New therapeutic strategies for malignant pleural mesothelioma

Our plain-English summary of New therapeutic strategies for malignant pleural mesothelioma, by M.A. Bonelli, C. Fumarola, S. La Monica, et al (Biochemical Pharmacology, 2017).

The study

• Authors: M.A. Bonelli, C. Fumarola, S. La Monica, R. Alfieri
• Journal: Biochemical Pharmacology
• Published: 2017;123:8-18
• Type of article: Review
• Cited by: 40 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is a rare and aggressive malignant disease affecting the mesothelium, commonly associated to asbestos exposure. Therapeutic actions are limited due to the late stage at which most patients are diagnosed and the intrinsic chemo-resistance of the tumor. The recommended systemic therapy for MPM is cisplatin/pemetrexed regimen with a mean overall survival of about 12months and a median progression free survival of less than 6months. Considering that the incidence of this tumor is expected to increase in the next decade and that its prognosis is poor, novel therapeutic approaches are urgently needed. For some tumors, such as lung cancer and breast cancer, druggable oncogenic alterations have been identified and targeted therapy is an important option for these patients. For MPM, clinical guidelines do not recommend biological targeted therapy, mainly because of poor target definition or inappropriate trial design. Further studies are required for a full comprehension of the molecular pathogenesis of MPM and for the development of new target agents. This review updates pre-clinical and clinical data on the efficacy of targeted therapy and immune checkpoint inhibition in the treatment of mesothelioma. Finally, future perspectives in this deadly disease are also discussed.

Copyright © 2016 Elsevier Inc. All rights reserved.

In plain English

This review, labeled a commentary, summarized research on new treatments for malignant pleural mesothelioma, which the authors describe as commonly associated with asbestos exposure. It studied no patients of its own. Earlier trials it described reported a median overall survival of 12.1 months with cisplatin and pemetrexed. In a phase III trial of 448 patients, adding bevacizumab to that chemotherapy improved overall survival, 18.8 versus 16.1 months (hazard ratio 0.77, 95% CI 0.62 to 0.95). Erlotinib and gefitinib were not effective alone, and everolimus showed no efficacy in unselected previously treated patients. In a tremelimumab trial of 29 patients (28 with MPM, 1 peritoneal), 9 (31%) achieved disease control, although the primary endpoint was not met. Preliminary phase I results for pembrolizumab, in 25 enrolled patients with PD-L1 positive tumors, showed partial responses in 6 (24%) and a disease control rate of 76%. In that trial PD-L1 expression did not show a predictive role, and the authors noted such a role had not yet been demonstrated in mesothelioma. The authors concluded that no relevant drug target has emerged, presumably because signaling pathways are interconnected.

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 (labeled 'Commentary') of pre-clinical and clinical studies of treatments for malignant pleural mesothelioma
• Who was studied: No original study population; the review covered published pre-clinical and clinical studies, plus ongoing clinical trials as of May 2016
• Exposure: Asbestos exposure was not studied. It is mentioned only as background: the authors describe malignant pleural mesothelioma as commonly associated with asbestos exposure. The 'exposures' reviewed are treatments: chemotherapy, targeted agents and immune checkpoint inhibitors.
• Main results:
  • Reported from earlier randomized phase III trials: median overall survival was 12.1 months with cisplatin/pemetrexed and 11.4 months with cisplatin/raltitrexed
  • Reported from a phase III trial (448 chemotherapy-naive patients with unresectable MPM): adding bevacizumab to cisplatin and pemetrexed improved overall survival, 18.8 months versus 16.1 months (HR 0.77, 95% CI 0.62 to 0.95)
  • Reported from phase II studies in advanced or recurrent MPM: the EGFR inhibitors erlotinib and gefitinib were not effective as single agents
  • Reported from a phase II study: single-agent everolimus showed no efficacy in unselected previously treated patients with advanced MPM
  • Reported from the MESOT-TREM-2008 phase II trial of tremelimumab: 29 patients were treated, 28 with MPM and 1 with peritoneal mesothelioma
  • In that tremelimumab trial: no complete responses, 2 long-lasting responses, and disease control in 9 patients (31%); median overall survival was 10.7 months, but the primary endpoint of the study was not met
  • Reported from preliminary results of the KEYNOTE-028 phase I trial of pembrolizumab: of 84 patients with MPM, 38 (45%) had PD-L1 positive tumors and 25 were enrolled
  • In those 25 enrolled PD-L1 positive MPM patients: partial response in 6 (24%), stable disease in 13 (52%), disease control rate 76%
  • In that trial, PD-L1 expression did not demonstrate a predictive role for response to pembrolizumab
  • The authors noted that a predictive role of PD-L1 expression for response to pembrolizumab in mesothelioma had not been demonstrated yet, and that an ongoing trial (NCT02399371) was designed to explore it
• The authors' conclusion: The authors concluded that although many molecular alterations have been found in MPM, no relevant drug target has emerged, presumably because the interconnection among signaling pathways limits the efficacy of single targeted agents.

Topics

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

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Mesothelium, Asbestos Exposure, Systemic Therapy, Cisplatin, Pemetrexed (Alimta), Overall Survival, Prognosis.

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