Pleural mesothelioma (PM) - The status of systemic therapy

Our plain-English summary of Pleural mesothelioma (PM) - The status of systemic therapy, by W. Cui, S. Popat (Cancer Treatment Reviews, 2021).

The study

• Authors: W. Cui, S. Popat
• Journal: Cancer Treatment Reviews
• Published: 2021;100:102265
• Type of article: Review
• Cited by: 10 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Pleural mesothelioma (PM) remains a malignancy with poor prognosis. Despite initial disappointing response rates to single-agent chemotherapy, upfront platinum and anti-folate-based combination chemotherapy has remained the backbone of treatment for PM for the last three decades. The role of maintenance chemotherapy remains unclear; switch-maintenance gemcitabine has shown improvements in progression-free but not overall survival. The addition of antiangiogenic agents to chemotherapy yielded modest improvements in survival, both upfront in combination with platinum-pemetrexed, and in the relapsed setting. Immunotherapy, particularly PD-(L)1 inhibitors, has shown important but variable effectiveness in relapsed PM when used as monotherapy, and is an important salvage treatment after first-line chemotherapy. Furthermore, the randomized phase 3 trial of ipilimumab-nivolumab versus platinum-pemetrexed chemotherapy demonstrated improved overall survival favouring ipilimumab-nivolumab (HR 0.74, 96.6% CI 0.60-0.91; p = 0.0020), establishing this regimen as the new standard first-line treatment for PM, particularly in those with non-epithelioid histology. Increased interest in PM genomics has led to development of novel personalized therapeutics, such as those targeting DNA repair and EZH2 pathways, however with variable outcomes in trials. Targeting the membrane glycoprotein mesothelin and arginine deprivation are other important strategies under ongoing investigation. The field of PM is changing and new treatments bring hope to a largely lethal and poor prognostic malignancy. Despite these developments, current challenges include understanding the role of combination and multimodality treatments, drivers of resistance to treatment, and establishing predictive biomarkers to improve patient selection and treatment sequencing.

Copyright © 2021 Elsevier Ltd. All rights reserved.

In plain English

This article was a review, not a new study. The authors summarized published trials of drug treatments (systemic therapy) for pleural mesothelioma: chemotherapy, anti-angiogenic drugs, immune checkpoint inhibitors and newer targeted drugs. Asbestos was mentioned only as background; the article did not study asbestos exposure. Among the trials it described, the EMPHACIS trial reported median survival of 12.1 months with cisplatin-pemetrexed versus 9.3 months with cisplatin alone. In the MAPS trial, adding bevacizumab to cisplatin-pemetrexed gave median overall survival of 18.8 versus 16.1 months. In the CheckMate-743 trial, median overall survival was 18.1 months with ipilimumab-nivolumab versus 14.1 months with platinum-pemetrexed chemotherapy (HR 0.74, 96.6% CI 0.60 to 0.91). The gap was larger in patients with non-epithelioid tumours (18.1 versus 8.8 months). The authors concluded that ipilimumab-nivolumab is a new standard first-line treatment, particularly for non-epithelioid histology, and that chemotherapy still has a role. They cautioned that older trials are hard to compare with modern standards and that some phase 2 results should be read carefully.

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: Review of published clinical trials of systemic therapy for pleural mesothelioma (no new patient data)
• Who was studied: Patients with pleural mesothelioma enrolled in the phase 1, 2 and 3 trials reviewed (trial sizes ranged from 25 to 605 patients in the tables)
• Exposure: The article reviewed drug treatments (platinum-pemetrexed and other chemotherapy, anti-angiogenic agents such as bevacizumab and nintedanib, immune checkpoint inhibitors such as nivolumab, ipilimumab and pembrolizumab, and targeted agents). Asbestos fibres were mentioned only once as background to how the disease develops; no fiber type or exposure data were given.
• Main results:
  • EMPHACIS trial (as reported in the review): median overall survival 12.1 months with cisplatin-pemetrexed vs 9.3 months with cisplatin alone (HR 0.77; P = 0.020)
  • MAPS trial (as reported in the review): adding bevacizumab to cisplatin-pemetrexed gave median overall survival of 18.8 vs 16.1 months (HR 0.77, 95% CI 0.62 to 0.95, P = 0.0167)
  • CheckMate-743 trial (as reported in the review): in first-line patients, median overall survival was 18.1 months with ipilimumab-nivolumab vs 14.1 months with platinum-pemetrexed chemotherapy (HR 0.74, 96.6% CI 0.60 to 0.91; P = 0.0020)
  • CheckMate-743 by histology: median overall survival with ipilimumab-nivolumab was 18.7 months (epithelioid) and 18.1 months (non-epithelioid), vs 16.5 and 8.8 months with chemotherapy
  • NVALT19 trial (as reported in the review): switch-maintenance gemcitabine improved progression-free survival (median 6.2 vs 3.2 months; HR 0.48; 95% CI 0.33 to 0.71; P = 0.0002) without a significant difference in overall survival (median 16.4 vs 13.3 months)
  • CONFIRM trial (as reported in the review): in mostly third-line patients, nivolumab vs placebo gave median overall survival of 9.2 vs 6.6 months (HR 0.72; 95% CI 0.55 to 0.94; P = 0.02)
• The authors' conclusion: The authors concluded that the phase 3 trial established ipilimumab-nivolumab as a new standard first-line treatment for pleural mesothelioma, particularly in non-epithelioid histologies, while chemotherapy still has a valid role
• Limitations the authors state:
  • The authors noted that older chemotherapy trials are difficult to compare with modern standards because diagnostics and response evaluation methods were inconsistent
  • The authors cautioned that the phase 2 RAMES result for gemcitabine-ramucirumab should be interpreted with caution because of the type 1 error rate of phase 2 trials

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Systemic Therapy, Prognosis, Chemotherapy, Gemcitabine, Overall Survival, Platinum-Pemetrexed, Immunotherapy.

Related studies

• Advances in the systemic therapy of malignant pleural mesothelioma — D.A. Fennell, G. Gaudino, et al. (2008)
• Combined systemic chemoimmunotherapy in advanced diffuse malignant mesothelioma. Report of a phase I-II study of weekly cisplatin/interferon alfa-2a — P. Soulié, P. Ruffié, et al. (1996)
• Local and systemic exposure of cisplatin during hyperthermic intrathoracic chemotherapy perfusion after pleurectomy and decortication for treatment of pleural malignancies — M. Ried, T. Potzger, et al. (2013)
• Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy? — D. Signorelli, M. Macerelli, et al. (2016)
• Comprehensive treatment of malignant mesothelioma patients after the failure of systemic chemotherapy — J. Chen, B. Liang, et al. (2012)
• Peritoneal mesothelioma: current status and future directions — T.C. Chua, C.H. Chong, et al. (2012)

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