biostudies-literatureFennell DACancer Research UK6688https://www.ebi.ac.uk/biostudies/studies/S-EPMC12280041biostudies-literatureUnknown16(1)Leveraging adaptive tumour immunity to control mesothelioma via immune checkpoint blockade is now a standard therapeutic approach. However, the determinants of sensitivity remain elusive. Low non-synonymous mutation burden and programmed death-ligand 1 expression, an abundance of immunosuppressive immune cell infiltration, and 9p21 deletion should all mitigate responses to therapy. To address this knowledge gap, we conducted a double blind, placebo-controlled, randomized phase III trial of the PD1 inhibitor, nivolumab (ClinicalTrial.gov registration: NCT03063450). After 37.2 months of follow-up, the primary endpoint of progression free-survival, but not overall survival was met. The nivolumab response rate was 10.3%, and related grade 3 or above adverse events occurred in 20.4% versus 7.2%Nature communicationsConstitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial.PMC12280041C16728/A21400Darlison LJohnson LNye MDzialo JCalifano RFaulkner DJama MZhang MMiddleton CHarber JPoile CGriffiths GOHollox EJMallard KPritchard CHanna GGWells-Jordan PHill KZhou HChan SLester JFYang HNusrat NSpicer JSteele NKlampatsa ALuo JLOttensmeier CKamata TZhou ZBaitei EYRichards CEwings SHahne JCFennell DARogel JBzura ADanson SLord JSzlosarek PfalseConstitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial.Leveraging adaptive tumour immunity to control mesothelioma via immune checkpoint blockade is now a standard therapeutic approach. However, the determinants of sensitivity remain elusive. Low non-synonymous mutation burden and programmed death-ligand 1 expression, an abundance of immunosuppressive immune cell infiltration, and 9p21 deletion should all mitigate responses to therapy. To address this knowledge gap, we conducted a double blind, placebo-controlled, randomized phase III trial of the PD1 inhibitor, nivolumab (ClinicalTrial.gov registration: NCT03063450). After 37.2 months of follow-up, the primary endpoint of progression free-survival, but not overall survival was met. The nivolumab response rate was 10.3%, and related grade 3 or above adverse events occurred in 20.4% versus 7.2%2025-01-01T00:00:00Z2025 Jul2026-07-15T10:55:03.152Z2025-08-23T03:06:31.244ZS-EPMC122800414069114310.1038/s41467-025-61691-4