The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?

Our plain-English summary of The resistance related to targeted therapy in malignant pleural mesothelioma: Why has not the target been hit yet?, by G. Bronte, L. Incorvaia, S. Rizzo, et al (Critical Reviews in Oncology/hematology, 2016).

The study

• Authors: G. Bronte, L. Incorvaia, S. Rizzo, F. Passiglia, A. Galvano, F. Rizzo, C. Rolfo, D. Fanale, A. Listì, C. Natoli, V. Bazan, A. Russo
• Journal: Critical Reviews in Oncology/hematology
• Published: 2016;107:20-32
• Type of article: Review
• Cited by: 28 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant pleural mesothelioma (MPM) is an aggressive tumor of the pleura with a poor prognosis. The most active first-line regimens are platinum compounds and pemetrexed. There is no standard second-line treatment in MPM. Advances in the understanding of tumor molecular biology have led to the development of several targeted treatments, which have been evaluated in clinical trials. Unfortunately none of the explored targeted treatments can currently be recommended as routine treatment in MPM. We reviewed the biological pathways involved in MPM, the clinical trials about targeted therapy, and possible related mechanisms of resistance. We suggest that specific genetic markers are needed as targets of selective therapy. By this way the selection of patients based on the molecular profile may facilitate a therapeutic strategy that allows the use of the most appropriate drug for each patient.

Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

In plain English

This article was a review, not a new study, and did not study asbestos exposure. The authors searched Medline–PubMed, EMBASE and the Cochrane Library and summarized other researchers' work on genetic changes in malignant pleural mesothelioma (MPM), trials of targeted drugs, and possible reasons tumors resist them. In a French trial of 448 patients, adding bevacizumab to cisplatin and pemetrexed lengthened median overall survival from 16.1 to 18.8 months (hazard ratio 0.76, 95% confidence interval 0.61–0.94). Vorinostat did not improve overall survival over placebo in 661 patients (VANTAGE-014). In the DETERMINE study, tremelimumab given alone was not superior to placebo for overall survival, the main outcome, in second- or third-line treatment. As possible explanations for resistance, the authors pointed to the rarity of activating EGFR mutations, loss of the PTEN protein, and compensating pathways. The authors concluded that cisplatin plus pemetrexed was the only treatment with a clinically significant impact on survival and quality of life, and that adequate second-line therapies were lacking. They added that selecting patients by their tumor's molecular profile may help match each patient to the most appropriate drug.

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 published research, based on a literature search of Medline–PubMed, EMBASE and the Cochrane Library
• Who was studied: Published studies on malignant pleural mesothelioma: biological pathways, clinical trials of targeted therapy, and mechanisms of resistance. The number of studies reviewed is not given.
• Exposure: Not an asbestos exposure study. The review covered targeted treatments for MPM, including anti-angiogenic drugs, PDGF, c-MET, mesothelin, PI3K, mTOR, FAK, histone deacetylase, HSP90 and NF-κB inhibitors, arginine deaminase, and immunotherapy.
• Main results:
  • Reported from a French randomized trial (Zalcman et al.) of 448 patients given cisplatin and pemetrexed with or without bevacizumab: median overall survival 16.1 vs. 18.8 months, hazard ratio 0.76 (95% confidence interval 0.61–0.94). The review's table lists 18.8 months for the bevacizumab arm.
  • Reported from the VANTAGE-014 trial (661 patients, second- or third-line): median overall survival was 30.7 weeks with vorinostat vs. 27.1 weeks with placebo (hazard ratio 0.98, P = 0.86).
  • Reported from the DETERMINE study: tremelimumab alone was not superior to placebo for the primary endpoint of overall survival in second- or third-line patients (median 7.7 vs 7.3 months; HR 0.92, 95% CI 0.76–1.12, p = 0.408).
  • Reported from the KEYNOTE-028 phase Ib study of pembrolizumab in PD-L1-positive MPM: partial response in 7 of 25 participants, and stable disease in 12.
  • Reported from a phase II single-arm trial: everolimus was negative in patients whose disease had progressed after first-line chemotherapy.
  • As possible resistance mechanisms, the authors discussed the rarity of activating EGFR mutations, and loss of PTEN expression leading to constant AKT activation.
• The authors' conclusion: The authors concluded that cisplatin plus pemetrexed was the only treatment with a clinically significant impact on survival and quality of life. They found no adequate second-line therapies and said predictive molecular markers were not yet used in routine practice. They suggested that selecting patients by molecular profile may allow use of the most appropriate drug for each patient.

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: Targeted Therapy, Pleural Mesothelioma, Pleura, Prognosis, Pemetrexed (Alimta), Clinical Trial.

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• Malignant pleural mesothelioma: genome-wide expression patterns reflecting general resistance mechanisms and a proposal of novel targets — O.D. Røe, E. Anderssen, et al. (2010)
• Molecular resistance fingerprint of pemetrexed and platinum in a long-term survivor of mesothelioma — O.D. Røe, A. Szulkin, et al. (2012)
• Prevalence of in vitro chemotherapeutic drug resistance in primary malignant pleural mesothelioma: result in a cohort of 203 resection specimens — A.A. Mujoomdar, T.R. Tilleman, et al. (2010)
• Vorinostat eliminates multicellular resistance of mesothelioma 3D spheroids via restoration of Noxa expression — D. Barbone, P. Cheung, et al. (2012)
• Interaction and cross-resistance of cisplatin and pemetrexed in malignant pleural mesothelioma cell lines — M. Kitazono-Saitoh, Y. Takiguchi, et al. (2012)

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