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

Our plain-English summary of Constitutive inflammation and epithelial-mesenchymal transition dictate sensitivity to nivolumab in CONFIRM: a placebo-controlled, randomised phase III trial, by D.A. Fennell, K. Hill, M. Zhang, et al (Nature Communications, 2025).

The study

• Authors: D.A. Fennell, K. Hill, M. Zhang, C. Poile, S. Ewings, E.Y. Baitei, J. Dzialo, N. Nusrat, J. Rogel, D. Faulkner, C. Ottensmeier, R. Califano, G.G. Hanna, S. Danson, N. Steele, M. Nye, L. Johnson, K. Mallard, J. Lord, C. Middleton, P. Szlosarek, S. Chan, L. Darlison, P. Wells-Jordan, C. Richards, J. Harber, A. Bzura, J. Spicer, C. Pritchard, T. Kamata, J.C. Hahne, M. Jama, E.J. Hollox, J.F. Lester, J.L. Luo, Z. Zhou, H. Yang, H. Zhou, A. Klampatsa, G.O. Griffiths
• Journal: Nature Communications
• Published: 2025;16(1):6688
• Type of article: Randomized trial
• Cited by: 6 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

© 2025. The Author(s).

In plain English

This article reported the final results of CONFIRM, a double-blind, placebo-controlled randomised phase III trial at 24 UK hospitals. Between May 2017 and March 2020, 332 adults with pleural or peritoneal mesothelioma that had progressed after chemotherapy were randomly assigned to the immunotherapy drug nivolumab (221 patients) or a saline placebo (111 patients). The trial did not study asbestos exposure. Median progression-free survival was 2.89 months with nivolumab versus 1.64 months with placebo (hazard ratio 0.65, 95% CI 0.51 to 0.82), so this primary endpoint was met. Median overall survival was 9.49 versus 6.77 months (adjusted hazard ratio 0.81, 95% CI 0.64 to 1.04), and the overall survival endpoint was not met. An objective tumour response occurred in 20/195 (10.3%) nivolumab patients and 0/102 placebo patients. Treatment-related grade 3 or higher adverse events occurred in 20.4% versus 7.2%, and there were no treatment-related deaths. An exploratory tissue comparison covered 16 responders and 13 non-responders. Responders' tumours had more immune cells and tertiary lymphoid structures. Non-responders' tumours had stronger gene-expression signatures related to epithelial-mesenchymal transition and mitosis. The authors called this small analysis hypothesis generating.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Multicentre, double-blind, placebo-controlled randomised phase III clinical trial (2:1 randomisation), with an exploratory, blinded multi-omic tissue analysis comparing responders and non-responders
• Who was studied: 332 participants with relapsed pleural or peritoneal mesothelioma, previously treated with chemotherapy, were enrolled at 24 UK hospitals from 10 May 2017 to 30 March 2020. 221 were randomised to nivolumab and 111 to placebo, and all were included in the analysis. 217 nivolumab patients and 110 placebo patients actually received treatment. The tissue sub-study included 16 responders and 13 non-responders.
• Exposure: Treatment, not asbestos: a flat dose of 240 mg nivolumab (an anti-PD1 immune checkpoint inhibitor) or saline placebo, given intravenously every 2 weeks for up to 12 months. Asbestos exposure and fiber types were not studied.
• Main results:
  • Median investigator-reported progression-free survival was 2.89 months (95% CI 2.76 to 4.11) in the nivolumab group and 1.64 months (95% CI 1.38 to 2.56) in the placebo group. The unadjusted hazard ratio was 0.65 (95% CI 0.51 to 0.82).
  • Median overall survival was 9.49 months in the nivolumab group and 6.77 months in the placebo group. The adjusted hazard ratio was 0.81 (95% CI 0.64 to 1.04; p = 0.096). The overall survival primary endpoint was not met.
  • The objective response rate (modified RECIST) was 20/195 (10.3%) in the nivolumab group and 0/102 (0.0%) in the placebo group.
  • Treatment-related grade 3 or above adverse events occurred in 20.4% of the nivolumab group and 7.2% of the placebo group. There were no treatment-related deaths in either arm.
  • Patients whose tumours had PD-L1 above 50% showed significantly longer progression-free survival (interaction hazard ratio 0.28, 95% CI 0.09 to 0.94, p = 0.04). This subgroup made up 15/258 (5.8%) of tested patients.
  • In the exploratory tissue comparison (16 responders, 13 non-responders), tumour mutation burden and predicted neoantigens were similar between groups. Responders' tumours had more CD8+ T cells and more tertiary lymphoid structures. Non-responders' tumours showed enrichment of gene-expression signatures related to epithelial-mesenchymal transition and mitosis.
• The authors' conclusion: The authors concluded that immune checkpoint blockade appears most effective in inflamed mesotheliomas with high IL24/CCL19 expression, tertiary lymphoid structures and low epithelial-mesenchymal transition. They also concluded that PD-L1 testing is unsuitable for selecting patients because the high-PD-L1 subgroup is small.
• Limitations the authors state:
  • The multi-omic cohort was small (29 patients), and the authors regarded that analysis as hypothesis generating.
  • The findings in the tissue analysis were associations, not mechanisms.
  • The survival curves for responders and non-responders are descriptive only and cannot be formally compared.
  • Degraded RNA may have reduced the ability to detect gene fusions.

Topics

Medical terms in this study, explained in our Lexicon: Inflammation, Nivolumab (Opdivo), Mesothelioma, Overall Survival, Immunotherapy.

Related studies

• Nivolumab versus placebo in patients with relapsed malignant mesothelioma (CONFIRM): a multicentre, double-blind, randomised, phase 3 trial — D.A. Fennell, S. Ewings, et al. (2021)
• CONFIRM: a double-blind, placebo-controlled phase III clinical trial investigating the effect of nivolumab in patients with relapsed mesothelioma: study protocol for a randomised controlled trial — D.A. Fennell, E. Kirkpatrick, et al. (2018)
• A gut microbiota rheostat forecasts responsiveness to PD-L1 and VEGF blockade in mesothelioma — M. Zhang, A. Bzura, et al. (2024)
• Nivolumab or nivolumab plus ipilimumab in patients with relapsed malignant pleural mesothelioma (IFCT-1501 MAPS2): a multicentre, open-label, randomised, non-comparative, phase 2 trial — A. Scherpereel, J. Mazieres, et al. (2019)
• Nintedanib in combination with pemetrexed and cisplatin for chemotherapy-naive patients with advanced malignant pleural mesothelioma (LUME-Meso): a double-blind, randomised, placebo-controlled phase 3 trial — G.V. Scagliotti, R. Gaafar, et al. (2019)
• Gemcitabine with or without ramucirumab as second-line treatment for malignant pleural mesothelioma (RAMES): a randomised, double-blind, placebo-controlled, phase 2 trial — C. Pinto, P.A. Zucali, et al. (2021)

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