Nintedanib Is Active in Malignant Pleural Mesothelioma Cell Models and Inhibits Angiogenesis and Tumor Growth <i>In Vivo</i>.

Abstract

<b>Purpose:</b> Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor type with limited treatment options and poor prognosis. The angiokinase inhibitor nintedanib has shown promising activity in the LUME-Meso phase II MPM trial and thus is currently being evaluated in the confirmatory LUME-Meso phase III trial. However, the anti-MPM potential of nintedanib has not been studied in the preclinical setting.<b>Experimental Design:</b> We have examined the antineoplastic activity of nintedanib in various <i>in vitro</i> and <i>in vivo</i> models of human MPM.<b>Results:</b> Nintedanib's target receptors were (co)expressed in all the 20 investigated human MPM cell lines. Nintedanib inhibited MPM cell growth in both short- and long-term viability assays. Reduced MPM cell proliferation and migration and the inhibition of Erk1/2 phosphorylation were also observed upon nintedanib treatment <i>in vitro</i> Additive effects on cell viability were detected when nintedanib was combined with cisplatin, a drug routinely used for systemic MPM therapy. In an orthotopic mouse model of human MPM, survival of animals receiving nintedanib <i>per os</i> showed a favorable trend, but no significant benefit. Nintedanib significantly reduced tumor burden and vascularization and prolonged the survival of mice when it was administered intraperitoneally. Importantly, unlike bevacizumab, nintedanib demonstrated significant <i>in vivo</i> antivascular and antitumor potential independently of baseline VEGF-A levels.<b>Conclusions:</b> Nintedanib exerts significant antitumor activity in MPM both <i>in vitro</i> and <i>in vivo</i> These data provide preclinical support for the concept of LUME-Meso trials evaluating nintedanib in patients with unresectable MPM. <i>Clin Cancer Res; 24(15); 3729-40. ©2018 AACR</i>.