137P - VEGFR-3 expression profiling by histology and mRNA signature to classify patient population for the selective VEGFR-3 inhibitor EVT801

Background

EVT801 is a highly selective small molecule inhibitor of VEGFR-3 and acts by inhibiting tumor lymphangiogenesis and angiogenesis. A phase I clinical study (NCT05114668) has started to characterize safety, tolerability, pharmacokinetics of EVT801. Clinical samples from these patients will be used to explore preliminary signals of clinical efficacy and investigate the biological activity of the drug using several biomarkers. Among them, we have investigated VEGFR3 expression profiling by histology.

Methods

We validated a highly specific protocol for VEGFR-3 immunohistochemistry labelling and a VEGFR-3 mRNA signature, readily transferable to clinical centers.

Results

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. In addition, we found that VEGFR-3 expression in metastases from kidney tumors matched the expression pattern of the primary tumor. Then, We have demonstrated that it exists a strong correlation between VEGFR-3 expression by histology and VEGFR-3 mRNA signature. We applied both VEGFR-3 signatures in different indications of interest like soft tissue sarcomas and lung cancers.

Conclusions

We were able to quantify VEGFR-3 expression by histology and mRNA signature in the kidney and soft tissue sarcoma cohorts plus several others, such as hepatocarcinoma and non-small cell lung cancer. This enables us to select 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 the EVT801 phase 1 clinical trial and may be used to stratify patients in the future.

Clinical trial identification

NCT05114668.

Editorial acknowledgement

Legal entity responsible for the study

Kazia Therapeutics Limited.

Funding

Kazia Therapeutics Limited.

Disclosure

C.A. Gomez-Roca: Financial Interests, Personal, Invited Speaker: BMS, Roche / Genentech, Pierre Fabre; Financial Interests, Personal, Other, IDMC member: Pharmamar; Financial Interests, Personal, Advisory Board: Macomics; Financial Interests, Institutional, Research Grant: Roche / Genentech; Financial Interests, Institutional, Coordinating PI: BMS, Amunix, Hookipa, Kazia Therapeutics, IDEAYA; Financial Interests, Personal, Steering Committee Member: BMS, Genentech; Non-Financial Interests, Member of Board of Directors: FITC (Société française d'Immuno-Thérapies du Cancer); Non-Financial Interests, Officer: ESMO Membership Committee, ESMO - MCBS Extended Working Group; Non-Financial Interests, Officer, Young Investigators Committee at imCORE: inFLAME; Non-Financial Interests, Member of Board of Directors, Network of Early Phase Units: OncoDistinct; Non-Financial Interests, Leadership Role: FITC (Société française d'Immuno-Thérapies du Cancer). P. Fons, P. Ancey, L. Davenne, M. Mandron, M.R. Paillasse: Financial Interests, Personal, Full or part-time Employment: Evotec. P. Cassier: Financial Interests, Personal, Advisory Board: Merck Serono/EMD, Roche, Amgen, Boehringer Ingelheim; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Other, Advisor: OSE Immunotherapeutics; Financial Interests, Institutional, Local PI: AbbVie, Blueprint, Exelixis, GSK, Janssen, Novartis, Roche, Taiho, LOXO/Eli Lilly; Financial Interests, Institutional, Coordinating PI: Amgen; Non-Financial Interests, Institutional, Product Samples: Plexxikon, Novartis, MSD, AstraZeneca, GSK. J. Delord: Financial Interests, Institutional, Advisory Board: BMS, MSD, Pierre Fabre, Roche; Financial Interests, Institutional, Invited Speaker: Merck Serono; Non-Financial Interests, Institutional, Research Grant: Amgen, AstraZeneca, BMS, Genentech, MSD, Transgene. M. Fitzgerald, J. Friend: Financial Interests, Personal, Full or part-time Employment: kazia therapeutics. P. Rochaix: Financial Interests, Institutional, Training: Roche Diagnostic.