Abstract B189: Synergistic effect of c-Met inhibitor savolitinib in combination with a VEGFR inhibitor fruquintinib in clear cell renal cell carcinoma xenograft models

Renal cell carcinoma (RCC) is the most common type of kidney tumor in human. Approximately 80∼85% of RCC is clear cell renal cell carcinoma (ccRCC). [1] Although VEGF/VEGFR targeted therapies bring significant advances in the treatment of RCC, ultimate resistance occurs in most cases following a transient period of clinical benefit. [2] The hepatocyte growth factor (HGF) receptor c-Met activation emerges as one of the mechanisms for resistance to anti-VEGF/VEGFR therapies in ccRCC, [3] implying that a combinational inhibition of c-Met and VEGFR pathways may induce a synergistic anti-tumor effect and could produce additional clinical benefit. The aim of this study was to assess the effect of a combination strategy targeting the VEGFR and c-Met pathways in ccRCC xenograft models. Savolitinib (AZD6094, HMPL-504) is a highly selective inhibitor against c-Met. Fruquintinib (HMPL-013) strongly inhibits VEGFR1, 2 and 3. Both of them were discovered by Hutchison MediPharma and are currently being evaluated in clinical trials for the treatment of various cancers. Several subcutaneous xenograft models were established in nude mice with human ccRCC cell lines or patient derived tumors (PDX) to investigate the anti-tumor effect of combination of savolitinib with fruquntinib. Treatment with savolitinib or fruquintinib at clinically relevant dose only exhibited mild to moderate tumor growth inhibition as a single agent in all of tested models, but significantly increased anti-tumor effect was observed in all of tested models for the combination group. It seemed that the enhanced anti-tumor effect was associated with c-Met inhibition. In a ccRCC PDX model KIN1T1342, the increased anti-tumor effect was correlated with dose increment of savolitinib. Immunohistochemistry (IHC) analysis revealed that combination treatment produced stronger inhibition on tumor proliferation marker Ki67 and angiogenesis marker CD31, compared to either savolitinib or fruquntinib alone, indicating that the observed synergistic effect might be attributed to the dual inhibition on tumor signaling and tumor microenvironment. C-Met expression was observed in all tested models, and treatment with savolitinib effectively suppressed phospho-Met. To evaluate c-Met expression in Chinese ccRCC patients, Formalin-Fixed and Parrffin-Embedded (FFPE) tumor sections were collected from sixty-two treatment-naive patients during surgical resection. Positive c-Met expression was found in 69% (43/62) of ccRCC samples under IHC staining.Overall our data demonstrated that c-Met was widely expressed in Chinese ccRCC patients and provided a rationale to test the combined HGF/c-Met and VEGF/VEGFR pathway blockade in the treatment of ccRCC in the clinical trials. References: 1. Harshman LC et al . Cancer J. 2013;19: 316-323 2. Swanton C et al . Genome Med. 2010; 2(8): 53 3.Ciamporcero E et al . Mol Cancer Ther. 2015: 14 (1); 101-10. Citation Format: Yongxin Ren, Shiming Fan, Yunxin Chen, Renxiang Tang, Wei Zhang, Jianxing Tang, Linfang Wang, Dongxia Shi, Hongbo Chen, Min Cheng, Weiguo Qing, Weiguo Su. Synergistic effect of c-Met inhibitor savolitinib in combination with a VEGFR inhibitor fruquintinib in clear cell renal cell carcinoma xenograft models. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B189.