Targeting the vasculature: anti-angiogenic agents for malignant mesothelioma

Our plain-English summary of Targeting the vasculature: anti-angiogenic agents for malignant mesothelioma, by P.L. Chia, P.A. Russell, A.M. Scott, et al (Expert Review of Anticancer Therapy, 2016).

The study

• Authors: P.L. Chia, P.A. Russell, A.M. Scott, T. John
• Journal: Expert Review of Anticancer Therapy
• Published: 2016;16(12):1235-1245
• Type of article: Review
• Cited by: 7 articles, as counted by NIH iCite
• Read it: PubMed · Publisher

Abstract

Malignant mesothelioma (MM) is an aggressive malignancy of the pleura and other serosal membranes originating from mesothelial cells that, despite decades of research, continues to have limited therapeutic options and is associated with a poor prognosis. Areas covered: MMs induce a strong inflammatory response that is also associated with neoangiogenesis and activation of proangiogenic factors. Given this, several anti-angiogenic agents have been trialled in a variety of malignancies including mesothelioma. Herein we summarise the role of angiogenesis in MM and the current available data targeting these pathways. Expert commentary: The addition of bevacizumab to cisplatin/pemetrexed chemotherapy is currently a therapeutic option with a proven 2.7 month overall survival benefit in fit patients less than 75. Other antiangiogenics such as nintedinib show early promise, although the Phase III trial results are eagerly awaited before this therapy enters treatment paradigms. Beyond this, it is likely that combinations of antiangiogenics with immunotherapies will be investigated in future studies.

In plain English

This article was a review, not a new study. The authors, from Melbourne, Australia, summarised what was known about new blood vessel growth (angiogenesis) in malignant mesothelioma and the trial results for drugs that target it. They described the MAPS phase III trial in pleural mesothelioma. In that trial, median overall survival was 18.8 months with cisplatin, pemetrexed and bevacizumab, compared with 16.1 months with cisplatin and pemetrexed alone. The authors noted that this trial mainly recruited relatively young, fit patients (under 76 years). They added that real-world patients are often elderly and have other illnesses. The review reported that several other trials either did not meet their main goals or showed limited activity. These included a phase II trial adding bevacizumab to cisplatin-gemcitabine, a phase III trial of thalidomide maintenance, a phase III trial of NGR-hTNF, and phase II trials of several tyrosine kinase inhibitors. The authors concluded that bevacizumab with first-line chemotherapy will likely become a new standard of care. They also concluded that most anti-angiogenic trials in mesothelioma had disappointing results, and that trial results for nintedanib were awaited.

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 and ongoing research
• Who was studied: Laboratory studies and clinical trials of anti-angiogenic and vessel-targeting drugs in malignant mesothelioma (MM), mostly pleural mesothelioma
• Exposure: Drug treatments targeting tumor blood vessels: VEGF/VEGFR inhibitors (e.g. bevacizumab), thalidomide, multi-targeted tyrosine kinase inhibitors, PDGF inhibitors and vascular disrupting agents. Asbestos exposure was not studied.
• Main results:
  • MAPS phase III trial (as described by the review): median overall survival was 18.8 months (95% CI 15.9 to 22.6) with cisplatin, pemetrexed and bevacizumab, compared with 16.1 months (14.0 to 17.9) with cisplatin and pemetrexed alone; hazard ratio 0.77 (0.62 to 0.95); p=0.0167
  • The MAPS trial included 448 patients
  • Randomized phase II trial in untreated MM patients: adding bevacizumab to cisplatin-gemcitabine did not improve response rate (25% vs 22%), progression-free survival (6.9 vs 6.0 months) or overall survival (15.6 vs 14.7 months) compared with chemotherapy alone
  • NVALT5/MATES phase III trial of thalidomide maintenance versus observation in 222 patients: hazard ratio 1.0 (p = 0.71) for time to progression and 1.2 (p = 0.30) for overall survival; the review described thalidomide as not effective in this role
  • NGR015 phase III trial in pretreated advanced pleural MM: overall survival did not differ significantly between NGR-hTNF plus chemotherapy and placebo plus chemotherapy (median 8.4 vs 7.9 months; HR 0.94, p = 0.61)
  • Vatalanib phase II trial: among 47 patients evaluated, partial responses were seen in 6% and stable disease in 72%
  • Sunitinib phase II trial: median overall survival was 6.1 months and median time to progression was 3.5 months
  • The authors' overall assessment was that most clinical trials of anti-angiogenic drugs in MM had disappointing results
• The authors' conclusion: The authors concluded that bevacizumab combined with first-line chemotherapy will likely become a new standard of care for MM. They also expected further trials of oral agents such as nintedanib, and combinations with immunotherapy.
• Limitations the authors state:
  • The authors noted that the MAPS trial selected relatively young and fit patients (age under 76 years). Real-world mesothelioma patients are often elderly with significant other illnesses.
  • The authors stated that studies of serum VEGF as a predictor of outcome had small sample sizes and varying cut-off levels, so they need independent confirmation
  • The authors noted that because MM is uncommon, it is difficult to run further trials of a drug once its first study fails

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: Malignant Mesothelioma, Pleura, Mesothelial Cells, Prognosis, Mesothelioma, Angiogenesis, Bevacizumab, Cisplatin.

Related studies

• Anti-angiogenic therapies for malignant pleural mesothelioma — G.L. Ceresoli, P.A. Zucali (2012)
• Closing faucets: the role of anti-angiogenic therapies in malignant pleural diseases — D. Marquez-Medina, S. Popat (2016)
• Current data on predictive markers for anti-angiogenic therapy in thoracic tumours — N. Reinmuth, M. Thomas, et al. (2010)
• Combinatorial anti-angiogenic gene therapy in a human malignant mesothelioma model — S. Kubo, M. Takagi-Kimura, et al. (2015)
• Novel therapies for malignant pleural mesothelioma — A. Scherpereel, F. Wallyn, et al. (2018)
• NGR-hTNF in combination with best investigator choice in previously treated malignant pleural mesothelioma (NGR015): a randomised, double-blind, placebo-controlled phase 3 trial — V. Gregorc, R.M. Gaafar, et al. (2018)

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