Constitutive 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% 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<sup>+</sup> T- and CD19<sup>+</sup> 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.

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Publication Details

Journal
Nature Communications
Published
2025-07-21
DOI
https://doi.org/10.1038/s41467-025-61691-4
Citations
3
Primary Topic
Cancer Immunotherapy and Biomarkers
Type
article
Field-Weighted Citation Impact
3.14

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article

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

J. Spicer, Joanna Działo, Dean A. Fennell, Sean Ewings et al.
3 citations
Nature Communications
Cancer Immunotherapy and Biomarkers
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article

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

J. Spicer, Joanna Działo, Dean A. Fennell, Sean Ewings, Peter W. Szlosarek, James Harber, Raffaele Califano, Jinli Luo, Joanne Lord, Jens C. Hahne, Maymun Jama, Lucy Johnson, Astero Klampatsa, Charlotte Poile, Edward J. Hollox, Essa Y. Baitei, Tamihiro Kamata, Mavis Nye, Kayleigh Hill, Peter Wells-Jordan, Huiyu Zhou, Sarah Danson, D.N. Faulkner, Christian H. Ottensmeier, J.F. Lester, Zisen Zhou, Aleksandra Bzura, Nada Nusrat, Gerard G. Hanna, Jan Rogel, Gareth Griffiths, Catrin Pritchard, Liz Darlison, Cathy Richards, Min Zhang, Hongji Yang, Kim Mallard, Sam W. Chan, Nicola Steele, Calley Middleton
article en
3 citations

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<sup>+</sup> T- and CD19<sup>+</sup> 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.

Nature CommunicationsVol. 16(1)
Institute of Cancer Research (GB), Loughborough University (GB), University of Liverpool (GB), University of Leicester (GB), Queen Mary University of London (GB), University of Tripoli (LY), University of Cambridge (GB), Harry Perkins Institute of Medical Research (AU), Beatson West of Scotland Cancer Centre (GB), Singleton Hospital (GB), King Faisal Specialist Hospital & Research Centre (SA), Cancer Research UK (GB), Loughborough College (GB), University Hospitals of Leicester NHS Trust (GB), University Hospital Southampton NHS Foundation Trust (GB), Queens University (BD), Novogene Bioinformatics Institute (CN), Sheffield Teaching Hospitals NHS Foundation Trust (GB), NIHR Southampton Respiratory Biomedical Research Unit (GB), York Teaching Hospital NHS Foundation Trust (GB), NIHR Southampton Biomedical Research Centre (GB), The Northern Ireland Cancer Centre (GB), Wythenshawe Hospital (GB), MRC Toxicology Unit (GB), NIHR Leicester Biomedical Research Centre (GB), University of Southampton (GB)
Bristol-Myers Squibb, Cancer Research UK, National Institute for Health and Care Research, Department of Health and Social Care, University of Leicester, University of Southampton, National Institutes of Health, Stand Up To Cancer, Medical Research Council, NIHR Leicester Biomedical Research Centre
Openalex Percentile: Top 7%
Cancer Immunotherapy and Biomarkers
3.14
DOIOpen Access PDFOpenAlex
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