Abstract 1015: VEGFR-3 expression profiling by histology to classify patient population for the selective VEGFR-3 inhbitor EVT801
Authors: Paillasse michael , Ancey pierre-benoit , Badet Gaelle , Gomez-Brouchet Anne , Selves Janik , Rochaix philippe , Battistella Maxime , Lebbe Celeste , Cassier philippe , Gomez-Roca carlos , Delord Jean-Pierre , Whittaker Mark , Davenne Lise , Friend John , Fitzgerald Michael , Garner James , Fons Pierre 
Published: June 2023

Abstract
Introduction: EVT801 is a highly selective small molecule inhibitor of VEGFR-3 and acts by inhibiting tumor lymphangiogenesis and angiogenesis. Among the tyrosine kinase inhibitors, EVT801 has shown compelling activity in a wide range of cancer models and favorable preclinical toxicology profile. A phase I clinical study (NCT05114668) is underway to characterize safety, tolerability, pharmacokinetics of EVT801, and explore patient stratification which will be key for further development. Literature reports VEGFR-3 expression in several tumor cells - especially in kidney and liver cancers. However, we did not detect VEGFR-3 in tumor cells in translational in vivo models we explored (i.e., chemo-induced liver cancer and panel of PDX models). To clarify the situation, we validated a highly specific protocol for VEGFR-3 immunohistochemistry labelling, readily transferable to clinical centers.
Results: We evaluated many different tumor types, and eventually focused our analysis on kidney cancer and soft tissue sarcomas. Initially, VEGFR-3 expression was assessed in 29 primary kidney cancer samples and 23 metastatic kidney cancer samples with CD34 to stain vessels and D2-40 to track lymphatics. We detected VEGFR-3 expression in the endothelial cells within the kidney tumor but not in the tumor cells. Remarkably, we observed a very distinct delineation between the kidney tumor vasculature, which showed high VEGFR-3 expression, and the normal adjacent tissue, which was devoid of VEGFR-3 expression. All vessels around and in the tumor were stained by CD34, whereas D2-40 staining was limited to the peritumoral regions. In addition, we found that VEGFR-3 expression in metastases from kidney tumors matched the expression pattern of the primary tumor. This held true even in patients treated with sunitinib, positioning EVT801 as a potential treatment option after failure of such multi tyrosine kinase inhibitors. Among the samples from 103 patients with soft tissue sarcomas, VEGFR-3 was generally highly expressed; however, 3 distinct groups emerged: i) tumors with high VEGFR-3 expression in tumor cells, tumor vessels and peritumoral vessels; ii) tumors with high expression in all vessels (tumor and peritumoral) but not in the tumor cells (similar to kidney tumors); iii) tumors with intermediate expression in peritumoral vessels.
Conclusion: We were able to quantify VEGFR-3 expression in the kidney and soft tissue sarcoma cohorts plus several others, such as hepatocarcinoma and non-small cell lung cancer. This enables us selecting indications that might benefit from EVT801 as a monotherapy (e.g., clear cell renal cell carcinoma and soft tissue sarcomas) or in combination with standard of care. Accordingly, VEGFR-3 expression is retrospectively quantified during EVT801 clinical trial phase 1 trial and may be used to stratify patients in the future.
Citation Format: michael Paillasse, pierre-benoit Ancey, Gaelle Badet, Anne Gomez-Brouchet, Janik Selves, philippe Rochaix, Maxime Battistella, Celeste Lebbe, philippe Cassier, carlos Gomez-Roca, Jean-Pierre Delord, Mark Whittaker, Lise Davenne, John Friend, Michael Fitzgerald, James Garner, Pierre Fons. VEGFR-3 expression profiling by histology to classify patient population for the selective VEGFR-3 inhbitor EVT801 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1015.