Immunotherapy, the promise for present and future of malignant pleural mesothelioma (MPM) treatment

Our plain-English summary of Immunotherapy, the promise for present and future of malignant pleural mesothelioma (MPM) treatment, by V. Gounant, S. Brosseau, G. Zalcman (Therapeutic Advances in Medical Oncology, 2021).

The study

• Authors: V. Gounant, S. Brosseau, G. Zalcman
• Journal: Therapeutic Advances in Medical Oncology
• Published: 2021;13:17588359211061956
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Due to occupational asbestosis exposure, the incidence of malignant pleural mesothelioma (MPM) has continuously increased over the last 30 years, with a plateau anticipated around the year 2030 in Western countries. Molecular MPM carcinogenesis involves alterations of NF2, RASSF1, LATS2WT1, p16, as well as BAP-1tumor-suppressor genes, which usually regulate apoptosis, cell invasion, motility, cell division, chromatin remodeling, as well as control of DNA repair. In few selected patients, debulking surgery consisting of pleurectomy-decortication is carried out, resulting in unsatisfactory long-term results. For about 15 years, first-line chemotherapy has been primarily based on a doublet of pemetrexed and cisplatin. Adding the monoclonal antibody bevacizumab (Avastin®), which targets vascular endothelial growth factor (VEGF), has been shown to improve overall survival (OS) by nearly 19 months. The emergence of immune check-point inhibitors (ICIs) in MPM treatment has recently been associated with substantial survival improvements in both second- and first-line settings. Similarly to non-small-cell lung cancer (NSCLC) patients, on-going trials are presently exploring the chemotherapy-ICI combination in MPM management, and depending on their results, this combination could represent a further major advance in this previously orphan disease. The current article reviews recent clinical trial results, as well as future clinical developments in this moving field.

© The Author(s), 2021.

In plain English

This article was a review, not a new study. The authors reviewed clinical trials of immune checkpoint inhibitor drugs for malignant pleural mesothelioma. It did not study asbestos exposure. In the DETERMINE trial of 571 patients, tremelimumab alone (an anti-CTLA-4 drug) gave no survival gain over placebo (median survival 7.7 versus 7.3 months). In the CONFIRM trial, median survival was 9.2 months with nivolumab versus 6.6 months with placebo. In the MAPS2 trial, median survival was 11.9 months with nivolumab and 15.9 months with nivolumab plus ipilimumab. In CheckMate 743 (605 patients, first treatment), median survival was 18.1 months with nivolumab plus ipilimumab versus 14.1 months with pemetrexed plus platinum. PROMISE-meso found no statistically significant difference between pembrolizumab and chemotherapy in progression-free or overall survival, but response was significantly more frequent with pembrolizumab (22% versus 6%). The authors concluded that the data support anti-PD-1 or anti-PD-L1 drugs, combined with an anti-CTLA-4 drug as first treatment or without one in second or third line, but not an anti-CTLA-4 drug alone. They noted that different PD-L1 tissue tests had given contradictory results.

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 (immune checkpoint inhibitors) in malignant pleural mesothelioma
• Who was studied: Patients with malignant pleural mesothelioma in the trials reviewed (some trials also included peritoneal mesothelioma), in second-line and first-line treatment settings. Examples are the DETERMINE trial (571 patients) and the CheckMate 743 trial (605 pleural mesothelioma patients).
• Exposure: No asbestos exposure was studied. The review covers immune checkpoint inhibitor drugs (tremelimumab, ipilimumab, pembrolizumab, nivolumab, avelumab, durvalumab), given alone, combined with each other, or combined with pemetrexed-platinum chemotherapy. The article attributes mesothelioma to occupational exposure in a single phrase, worded as 'asbestosis exposure', with no further detail.
• Main results:
  • DETERMINE trial (as reviewed): tremelimumab versus placebo in previously treated patients. Median overall survival was 7.7 months in the tremelimumab group versus 7.3 months in the placebo group (HR = 0.92; p = 0.408). There was no survival gain.
  • CONFIRM trial (as reviewed, presented at a 2021 meeting): median overall survival was 9.2 months (95% CI 7.5 to 10.8) in nivolumab-treated patients versus 6.6 months in placebo-treated patients. The article prints HR = 0.72, p = 0.01, with a 95% CI of 0.55 to 0.94 placed next to the placebo figure.
  • PROMISE-meso trial (as reviewed): 144 previously treated patients. There was no statistically significant difference between pembrolizumab and single-agent chemotherapy in progression-free survival or overall survival.
  • PROMISE-meso trial (as reviewed): the centrally reviewed best overall response was significantly higher in the pembrolizumab arm (22%) than in the chemotherapy arm (6%, p = 0.004 stratified).
  • MAPS2 trial (as reviewed): 125 previously treated patients in a non-comparative randomized phase 2 trial. Median overall survival was 11.9 months (95% CI 6.7 to 17.4) with nivolumab and 15.9 months (95% CI 10.7 to 22.2) with nivolumab plus ipilimumab.
  • CheckMate 743 trial (as reviewed): 605 pleural mesothelioma patients receiving first-line treatment. Median overall survival was 18.1 months (95% CI 16.8 to 21.4) with nivolumab plus ipilimumab versus 14.1 months (95% CI 12.4 to 16.2) with pemetrexed plus platinum (HR = 0.74, p = 0.002).
  • DREAM trial (as reviewed): single-arm trial of durvalumab plus cisplatin-pemetrexed in 54 first-line patients. Median overall survival was 18.4 months (95% CI 13.1 to 24.8), and 24-month survival was 37%.
• The authors' conclusion: The authors concluded that the accumulating data support anti-PD-1 or anti-PD-L1 antibodies in combination with an anti-CTLA-4 antibody in the first-line setting, or without one in the second- or third-line settings, but not anti-CTLA-4 single therapy. They wrote that available data support an adverse prognostic effect of PD-L1 expression in mesothelioma. They noted that results of further trials, including chemotherapy-immunotherapy combinations, were awaited.
• Limitations the authors state:
  • The authors noted that studies of PD-L1 expression in mesothelioma used different antibodies and staining machines, which gave contradictory results.
  • The authors stated that the choice of chemotherapy comparison arm in the CheckMate 743 trial could be debated.

Topics

Medical terms in this study, explained in our Lexicon: Immunotherapy, Pleural Mesothelioma, Carcinogenesis, Apoptosis, Cytoreductive Surgery, Pleurectomy/Decortication (P/D), Chemotherapy, Pemetrexed (Alimta).

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• Surgical treatment of malignant peritoneal mesothelioma: past, present, and future — H.R. Alexander (2010)
• Malignant Pleural Mesothelioma: State-of-the-Art on Current Therapies and Promises for the Future — F. Nicolini, M. Bocchini, et al. (2019)
• Asbestos use and asbestos-related diseases in Asia: past, present and future — G.V. le, K. Takahashi, et al. (2011)
• Interventional therapies for malignant pleural effusions: the present and the future — R. Thomas, R. Francis, et al. (2014)
• Exposure to asbestos: past, present and future — E. Pira, F. Donato, et al. (2018)

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