The Evolving Role of Immune-Checkpoint Inhibitors in Malignant Pleural Mesothelioma

Our plain-English summary of The Evolving Role of Immune-Checkpoint Inhibitors in Malignant Pleural Mesothelioma, by M. Borgeaud, F. Kim, A. Friedlaender, et al (Journal of Clinical Medicine, 2023).

The study

• Authors: M. Borgeaud, F. Kim, A. Friedlaender, F. Lococo, A. Addeo, F. Minervini
• Journal: Journal of Clinical Medicine
• Published: 2023;12(5)
• Type of article: Review
• Cited by: 9 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is a rare cancer usually caused by asbestos exposure and associated with a very poor prognosis. After more than a decade without new therapeutic options, immune checkpoint inhibitors (ICIs) demonstrated superiority over standard chemotherapy, with improved overall survival in the first and later-line settings. However, a significant proportion of patients still do not derive benefit from ICIs, highlighting the need for new treatment strategies and predictive biomarkers of response. Combinations with chemo-immunotherapy or ICIs and anti-VEGF are currently being evaluated in clinical trials and might change the standard of care in the near future. Alternatively, some non-ICI immunotherapeutic approaches, such as mesothelin targeted CAR-T cells or denditric-cells vaccines, have shown promising results in early phases of trials and are still in development. Finally, immunotherapy with ICIs is also being evaluated in the peri-operative setting, in the minority of patients presenting with resectable disease. The goal of this review is to discuss the current role of immunotherapy in the management of malignant pleural mesothelioma, as well as promising future therapeutic directions.

In plain English

This article was a review, not a new study. The authors described published and ongoing trials of immune checkpoint inhibitors, drugs that help the immune system attack cancer, in malignant pleural mesothelioma. They collected no new patient data. Among the trials they described, CheckMate 743 compared nivolumab plus ipilimumab with platinum-pemetrexed chemotherapy as first treatment for unresectable disease. Median overall survival was 18.1 months with the drug combination and 14.1 months with chemotherapy. The CONFIRM trial treated patients with pleural or peritoneal mesothelioma that had progressed after chemotherapy. It reported overall survival of 10 months with nivolumab and 6.9 months with placebo. The authors described the DETERMINE (tremelimumab) and PROMISE-meso (pembrolizumab) trials as negative. They wrote that predictive markers of who benefits remain elusive. They also covered combinations with chemotherapy, surgery and other immune treatments, most still early or ongoing. The authors concluded that combination immunotherapy is a new standard of care for unresectable disease, but that the share of patients with prolonged response and survival remains low.

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: Narrative review of clinical trials of immunotherapy, mainly immune checkpoint inhibitors, in malignant pleural mesothelioma
• Who was studied: No new population was studied. The review covered published and ongoing trials in patients with malignant pleural mesothelioma, both resectable and unresectable, plus a few trials in peritoneal mesothelioma.
• Exposure: The review concerned treatments, not asbestos exposure. These were immune checkpoint inhibitors (nivolumab, ipilimumab, pembrolizumab, durvalumab, tremelimumab, atezolizumab), alone or combined with chemotherapy or surgery, and other immunotherapies (CAR-T cells, dendritic-cell vaccines, adenovirus-delivered interferon).
• Main results:
  • In the CheckMate 743 trial (as reported by the review), median overall survival in first-line unresectable MPM was 18.1 months with nivolumab plus ipilimumab and 14.1 months with platinum-pemetrexed chemotherapy.
  • In CheckMate 743, grade 3–4 adverse events occurred in 30.3% of patients on nivolumab plus ipilimumab, and 23% stopped treatment because of adverse events. On chemotherapy, the figures were 32% and 15%.
  • In the CONFIRM trial (as reported by the review), overall survival in previously treated patients was 10 months with nivolumab and 6.9 months with placebo (HR 0.69, 95% CI 0.52–0.91; p = 0.009).
  • The authors described the DETERMINE trial of tremelimumab versus placebo as negative, with no difference in overall survival (7.7 vs. 7.3 months).
  • The authors described the PROMISE-meso trial of pembrolizumab versus chemotherapy as negative for its primary outcome: progression-free survival was 2.5 vs. 3.4 months (HR 1.06; 95% CI 0.73–1.53).
  • The authors judged that tumor subtype is not a true predictive marker of checkpoint inhibitor benefit, and that predictive markers in general remain elusive.
• The authors' conclusion: The authors concluded that combination immunotherapy is a new standard of care for unresectable malignant pleural mesothelioma. They added that the proportion of patients with prolonged response and survival remains low, and that chemotherapy combined with checkpoint inhibitors likely represents the next step.
• Limitations the authors state:
  • The authors noted that no direct comparison exists between nivolumab-ipilimumab and platinum-pemetrexed-bevacizumab.
  • The authors noted that the neoadjuvant durvalumab/tremelimumab study was too small to draw further conclusions from.
  • The authors noted that clinical data on combining checkpoint inhibitors with radiotherapy are lacking.

Topics

Medical terms in this study, explained in our Lexicon: checkpoint inhibitors, Pleural Mesothelioma, Asbestos Exposure, Prognosis, Chemotherapy, Overall Survival, Biomarker, Immunotherapy.

Related studies

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• Immune checkpoint inhibitor associated reactivation of primary membranous nephropathy responsive to rituximab — J.S. Lin, D.Y. Wang, et al. (2020)
• Pre-treatment high-sensitivity troponin T for the short-term prediction of cardiac outcomes in patients on immune checkpoint inhibitors — S. Petricciuolo, M.G. Delle Donne, et al. (2021)
• Epigenetic Alterations and Biomarkers for Immune Checkpoint Inhibitors-Current Standards and Future Perspectives in Malignant Pleural Mesothelioma Treatment — Y. Yoshikawa, K. Kuribayashi, et al. (2020)
• PD-L1 Testing for Immune Checkpoint Inhibitors in Mesothelioma: For Want of Anything Better? — S. Lantuejoul, N. Le Stang, et al. (2017)
• Immune checkpoint inhibitors in malignant pleural mesothelioma — G.L. Ceresoli, A. Mantovani (2017)

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