Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial
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.
Article Details
Authors (40)
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