Antiangiogeneic Strategies in Mesothelioma

Our plain-English summary of Antiangiogeneic Strategies in Mesothelioma, by A.K. Nowak, S. Brosseau, A. Cook, et al (Frontiers in Oncology, 2020).

The study

• Authors: A.K. Nowak, S. Brosseau, A. Cook, G. Zalcman
• Journal: Frontiers in Oncology
• Published: 2020;10:126
• Type of article: Review
• Cited by: 35 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

There is a strong rationale for inhibiting angiogenesis in mesothelioma. Vascular endothelial growth factor (VEGF) is an autocrine growth factor in mesothelioma and a potent mitogen for mesothelial cells. Further, the abnormal tumor vasculature promotes raised interstitial pressure and hypoxia, which may be detrimental to both penetration and efficacy of anticancer agents. Antiangiogenic agents have been trialed in mesothelioma for close to two decades, with early phase clinical trials testing vascular targeting agents, the VEGF-A targeting monoclonal antibody bevacizumab, and numerous tyrosine kinase inhibitors, many with multiple targets. None of these have shown efficacy which has warranted further development as single agents in any line of therapy. Whilst a randomized phase II trial combining the multitargeted tyrosine kinase inhibitor nintedanib with platinum/pemetrexed chemotherapy was positive, these results were not confirmed in a subsequent phase III study. The combination of cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only anti-angiogenic combination showing efficacy in mesothelioma. Extensive efforts to identify biomarkers of response have not yet been successful.

Copyright © 2020 Nowak, Brosseau, Cook and Zalcman.

In plain English

This article is a review, not a new study. The authors summarized published clinical trials of drugs meant to block the growth of tumor blood vessels (antiangiogenic drugs) in malignant pleural mesothelioma. The drugs covered included the antibody bevacizumab, tyrosine kinase inhibitors such as sunitinib, cediranib and nintedanib, and other vascular-targeting agents. The review reported that in the MAPS trial of 448 patients, adding bevacizumab to cisplatin/pemetrexed chemotherapy lengthened median overall survival (18.8 vs. 16.1 months). That trial also saw more grade 3 high blood pressure (22 vs. 0%). Tyrosine kinase inhibitors given alone mostly produced response rates below 15%. Nintedanib looked promising in a randomized phase II trial, but a later phase III trial of 458 patients found no difference in progression-free survival. In MAPS, serum VEGF levels did not predict who benefited from bevacizumab. The authors concluded that cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only antiangiogenic combination showing efficacy in mesothelioma.

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 clinical trial data on antiangiogenic treatment in mesothelioma
• Who was studied: No new patients were studied. The review covered published clinical trials, focusing on malignant pleural mesothelioma (MPM).
• Exposure: Antiangiogenic drug treatments: the anti-VEGF antibody bevacizumab, various tyrosine kinase inhibitors, and other small-molecule and vascular-targeting agents. Asbestos exposure itself was not studied.
• Main results:
  • The review reports that in the MAPS trial (448 randomized patients), patients given bevacizumab with cisplatin/pemetrexed had longer median progression-free survival (9.2 vs. 7.3 months; adjusted HR 0.61; P < 0.0001) and longer median overall survival (18.8 vs. 16.1 months; adjusted HR 0.75; P = 0.0167) than those given chemotherapy alone.
  • The review reports that in MAPS, the bevacizumab arm had more grade 3 hypertension (22 vs. 0%), cardiovascular events (29 vs. 1%) and thrombotic events (6 vs. 1%) than the control arm.
  • The review reports that in an earlier randomized phase II trial (108 patients), adding bevacizumab to gemcitabine/cisplatin did not significantly improve progression-free survival (6.9 vs. 6 months, p = 0.88) or overall survival (15.6 vs. 14.7 months, p = 0.91).
  • The review reports that tyrosine kinase inhibitors given as single agents, mostly in single-arm phase II trials, gave objective response rates mostly below 15%, and none proceeded to randomized phase III trials.
  • The review reports that in the randomized phase II LUME-Meso trial (87 participants), adding nintedanib to cisplatin/pemetrexed favored the nintedanib arm for progression-free survival (HR 0.54; 95% CI 0.33 to 0.87; P = 0.010).
  • The review reports that in the phase III LUME-Meso trial (458 patients), there was no difference in progression-free survival (HR 1.01; 95% CI 0.79 to 1.30; p = 0.91). Median progression-free survival was 6.8 months in the nintedanib arm and 7.0 months in the placebo arm.
  • The review reports that in the randomized phase II S0905 trial (92 patients), adding cediranib to chemotherapy numerically improved progression-free survival (HR 0.71; p = 0.062; 7.2 vs. 5.6 months). There was no significant difference in overall survival (10 vs. 8.5 months; HR 0.88, p = 0.28).
  • The review reports that in MAPS, baseline serum VEGF did not predict benefit from bevacizumab: the interaction between treatment group and VEGF concentration was not significant for progression-free survival (p = 0.60) or overall survival (p = 0.99).
• The authors' conclusion: The authors concluded that cisplatin and pemetrexed with bevacizumab, in appropriately selected patients, remains the only antiangiogenic combination showing efficacy in mesothelioma.
• Limitations the authors state:
  • The authors note that MAPS patients were younger than 76 years, and that a higher risk of bleeding has been reported in older patients.
  • The authors note that their explanation for why bevacizumab succeeded and nintedanib failed is a hypothesis that has not been experimentally proven.

Topics

Medical terms in this study, explained in our Lexicon: Mesothelioma, Angiogenesis, Mesothelial Cells, Interstitial, Hypoxia, Clinical Trial, Monoclonal Antibody, Bevacizumab.

Related studies

• Novel targeted therapies and vaccination strategies for mesothelioma — M. Bagia, A.K. Nowak (2011)
• Occupational lung diseases: from old and novel exposures to effective preventive strategies — P. Cullinan, X. Muñoz, et al. (2017)
• Malignant pleural mesothelioma: update, current management, and newer therapeutic strategies — M. Pistolesi, J. Rusthoven (2004)
• Testing of fibrous particles: short-term assays and strategies — D. Bernstein, V. Castranova, et al. (2005)
• Malignant pleural mesothelioma: new hope in the horizon with novel therapeutic strategies — J. Remon, N. Reguart, et al. (2015)
• New therapeutic strategies for malignant pleural mesothelioma — M.A. Bonelli, C. Fumarola, et al. (2017)

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