Abstract 4079: EVT801: a selective VEGFR3 inhibitor with the potential for combination with immune-checkpoint therapies, preclinical evidences and plans for first-in-human evaluation

• Published in: Cancer research (Chicago, Ill.) Ill.), 2019-07, Vol.79 (13_Supplement), p.4079-4079
• Main Authors: Fons, Pierre, Esquerre, Michael, Paillasse, Michael, Visentin, Virgile, Dol, Frederique, Meneyrol, Jerome, Badet, Gaelle, Cogo, Eric, Vidaud, Lionel, Alam, Antoine, Blanc, Isabelle, Bono, Francoise, Lisztwan, Joanna, Poublanc, Muriel, Filleron, Thomas, Hunneyball, Ian, Delord, Jean-Pierre, Whittaker, Mark
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2019-4079

We have identified a highly selective VEGFR3 inhibitor drug candidate, which strongly inhibits angiogenesis without inducing hypoxia, reputed as one of the main causes of cancer-associated immunosuppression. Combination of EVT801 and Immune Checkpoint Therapy (ICT) could be synergistic as hypoxia-induced-immunosuppression should be avoided. We have demonstrated that EVT801 is a narrow spectrum inhibitor of the VEGFR3 tyrosine kinase with residual activity against VEGFR2 and TAK1 and with an activity on VEGFRs different from Fruquitinib and Lenvatinib. We then showed that EVT801 inhibited human endothelial cell proliferation in vitro and tumor angiogenesis on ex-vivo mouse ring aortic assay. EVT801 was active in vivo in the RIP1-Tag2 mouse model during the angiogenic switch. In comparison to sorafenib, EVT801 in 2 different tumors mouse model decreased tumor development without inducing increase of hypoxia which is in favor to a sustained blood vessel tumor normalization. In orthotopic 4T1 mammary carcinoma, we demonstrated that EVT801 in combination with PD1 mAb was significantly superior than single agent treatment and a decrease of lung metastasis spreading was observed. We observed that decrease of MDSCs in blood in response to EVT801 was correlated with decrease in tumor weight. By IHC analysis, we showed that treatment with EVT801 increases CD8+ T-cells infiltration inside the tumor. Taken together, these results indicated that EVT801 represents an innovative anti-angiogenic drug for cancer immunotherapy which may improve the frequency of response to ICT. Clinical trial design including patient stratification and biomarkers of activity has been proposed in order to be ready for first-in-human evaluation by mid-2019. Citation Format: Pierre Fons, Michael Esquerre, Michael Paillasse, Virgile Visentin, Frederique Dol, Jerome Meneyrol, Gaelle Badet, Eric Cogo, Lionel Vidaud, Antoine Alam, Isabelle Blanc, Francoise Bono, Joanna Lisztwan, Muriel Poublanc, Thomas Filleron, Ian Hunneyball, Jean-Pierre Delord, Mark Whittaker. EVT801: a selective VEGFR3 inhibitor with the potential for combination with immune-checkpoint therapies, preclinical evidences and plans for first-in-human evaluation [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 4079.