantigen (mRNA) vaccines.
- Key paperKEYNOTE-177: pembrolizumab instead of chemotherapy as first treatment for mismatch-repair-deficient metastatic colorectal cancer
Shares Tumour mutational burden (TMB), Merck & Co. (MSD), No one can predict who responds to immunotherapy, Trial design, endpoints and cost.
- Key paperLe 2015: PD-1 blockade works in tumours with mismatch-repair deficiency, whatever the organ
Shares Tumour mutational burden (TMB), Neoantigen, No one can predict who responds to immunotherapy, PD-1.
- PersonTimothy A. Chan
Shares Tumour mutational burden (TMB), Neoantigen, Melanoma, Immune checkpoint inhibitors.