GROUNDING — KEYNOTE-942 primary publication: mechanism, route, formulation
- Source: Weber JS et al., “Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study.” Lancet 2024 Feb 17;403(10427):632-644. doi:10.1016/S0140-6736(23)02268-7. PMID 38246194.
- Accessed: 2026-08-21
- Exact query:
curl -s "https://eutils.ncbi.nlm.nih.gov/entrez/eutils/efetch.fcgi?db=pubmed&id=38246194&rettype=abstract&retmode=text"(PubMed and Lancet HTML both blocked WebFetch — 403 / cookie wall; NCBI E-utilities used instead)
Verbatim passages (abstract, as returned by E-utilities)
“BACKGROUND: Checkpoint inhibitors are standard adjuvant treatment for stage IIB-IV resected melanoma, but many patients recur. Our study aimed to evaluate whether mRNA-4157 (V940), a novel mRNA-based individualised neoantigen therapy, combined with pembrolizumab, improved recurrence-free survival and distant metastasis-free survival versus pembrolizumab monotherapy in resected high-risk melanoma.”
“METHODS: We did an open-label, randomised, phase 2b, adjuvant study of mRNA-4157 plus pembrolizumab versus pembrolizumab monotherapy in patients, enrolled from sites in the USA and Australia, with completely resected high-risk cutaneous melanoma. Patients with completely resected melanoma (stage IIIB-IV) were assigned 2:1 to receive open-label mRNA-4157 plus pembrolizumab or pembrolizumab monotherapy. mRNA-4157 was administered intramuscularly (maximum nine doses) and pembrolizumab intravenously (maximum 18 doses) in 3-week cycles. The primary endpoint was recurrence-free survival in the intention-to-treat population. This ongoing trial is registered at ClinicalTrials.gov, NCT03897881.”
“FINDINGS: From July 18, 2019, to Sept 30, 2021, 157 patients were assigned to mRNA-4157 plus pembrolizumab combination therapy (n=107) or pembrolizumab monotherapy (n=50); median follow-up was 23 months and 24 months, respectively. Recurrence-free survival was longer with combination versus monotherapy (hazard ratio [HR] for recurrence or death, 0·561 [95% CI 0·309-1·017]; two-sided p=0·053)”
“INTERPRETATION: … These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting.”
Secondary source for the LNP/mechanism sentence
- Source: WebSearch result synthesis over the Lancet/ScienceDirect/Wikipedia/PatSnap hits, query
mRNA-4157 intismeran intramuscular administration lipid nanoparticle formulation neoantigen T cell priming mechanism KEYNOTE-942 Lancet, accessed 2026-08-21. Reported text:
“mRNA-4157 is an mRNA-based individualised neoantigen therapy encoding up to 34 neoantigens in a lipid nanoparticle formulation and is tailored specifically to an individual’s tumour mutanome and human leukocyte antigen type.”
“Neoantigens encoded in mRNA-4157 can be endogenously translated to enter the natural cellular antigen processing and presentation pathways, and subsequently can stimulate reactive T cells targeting patient-specific tumour neoantigens.”
- Source: Wikipedia “Intismeran autogene”, accessed 2026-08-21, WebFetch. Verbatim fragments: the vaccine contains “34 mRNA sequences” generated through an automated algorithm and massive parallel sequencing of patient tumor tissue; delivery system is “solid lipid nanoparticles”; the drug works by producing abnormal proteins found in cancer tissues to “invoke an immune response”.
Evidential weight
- STATES (primary, Lancet abstract): route is intramuscular; max nine doses; 3-week cycles; the therapy is individualised neoantigen therapy; KEYNOTE-942 n=157; KEYNOTE-942 registration is NCT03897881 (distinct from the Phase 3 NCT05933577); the 2024 primary-analysis RFS HR was 0.561 (95% CI 0.309-1.017, p=0.053) — i.e. the 2024 readout did NOT reach two-sided significance; the 0.510 figure is the later 5-year follow-up.
- STATES (secondary, lower weight): lipid-nanoparticle formulation; tailoring to tumour mutanome and HLA type; the mechanism is endogenous translation → natural antigen processing and presentation → stimulation of reactive T cells. The mechanism sentence is drawn from search-result synthesis of the Lancet/related text, not from a directly-fetched primary paragraph — it is standard and uncontested, but I mark it SECONDARY weight.
- DOES NOT STATE anywhere in any source retrieved: the LNP composition; any ionizable-lipid identity; any tissue-tropism data outside muscle/lymphoid; anything about inner ear, cochlea, or non-IM routes.
- Bridging derivation (mine, explicitly labelled INFERENCE): “endogenously translated → antigen processing and presentation → stimulate reactive T cells” means the delivered mRNA’s job ends at producing antigen inside a transfected cell; every subsequent step (clonal T-cell expansion, memory, tumour killing) is performed by the host immune system, not by the delivered dose. That is what I mean by amplification. The sources state the pathway; the word “amplification” and the ratio-argument built on it are my inference from it.