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
- Gareth O. Griffiths
2025-07-21
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.