Tsunami of immunotherapy reaches mesothelioma

Our plain-English summary of Tsunami of immunotherapy reaches mesothelioma, by X. Mielgo-Rubio, A. Cardeña Gutiérrez, V. Sotelo Peña, et al (World Journal of Clinical Oncology, 2022).

The study

• Authors: X. Mielgo-Rubio, A. Cardeña Gutiérrez, V. Sotelo Peña, M.V. Sánchez Becerra, A.M. González López, A. Rosero, J.C. Trujillo-Reyes, F. Couñago
• Journal: World Journal of Clinical Oncology
• Published: 2022;13(4):267-275
• Type of article: Review
• Cited by: 5 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant pleural mesothelioma (MPM) is the most common type of malignant mesothelioma. It is a rare tumor linked to asbestos exposure and is associated with a poor prognosis. Until very recently, patients with advanced or unresectable disease had limited treatment options, primarily based on doublet chemotherapy with cisplatin and pemetrexed. In 2020 and 2021, after more than a decade with no major advances or new drugs, two phase III clinical trials published results positioning immunotherapy as a promising option for the first- and second-line treatment of MPM. Immunotherapy has revolutionized the treatment of many cancers and is also showing encouraging results in malignant mesothelioma. Both immune checkpoint inhibition and dual cytotoxic T-lymphocyte-associated antigen 4 and programmed death-ligand 1 pathway blockade resulted in significantly improved overall survival in randomized phase III trials. In the CheckMate 743 trial, first-line therapy with nivolumab plus ipilimumab outperformed standard chemotherapy, while in the CONFIRM trial, nivolumab outperformed placebo in patients previously treated with chemotherapy. These two trials represent a major milestone in the treatment of MPM and are set to position immunotherapy as a viable alternative for treatment-naïve patients and patients with progressive disease after chemotherapy.

©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.

In plain English

This article was a short review (a 'minireview') of drug treatments for malignant pleural mesothelioma, focusing on immunotherapy. It did not collect new patient data and did not study asbestos exposure, which it mentioned only as background. The authors summarized two phase III trials published in 2020 and 2021. In CheckMate 743, 605 previously untreated patients with unresectable malignant pleural mesothelioma were randomly assigned to nivolumab plus ipilimumab or to standard chemotherapy. Median overall survival was 18.1 months with immunotherapy versus 14.1 months with chemotherapy. Grade 3-4 adverse events occurred in 30.3% and 32% of patients. In CONFIRM, previously treated patients with unresectable mesothelioma (pleural or peritoneal) received nivolumab (221 patients) or placebo (111 patients). Median overall survival was 9.2 versus 6.6 months, with significant benefit in the epithelioid subtype but not in non-epithelioid disease. The authors concluded that these trials position immune checkpoint inhibitors as first- and second-line options. They noted that CONFIRM compared nivolumab with placebo rather than chemotherapy, and that biomarker results have varied widely.

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 minireview of published and presented clinical trials; no new patient data
• Who was studied: Clinical trials of treatment for malignant pleural mesothelioma (MPM), from pre-immunotherapy chemotherapy trials to the phase III CheckMate 743 and CONFIRM immunotherapy trials
• Exposure: Not studied. The article concerns treatments (chemotherapy, antiangiogenic drugs, immune checkpoint inhibitors). Asbestos is mentioned only as background, citing other sources.
• Main results:
  • CheckMate 743 (as reviewed): 605 previously untreated patients with unresectable MPM were randomly assigned 1:1 to nivolumab plus ipilimumab or to standard chemotherapy.
  • CheckMate 743: at the first prespecified interim analysis, median overall survival was 18.1 months in the immunotherapy group vs 14.1 months in the chemotherapy group (HR 0.74; P = 0.002).
  • CheckMate 743: grade 3-4 adverse events occurred in 30.3% of the immunotherapy group and 32% of the chemotherapy group.
  • CheckMate 743: overall survival benefit for immunotherapy vs chemotherapy in patients with PD-L1 expression of 1% or more (HR 0.69; 95% CI 0.55-0.87); similar overall survival in the two groups with PD-L1 below 1% (HR 0.94; 95% CI 0.62-1.40).
  • CONFIRM (as reviewed): 221 patients with previously treated unresectable mesothelioma were randomized to nivolumab and 111 to placebo.
  • CONFIRM: median overall survival 9.2 months with nivolumab vs 6.6 months with placebo (HR 0.72; 95% CI 0.55-0.94); the article notes overall survival data were not mature.
  • CONFIRM: in the subgroup analysis by histologic subtype, significant overall survival benefit was found in the epithelioid subtype but not in the non-epithelioid subtype.
  • CONFIRM: grade 3-4 treatment-related adverse effects in 19% on nivolumab vs 6.3% on placebo.
  • CONFIRM: subgroup analyses by PD-L1 expression found no significant differences supporting PD-L1 as a predictor of benefit.
  • The article reports that the US Food and Drug Administration approved nivolumab plus ipilimumab as first-line treatment for MPM in October 2020.
• The authors' conclusion: The authors concluded that the two phase III trials are set to position immune checkpoint inhibitors as first- and second-line treatment options for MPM, and that efforts to find reliable biomarkers must be intensified.
• Limitations the authors state:
  • Because CONFIRM compared nivolumab with placebo, the authors state it remains unclear whether nivolumab is better than chemotherapy or gemcitabine plus ramucirumab in that setting.
  • The authors state that results for biomarkers of response to immunotherapy have varied widely, precluding definitive conclusions.
  • The CONFIRM data reviewed were preliminary, and overall survival was not mature.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Mesothelioma, Pleural Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Prognosis, Unresectable, Chemotherapy.

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• Activity of chemotherapy and immunotherapy on malignant mesothelioma: a systematic review of the literature with meta-analysis — T. Berghmans, M. Paesmans, et al. (2002)
• Depletion of Tumor-Associated Macrophages with a CSF-1R Kinase Inhibitor Enhances Antitumor Immunity and Survival Induced by DC Immunotherapy — F. Dammeijer, L.A. Lievense, et al. (2017)
• Generation of Potent T-cell Immunotherapy for Cancer Using DAP12-Based, Multichain, Chimeric Immunoreceptors — E. Wang, L.C. Wang, et al. (2015)
• Intrapleural recombinant IL-2 in passive immunotherapy for malignant pleural effusion — P. Astoul, J.R. Viallat, et al. (1993)
• Palliative and therapeutic activity of IL-2 immunotherapy in unresectable malignant pleural mesothelioma with pleural effusion: Results of a phase II study on 31 consecutive patients — B. Castagneto, S. Zai, et al. (2001)

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