Journal Article

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

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

2025

Overview

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. The sensitivity of mesothelioma to the treatment of immune checkpoint blockade remains elusive. Here this group reports a double blind, placebo-controlled, randomized phase III trial of PD1 inhibitor (Nivolumab) on 332 patients with relapsed mesothelioma, and to uncover determinants of efficacy.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/105 / 38/23 / 38/39 / 38/91 / 45 / 45/23 / 45/91 / 59 / 692/308/2779/777 / 692/4028/67/1641 / 692/699/67/1059/2325 / 82/51 / Adult / Aged / Antineoplastic Agents, Immunological - therapeutic use / Apoptosis / CD19 antigen / CD8 antigen / Chemokines / Clinical trials / Clonal deletion / Double-Blind Method / Epithelial-Mesenchymal Transition - drug effects / Epithelial-Mesenchymal Transition - genetics / Epithelial-Mesenchymal Transition - immunology / Female / Humanities and Social Sciences / Humans / Immune checkpoint inhibitors / Immune Checkpoint Inhibitors - therapeutic use / Immune system / Immunotherapy / Infiltration / Inflammation - genetics / Inflammation - immunology / Inhibitors / Lymphocytes / Lymphocytes B / Male / Mesothelioma / Metastases / Middle Aged / Mitosis / multidisciplinary / Mutation / Neoantigens / Nivolumab - adverse effects / Nivolumab - pharmacology / Nivolumab - therapeutic use / Patients / PD-1 protein / Placebos / Programmed Cell Death 1 Receptor - antagonists & inhibitors / Progression-Free Survival / Response rates / Science / Science (multidisciplinary) / Sensitivity / Subgroups / Survival / Transcriptomes