Abstract 1214: Enhancement of anti-PD-1 antitumor efficacy in syngeneic preclinical models by the angiogenesis inhibitor lucitanib
Authors: Rachel L. Dusek, Liliane Robillard, Thomas C. Harding, Andrew D. Simmons, Minh Nguyen
Journal: Cancer Research (2019)

Abstract Background: Lucitanib is a small molecule inhibitor of multiple tyrosine kinases, including some that promote angiogenesis. Lucitanib monotherapy has demonstrated potent tumor growth inhibition in xenograft models of various carcinomas, mediated predominately through the inhibition of angiogenesis. In addition to its role in angiogenesis, vascular endothelial growth factor (VEGF) and other angiogenic factors are thought to dampen antitumor immune responses by promoting inhibitory immune subsets, suppressing dendritic cell maturation, and altering lymphocyte development and trafficking. In these studies, we further characterized lucitanib’s kinase selectivity and investigated the antitumor efficacy of lucitanib in combination with anti-PD-1 therapy. Methods &amp; Results: The inhibitory profile of lucitanib was evaluated against 376 wild-type kinases in functional enzymatic assays. At 500 nM, lucitanib demonstrated &amp;gt;35% inhibition of 5.1% (19/376) of the kinases evaluated. The IC50 values of lucitanib against VEGF receptors 1-3 (VEGFR1-3), platelet-derived growth factor receptors alpha/beta (PDGFRα/β), and fibroblast growth factor receptors 1-3 (FGFR1-3) ranged from 8.96 to 95.7 nM. In addition, inhibition was observed against DDR1, CSF1R, RET, and KIT. Cell-based kinase assays confirmed that lucitanib is a potent and selective VEGFR1-3, PDGFRα/β, and FGFR1-3 inhibitor. Lucitanib antitumor activity was evaluated in combination with an anti-PD-1 antibody in a panel of syngeneic murine models. The combination treatment was generally well tolerated. In the H22 hepatocellular carcinoma model, the tumor growth inhibition in animals treated with lucitanib (10 mg/kg once daily), anti-PD-1 (5 mg/kg biweekly), or the combination was 58.6%, 50.4%, and 81.4%, respectively, following 16 days of treatment. The median survival time (MST) for lucitanib and anti-PD-1 treated animals was 35.0 and 46.5 days, respectively, whereas the MST had not been reached for the combination group when the study was terminated on day 63. Importantly, the combination treatment resulted in 2/10 mice that were tumor free at the end of the study; however, there were no tumor-free animals in the groups treated with the single agents. Antitumor efficacy was also greater with the combination of lucitanib and anti-PD-1 therapy than with treatment with the single agents in the MC38 and CT26 syngeneic murine models of colon cancer. Conclusions: Lucitanib demonstrated potent and selective targeting of VEGFR1-3, PDGFRα/β, and FGFR1-3 and enhanced antitumor activity when combined with PD-1 inhibition in multiple syngeneic models. Results from these studies support the clinical development of combined lucitanib and anti-PD-1 treatments to further evaluate the safety and efficacy of the combination in multiple tumor types. Citation Format: Rachel L. Dusek, Liliane Robillard, Thomas C. Harding, Andrew D. Simmons, Minh Nguyen. Enhancement of anti-PD-1 antitumor efficacy in syngeneic preclinical models by the angiogenesis inhibitor lucitanib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1214.