Correlation of FGF2 tumor expression with tumor response, PFS, and changes in plasma pharmacodynamic (PD) markers following treatment with brivanib alaninate, an oral dual inhibitor of VEGFR and FGFR tyrosine kinases

Abstract

3506 Background: Many tumors express the FGFR ligand FGF2, and increased levels of FGF are correlated with poor prognosis in pts with RCC, HCC, NSCLC, esophageal, and pancreatic cancer. Brivanib is an oral prodrug of BMS-540215, a dual tyrosine kinase inhibitor of VEGFR and FGFR signaling. Brivanib inhibits FGF-stimulated and FGF-dependent cell lines. Methods: An open-label Phase I dose- escalation study of brivanib was conducted in pts with cancer who failed prior therapy (ASCO #3559, 2007). Tumor response (modified WHO) was evaluated q 8 weeks. Immunohistochemistry was used to assess expression of FGF2 in archival tumor tissue. Pts were scored positive if ≥10% of tumor cells had weak staining and negative if <10% of tumor cells had positive staining. Plasma samples were collected pretreatment (x2) and on select days during treatment. Plasma PD markers collagen IV (COL IV) and sVEGFR2 were measured using ELISA. Results: 43 evaluable pts with available archival tumor tissue were analyzed for correlations between FGF2 status (+ or -) and treatment dose with tumor response, PFS, and changes in PD plasma markers. 19 pts were FGF2- and 24 pts were FGF2+. Low (<600 mg) and high (≥600 mg) doses of brivanib were given to 17 and 26 pts, respectively. All groups of pts except high-dose FGF2+ pts had an increased average change in mean tumor size. Median PFS was longer in FGF2+ pts than FGF2- pts (Table). A greater decline from baseline in COL IV was measured in FGF2+ pts than FGF2- pts. Differences in tumor responses, PR, and SD ≥8 wks for FGF2+ and FGF2- pts are shown in the table. Conclusions: Whereas FGF overexpression is typically correlated with poor prognosis, FGF2+ tumor expression is associated with a trend for improved tumor response, PFS, and changes in plasma PD markers following treatment with brivanib compared with pts whose tumors do not express FGF2. Mean change in tumor size (%) (∼8 wks) Median PFS (days) COL IV change from baseline (%) (Day 26) (n = 42) sVEGFR2 change from baseline (%) (Day 26) (n = 39) PR SD ≥8 wks PD Low (<600 mg) (n = 17) High (≥600 mg) (n = 26) Low (<600 mg) (n = 17) High (≥600 mg) (n = 26) FGF2- (n = 19) 71 24 54 56 -16 -15 0 5 14 FGF2+ (n = 24) 28 0.9 71 107 -30 -23 2 13 9 P value 0.03* 0.075† 0.029* 0.138* * Wilcoxon rank-sum test (combined low and high dose assessing FGF2- vs FGF2+). † Log-rank test (combined low and high dose assessing FGF2- vs FGF2+). Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb