Promising investigational drug candidates in phase I and phase II clinical trials for mesothelioma

Our plain-English summary of Promising investigational drug candidates in phase I and phase II clinical trials for mesothelioma, by A. Guazzelli, E. Bakker, K. Tian, et al (Expert Opinion on Investigational Drugs, 2017).

The study

• Authors: A. Guazzelli, E. Bakker, K. Tian, C. Demonacos, M. Krstic-Demonacos, L. Mutti
• Journal: Expert Opinion on Investigational Drugs
• Published: 2017;26(8):933-944
• Type of article: Review
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma is a rare and lethal malignancy primarily affecting the pleura and peritoneum. Mesothelioma incidence is expected to increase worldwide and current treatments remain ineffective, leading to poor prognosis. Within this article potential targets to improve the quality of life of the patients and assessment of further avenues for research are discussed. Areas covered: This review highlights emerging therapies currently under investigation for malignant mesothelioma with a specific focus on phase I and phase II clinical trials. Three main areas are discussed: immunotherapy (immune checkpoint blockade and cancer vaccines, among others), multitargeted therapy (such as targeting pro-angiogenic genes) and gene therapy (such as suicide gene therapy). For each, clinical trials are described to detail the current or past investigations at phase I and II. Expert opinion: The approach of applying existing treatments from other cancers does not show significant benefit, with the most promising outcome being an increase in survival of 2.7 months following combination of chemotherapy with bevacizumab. It is our opinion that the hypoxic microenvironment, the role of the stroma, and the metabolic status of mesothelioma should all be assessed and characterised to aid in the development of new treatments to improve patient outcomes.

In plain English

This article is a review, not an original study. The authors summarised phase I and phase II clinical trials of new drug treatments for malignant mesothelioma, noting 256 mesothelioma trials listed on ClinicalTrials.gov. They grouped the treatments into three areas: immunotherapy (including cancer vaccines, antibodies, engineered T cells and immune checkpoint inhibitors), targeted drugs such as those aimed at EGFR and VEGF, and gene therapy. The review did not study asbestos exposure. Among the trials it described, a phase III trial found that adding bevacizumab to pemetrexed and cisplatin improved overall survival by 2.7 months compared with pemetrexed and cisplatin alone. Gefitinib showed no clinical benefit in 40 patients. In a phase II tremelimumab trial, two patients (7%) had a durable partial response. In the pembrolizumab KEYNOTE-028 trial, five patients (20%) had a partial response and sixteen (64%) had a treatment-related side effect. The authors concluded that tumour metabolism, the low-oxygen (hypoxic) tumour environment and the surrounding tissue (stroma) are areas that offer promising points of interest for developing new treatments.

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 phase I and phase II clinical trials, with the authors' expert opinion
• Who was studied: Clinical trials of treatments for malignant mesothelioma registered on ClinicalTrials.gov (256 trials reported), with a focus on phase I and II trials
• Exposure: Investigational treatments, not asbestos exposure: immunotherapy, gene therapy and multiple targeted therapies
• Main results:
  • In a phase III trial the review describes, bevacizumab added to pemetrexed and cisplatin improved overall survival by 2.7 months compared with pemetrexed and cisplatin alone
  • In a reviewed trial of bevacizumab with cisplatin plus gemcitabine (108 chemo-naive patients), progression-free survival was 6.9 months with bevacizumab versus 6 months with placebo, and overall survival was 15.6 versus 14.7 months
  • In a reviewed trial of gefitinib in 40 mesothelioma patients with unresectable disease, the drug showed no clinical benefit
  • In a reviewed phase II trial of tremelimumab (29 patients with chemotherapy-resistant advanced malignant mesothelioma), two patients (7%) had a durable partial response, one lasting 6 months and one lasting 18 months
  • In the reviewed phase Ib KEYNOTE-028 trial of pembrolizumab, five patients (20%) had a partial response, thirteen (52%) had stable disease, and sixteen (64%) had a treatment-related adverse event
  • In a reviewed phase I trial of the CRS-207 vaccine with pemetrexed and cisplatin (38 patients), 59% had an objective partial response and median progression-free survival was 8.5 months
  • In a reviewed gene therapy study (adenovirus HSVtk/ganciclovir given into the pleural space), treatment was safe in 34 patients, but only 2 patients had long-term durable responses
• The authors' conclusion: The authors concluded that tumour metabolic reprogramming, the hypoxic microenvironment and the stroma offer promising points of interest for developing new mesothelioma treatments

Topics

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

Medical terms in this study, explained in our Lexicon: Clinical Trial, Mesothelioma, Pleura, Peritoneum, Prognosis, Quality of Life, Immunotherapy, Chemotherapy.

Related studies

• Therapies currently in Phase II trials for malignant pleural mesothelioma — G. Pinton, A.G. Manente, et al. (2013)
• Clinical outcomes and prognostic factors of patients with advanced mesothelioma treated in a phase I clinical trials unit — D. Papadatos-Pastos, D. Roda, et al. (2017)
• What can independent research for mesothelioma achieve to treat this orphan disease? — A. Guazzelli, P. Meysami, et al. (2019)
• Brief report: a phase II study of sunitinib in malignant pleural mesothelioma. the NCIC Clinical Trials Group — S.A. Laurie, A. Gupta, et al. (2011)
• Adjuvant dendritic cell based immunotherapy (DCBI) after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for peritoneal mesothelioma, a phase II single centre open-label clinical trial: rationale and design of the MESOPEC trial — N.L. de Boer, J.P. van Kooten, et al. (2019)
• Clinical safety and activity of pembrolizumab in patients with malignant pleural mesothelioma (KEYNOTE-028): preliminary results from a non-randomised, open-label, phase 1b trial — E.W. Alley, J. Lopez, et al. (2017)

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