Target Therapy in Malignant Pleural Mesothelioma: Hope or Mirage?

Our plain-English summary of Target Therapy in Malignant Pleural Mesothelioma: Hope or Mirage?, by F. Borea, M.A. Franczak, M. Garcia, et al (International Journal of Molecular Sciences, 2023).

The study

• Authors: F. Borea, M.A. Franczak, M. Garcia, M. Perrino, N. Cordua, R.T. Smolenski, G.J. Peters, R. Dziadziuszko, A. Santoro, P.A. Zucali, E. Giovannetti
• Journal: International Journal of Molecular Sciences
• Published: 2023;24(11)
• Type of article: Review
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Malignant Pleural Mesothelioma (MPM) is a rare neoplasm that is typically diagnosed in a locally advanced stage, making it not eligible for radical surgery and requiring systemic treatment. Chemotherapy with platinum compounds and pemetrexed has been the only approved standard of care for approximately 20 years, without any relevant therapeutic advance until the introduction of immune checkpoint inhibitors. Nevertheless, the prognosis remains poor, with an average survival of only 18 months. Thanks to a better understanding of the molecular mechanisms underlying tumor biology, targeted therapy has become an essential therapeutic option in several solid malignancies. Unfortunately, most of the clinical trials evaluating potentially targeted drugs for MPM have failed. This review aims to present the main findings of the most promising targeted therapies in MPM, and to explore possible reasons leading to treatments failures. The ultimate goal is to determine whether there is still a place for continued preclinical/clinical research in this area.

In plain English

This article was a review, not a new study. The authors summarized published laboratory and clinical research on targeted drugs for malignant pleural mesothelioma (MPM), a cancer they noted has been linked to asbestos. They also looked at why such treatments have failed. They wrote that most clinical trials of potential targeted drugs had failed to deliver, despite promising laboratory results. Among the trials they described, the MAPS trial reported median overall survival of 18.8 versus 16.1 months when bevacizumab was added to pemetrexed and cisplatin. The RAMES trial reported 13.8 versus 7.5 months for second-line ramucirumab plus gemcitabine compared with placebo plus gemcitabine. Other trials they described did not show a statistically significant improvement in their main outcomes: the phase III part of LUME-Meso (nintedanib), VANTAGE-014 (vorinostat) and COMMAND (defactinib). Two smaller single-arm trials met their primary endpoints for disease control: MiST1 (rucaparib) and MiST2 (abemaciclib). The authors concluded that it may be necessary to reconsider the idea that targeting a single factor can manage MPM, and to focus instead on combination strategies.

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 preclinical and clinical studies of targeted therapies in malignant pleural mesothelioma
• Who was studied: published laboratory studies and clinical trials of targeted drugs in malignant pleural mesothelioma (some trials also included peritoneal mesothelioma or other cancers); no new patients were studied
• Exposure: The review covered targeted drugs (anti-angiogenic, growth factor, mTOR/PI3K, CDK4/6, FAK, PARP, histone deacetylase, EZH2, mesothelin and arginine-depleting agents), not asbestos exposure. Asbestos was mentioned only as linked to MPM. No fiber types were named.
• Main results:
  • The authors stated that most clinical trials of potential targeted drugs in MPM gave unsatisfactory results, despite promising preclinical results.
  • MAPS phase III trial (as described in the review), in 448 chemo-naive patients: median overall survival was 18.8 months with pemetrexed, cisplatin and bevacizumab versus 16.1 months with chemotherapy alone.
  • RAMES phase II trial (as described in the review), in 165 patients given second-line treatment: median overall survival was 13.8 months with ramucirumab plus gemcitabine versus 7.5 months in the control group.
  • LUME-Meso phase III part (as described in the review), nintedanib versus placebo with chemotherapy: both groups had a median progression-free survival of 6.8 months.
  • VANTAGE-014 phase III trial (as described in the review), 661 previously treated patients: there was no statistically significant improvement in overall survival with vorinostat versus placebo (30.7 versus 27.1 weeks).
  • COMMAND trial (as described in the review), 344 patients given defactinib or placebo as maintenance: neither progression-free survival nor overall survival was greater in the defactinib arm.
  • MiST2 (as described in the review): with abemaciclib, 14 of 26 treated patients with p16ink4A-negative MPM had disease control at 12 weeks (54%).
  • MiST1 (as described in the review): with rucaparib, 15 of 26 treated patients with BAP1- or BRCA1-deficient mesothelioma had disease control at 12 weeks (58%), meeting the primary endpoint.
  • ARCS-M trial (as described in the review), 248 patients: there was no statistically significant difference in progression-free survival between anetumab ravtansine and vinorelbine (median 4.3 versus 4.5 months).
  • ADAM phase II trial (as described in the review), 68 ASS1-deficient patients: median progression-free survival was 3.2 months with ADI-PEG20 versus 2.0 months with best supportive care.
• The authors' conclusion: The authors concluded that it may be necessary to reconsider the notion that targeting a single factor can effectively manage MPM, and to focus instead on designing combination strategies that work at multiple levels.

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, Neoplasm, Chemotherapy, Pemetrexed (Alimta), checkpoint inhibitors, Prognosis, Targeted Therapy, Clinical Trial.

Related studies

• Searching for targets for the systemic therapy of mesothelioma — R.A. Stahel, W. Weder, et al. (2015)
• Systemic treatment of malignant pleural mesothelioma: new agents in clinical trials raise hope of relevant improvements — D.C. Christoph, W.E. Eberhardt (2014)
• Molecular Alterations in Malignant Pleural Mesothelioma: A Hope for Effective Treatment by Targeting YAP — F. Dubois, C. Bazille, et al. (2022)
• 3D Culture Models of Malignant Mesothelioma Reveal a Powerful Interplay Between Photodynamic Therapy and Kinase Suppression Offering Hope to Reduce Tumor Recurrence — B.Q. Spring, D. Kessel (2019)
• Phase II study of pemetrexed and carboplatin plus bevacizumab as first-line therapy in malignant pleural mesothelioma — G.L. Ceresoli, P.A. Zucali, et al. (2013)
• A phase II study of the combination of gemcitabine and imatinib mesylate in pemetrexed-pretreated patients with malignant pleural mesothelioma — P.A. Zucali, M. Perrino, et al. (2020)

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