Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial

Dean A. Fennell (), Kayleigh Hill, Min Zhang, Charlotte Poile, Sean Ewings, Essa Y. Baitei, Joanna Dzialo, Nada Nusrat, Jan Rogel, Daniel Faulkner, Christian Ottensmeier, Raffaele Califano, Gerard G. Hanna, Sarah Danson, Nicola Steele, Mavis Nye, Lucy Johnson, Kim Mallard, Joanne Lord, Calley Middleton, Peter Szlosarek, Sam Chan, Liz Darlison, Peter Wells-Jordan, Cathy Richards, James Harber, Aleksandra Bzura, Jake Spicer, Catrin Pritchard, Tamihiro Kamata, Jens C. Hahne, Maymun Jama, Edward J. Hollox, Jason F. Lester, Jin-Li Luo, Zisen Zhou, Hongji Yang, Huiyu Zhou, Astero Klampatsa and Gareth O. Griffiths
Additional contact information
Dean A. Fennell: UK Robert Kilpatrick Clinical Sciences Building
Kayleigh Hill: University of Southampton
Min Zhang: UK Robert Kilpatrick Clinical Sciences Building
Charlotte Poile: UK Robert Kilpatrick Clinical Sciences Building
Sean Ewings: University of Southampton
Essa Y. Baitei: UK Robert Kilpatrick Clinical Sciences Building
Joanna Dzialo: UK Robert Kilpatrick Clinical Sciences Building
Nada Nusrat: UK Robert Kilpatrick Clinical Sciences Building
Jan Rogel: UK Robert Kilpatrick Clinical Sciences Building
Daniel Faulkner: UK Robert Kilpatrick Clinical Sciences Building
Christian Ottensmeier: University of Liverpool
Raffaele Califano: Wythenshawe Hospital
Gerard G. Hanna: Queens University Belfast
Sarah Danson: Sheffield Teaching Hospitals NHS Foundation
Nicola Steele: Beatson West of Scotland Cancer Centre
Mavis Nye: c/o University of Southampton
Lucy Johnson: University of Southampton
Kim Mallard: University of Southampton
Joanne Lord: University of Southampton
Calley Middleton: University of Southampton
Peter Szlosarek: Queen Mary University of London
Sam Chan: York Teaching Hospital NHS Foundation Trust
Liz Darlison: Mesothelioma UK
Peter Wells-Jordan: UK Robert Kilpatrick Clinical Sciences Building
Cathy Richards: University Hospitals of Leicester NHS Trust
James Harber: UWA Centre for Medical Research & Harry Perkins Institute of Medical Research
Aleksandra Bzura: UK Robert Kilpatrick Clinical Sciences Building
Jake Spicer: UK Robert Kilpatrick Clinical Sciences Building
Catrin Pritchard: UK Robert Kilpatrick Clinical Sciences Building
Tamihiro Kamata: Tennis Court Road
Jens C. Hahne: UK Robert Kilpatrick Clinical Sciences Building
Maymun Jama: UK Robert Kilpatrick Clinical Sciences Building
Edward J. Hollox: University of Leicester
Jason F. Lester: Singleton & Morrison Hospitals
Jin-Li Luo: University of Leicester
Zisen Zhou: University of Leicester
Hongji Yang: University of Leicester
Huiyu Zhou: University of Leicester
Astero Klampatsa: The Institute of Cancer Research
Gareth O. Griffiths: University of Southampton

Nature Communications, 2025, vol. 16, issue 1, 1-13

Abstract: Abstract 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% for placebo. Progression-free and overall survival were longer in nivolumab-treated responders versus non-responders. In an exploratory multiomic analysis, blinded whole exome, transcriptome and multiplex immune profiling were used to interrogate R- versus NR-subgroups. Non-synonymous and neoantigen mutation burden were no different between groups, however R-mesotheliomas were infiltrated with activated CD8+ T- and CD19+ B-lymphocytes, organised into tertiary lymphoid structures. B-cell infiltration correlated with pro-inflammatory chemokines including IL24 and CCL19. Conversely, epithelial-mesenchymal transition and mitosis were associated with resistance to nivolumab. These findings illuminate features which can be leveraged to advance precision immunotherapy in this rare cancer setting.

Date: 2025
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DOI: 10.1038/s41467-025-61691-4

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