Searching for targets for the systemic therapy of mesothelioma

Our plain-English summary of Searching for targets for the systemic therapy of mesothelioma, by R.A. Stahel, W. Weder, E. Felley-Bosco, et al (Annals of Oncology, 2015).

The study

• Authors: R.A. Stahel, W. Weder, E. Felley-Bosco, U. Petrausch, A. Curioni-Fontecedro, I. Schmitt-Opitz, S. Peters
• Journal: Annals of Oncology
• Published: 2015;26(8):1649-60
• Type of article: Review
• Cited by: 30 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is an incurable disease associated with asbestos exposure arising in the pleural cavity and less frequently in the peritoneal cavity. Platinum-based combination chemotherapy with pemetrexed is the established standard of care. Multimodality approaches including surgery and radiotherapy are being investigated. Increasing knowledge about the molecular characteristics of mesothelioma had led to the identification of novel potential targets for systemic therapy. Current evidence suggests pathways activated in response to merlin deficiency, including Pi3K/mTOR and the focal adhesion kinase, as well as immunotherapeutic approaches to be most promising. This review elaborates on the rationale behind targeted approaches that have been and are undergoing exploration in mesothelioma and summarizes available clinical results and ongoing efforts to improve the systemic therapy of mesothelioma.

© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].

In plain English

This article was a narrative review of targeted drug and immune therapies being explored for malignant mesothelioma. The authors described mesothelioma as an incurable disease associated with asbestos exposure, but the review did not study asbestos exposure itself. The authors summarized laboratory research and earlier and ongoing clinical trials. Among the trials they reviewed, four phase II trials of imatinib as a single agent, with 94 patients in total, produced no objective responses. A placebo-controlled phase III trial of vorinostat in 660 previously treated patients was negative for all end points. In a phase III trial of thalidomide maintenance in 222 patients, time to progression was 3.6 months with thalidomide and 3.5 months in the comparison arm. The review's text calls that arm placebo, but its cited reference describes it as active supportive care. Preliminary results of a trial adding bevacizumab to cisplatin and pemetrexed showed disease control at 6 months in 73.5% of the bevacizumab group versus 43.2% of the comparison group. The authors concluded that the most promising approaches were immunotherapy and pathways activated when cells lack the protein merlin, including PI3K/mTOR and focal adhesion kinase.

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 (no systematic search method described)
• Who was studied: Published and ongoing clinical trials and laboratory studies of systemic (drug) therapy for mesothelioma, mostly malignant pleural mesothelioma. The review gives no total number of studies and no search dates.
• Exposure: The review did not study asbestos exposure. Asbestos is mentioned only as the established association with mesothelioma. The review covered drug treatments, including focal adhesion kinase inhibitors, PI3K/mTOR inhibitors, tyrosine kinase inhibitors, HDAC inhibitors, proteasome inhibitors, bevacizumab, thalidomide and immunotherapies.
• Main results:
  • Reviewed trials of imatinib: four published phase II trials of imatinib as a single agent, with 94 patients treated in total, showed no objective response.
  • Reviewed trial of vorinostat: a placebo-controlled phase III trial in 660 mesothelioma patients who had progressed after pemetrexed and platinum was negative for all end points.
  • Reviewed trial of thalidomide maintenance: a phase III trial in 222 patients found time to progression of 3.6 months in the thalidomide arm versus 3.5 months in the comparison arm. The review's text calls the comparison arm placebo. Its cited reference (ref. 74) describes the comparison as active supportive care in an open-label trial.
  • Reviewed trial of bevacizumab: in a phase II/III trial of cisplatin and pemetrexed with or without bevacizumab, preliminary analysis showed disease control at 6 months of 73.5% in the bevacizumab arm versus 43.2% in the other arm, P = 0.010. Final results were awaited.
  • Reviewed trial of GDC-0980 (a PI3K/mTOR inhibitor): a phase I extension cohort showed two objective responses among 26 mesothelioma patients (preliminary result).
  • Reviewed trial of tremelimumab (an immune checkpoint inhibitor): in a phase II trial, 2 of 29 patients had durable partial responses. The primary end point was not met.
• The authors' conclusion: The authors concluded that current evidence points to two approaches as most promising: pathways activated by merlin deficiency, including PI3K/mTOR and focal adhesion kinase, and immunotherapy.

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: Systemic Therapy, Mesothelioma, Malignant Mesothelioma, Asbestos Exposure, Pleural Cavity, Peritoneal Cavity, Chemotherapy, Pemetrexed (Alimta).

Related studies

• Multipoint targeting of the PI3K/mTOR pathway in mesothelioma — S. Zhou, L. Liu, et al. (2014)
• Systemic approach to malignant pleural mesothelioma: what news of chemotherapy, targeted agents and immunotherapy? — D. Signorelli, M. Macerelli, et al. (2016)
• Inhibition of autophagy sensitizes malignant pleural mesothelioma cells to dual PI3K/mTOR inhibitors — N. Echeverry, G. Ziltener, et al. (2015)
• Advances in systemic therapy for malignant mesothelioma: future perspectives — N. Sobhani, S.P. Corona, et al. (2017)
• Inhibition of phosphoinositide-3 kinase pathway down regulates ABCG2 function and sensitizes malignant pleural mesothelioma to chemotherapy — B. Fischer, C. Frei, et al. (2012)
• p90 ribosomal S6 kinase: a potential therapeutic target in lung cancer — N. Poomakkoth, A. Issa, et al. (2016)

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