Background:

BMS-540215 is an ATP-competitive inhibitor of human VEGFR -2, with an IC50 of 25 nmol/L and Ki of 26 nmol/L. In addition, it inhibits VEGFR-1 (IC50 = 380 nmol/L) and VEGFR-3 (IC50 = 10 nmol/L). BMS-540215 also showed good selectivity for FGFR-1 (IC50 = 148 nmol/L), FGFR-2 (IC50 =125 nmol/L), and FGFR-3 (IC50 = 68 nmol/L).
Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are known to be involved in growth and neovascularization of HCC. Therefore, agents that target these pathways may be effective in the treatment of HCC. Brivanib alaninate is a dual inhibitor ofVEGF receptor (VEGFR) and FGF receptor (FGFR) signaling pathways. Brivanib is hydrolyzed to the active moiety BMS-540215 in vivo.
In vitro: InVEGF-stimulated and basic FGF stimulated SK-HEP1 cells, brivanib significantly inhibited VEGFR-2, FGFR-1, extracellular signal-regulated kinase 1/2, and Akt phosphorylation [1].
In vivo: Six different s.c. patient-derived HCC xenografts were implanted into mice. Tumor growth was evaluated in mice treated with brivanib compared with control. Brivanib significantly suppressed tumor growth in five of six xenograft lines. Tumor weights in these mice that were treated with 50 and 100 mg/kg brivanib by gavage daily for 12 days were approximately 55% and 13%, respectively, compared with vehicle-treated mice. Furthermore, brivanib, at a dose of 100 mg/kg, also inhibited tumor growth in mice with patientderived xenograft lines 2-1318 and 26-1004 [1].
Clinical trial: A total of 750 patients were randomly assigned (376 in arm A and 374 in arm B). Median OS in the intent-to-treat population was 8.8 months in arm A and 8.1 months in arm B. Median progression-free survival (PFS) was 5.0 months in arm A and 3.4 months in arm B. Partial responses observed (13.6% v 7.2%) were higher in arm A. Despite positive effects on PFS and objective response, cetuximab plus brivanib increased toxicity and did not significantly improve OS in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal cancer.
参考文献:
[1] Huynh H, Ngo VC, Fargnoli J, Ayers M, Soo KC, Koong HN, Thng CH, Ong HS, Chung A, Chow P, Pollock P, Byron S, Tran E. Brivanib alaninate, a dual inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor tyrosine kinases, induces growth inhibition in mouse models of human hepatocellular carcinoma. Clin Cancer Res. 2008;14(19):6146-53.
[2] Siu LL, Shapiro JD, Jonker DJ, Karapetis CS, Zalcberg JR, Simes J, Couture F, Moore MJ, Price TJ, Siddiqui J, Nott LM, Charpentier D, Liauw W, Sawyer MB, Jefford M, Magoski NM, Haydon A, Walters I, Ringash J, Tu D, O'Callaghan CJ. Phase III randomized, placebo-controlled study of cetuximab plus brivanib alaninate versus cetuximab plus placebo in patients with metastatic, chemotherapy-refractory, wild-type K-RAS colorectal carcinoma: the NCIC Clinical Trials Group and AGITG CO.20 Trial. J Clin Oncol. 2013;31(19):2477-84.