Antiangiogeneic Strategies in Mesothelioma.

Anna K Nowak,Gérard Zalcman,Alistair Cook,Solenn Brosseau

doi:10.3389/fonc.2020.00126

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.

Highlights

Malignant mesothelioma is an almost uniformly fatal malignancy aetiologically linked to asbestos fiber inhalation, mainly through occupational exposure
Most systemic therapy research has been conducted in malignant pleural mesothelioma (MPM), which will be the focus of this review
A subsequent 14-patient cohort was treated weekly, with 50% stable disease and median PFS of 3.0 months [56]. This is consistent with or even lower than the PFS seen in best supportive care and does not indicate significant activity [77]. Given that this agent had the potential to improve the activity of chemotherapy through enhancing penetration into tumor, the international randomized phase III NGR015 study was designed to assess the activity of NGRhTNF or placebo in combination with investigator choice of management in 400 patients with pre-treated mesothelioma

Summary

Introduction

Malignant mesothelioma is an almost uniformly fatal malignancy aetiologically linked to asbestos fiber inhalation, mainly through occupational exposure. The first demonstration of benefit from systemic therapy of mesothelioma was in 2003, with the EMPHACIS study showing a modest improvement in overall survival (OS) for patients receiving cisplatin/pemetrexed, over cisplatin alone [3]. The first multicenter, double-blind, placebo-controlled, randomized phase II trial of gemcitabine/cisplatin plus bevacizumab in 108 patients with previously untreated and unresectable mesothelioma was published in 2012 [49].

Results

Conclusion