Phase II, Open-Label Study of Brivanib as First-Line Therapy in Patients with Advanced Hepatocellular Carcinoma

Abstract

Purpose: Brivanib, a selective dual inhibitor of fibroblast growth factor and VEGF signaling, has demonstrated encouraging antitumor activity in preclinical and phase I studies. We performed a phase II open-label study of brivanib as first-line therapy in patients with unresectable, locally advanced, or metastatic hepatocellular carcinoma.Experimental Design: Brivanib was administered orally at a dose of 800 mg once daily. The primary objective was 6-month progression-free survival, progression-free survival rate; secondary objectives were tumor response rate, time to response, duration of response, median progression-free survival, median overall survival, disease control rate (complete response, partial response, or stable disease ! 42 days), and safety and tolerability.Results: Between March 2007 and May 2009, 55 patients were treated and were evaluable for response. Patients were assessed using modified World Health Organization (mWHO) criteria. According to mWHO criteria and as assessed by Independent Response Review Committee, the six-month progression-free survival rate (95% CI) was 18.2% (9.1%-30.9%). Median progression-free survival (95% CI) was 2.7 months (1.4-3.0). One patient achieved a complete response and three achieved a partial response. Twenty-two had stable disease. Median overall survival (95% CI) was 10 (6.8-15.2) months. Brivanib was generally well tolerated; the most common adverse events included fatigue, hypertension, and diarrhea.Conclusion: Brivanib as first-line therapy demonstrates promising antitumor activity and a manageable safety profile in patients with advanced, unresectable HCC.

Targeting FGFR Pathway in Human Hepatocellular Carcinoma: Expressing pFGFR and pMET for Antitumor Activity

“…The FGFR inhibitor that has been most extensively studied in patients with HCC is brivanib, an ATP-competitive dual inhibitor of VEGFR and FGFR1-3 (24). Despite strong preclinical and phase II data of HCC (25,26), brivanib failed in large randomized phase III trials in both the first-and second-line settings for patients with advanced HCC (27,28). Nonetheless, FGFR inhibition remains an attractive therapeutic target for HCC, and requires further investigation of its possible clinical applications.…”

Current management of hepatocellular carcinoma: An Eastern perspective

“…Although an overall survival time of 9.8 mo was observed in a phase Ⅱ study [85] , sunitinib did not outperform sorafenib in a phase Ⅲ randomized study (overall survival, 8.1 and 10.0 mo, respectively; P = 0.0019) [86] . Brivanib, a selective dual inhibitor of fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) signaling, was associated with a median overall survival of 10 mo in a phase Ⅱ trial [87] and was considered a promising new drug for advanced HCC. However, the primary endpoint of brivanib not being non-inferior to sorafenib was not met in a subsequent phase Ⅲ trial (overall survival, 9.5 and 9.9 mo, respectively, P value is nonsignificant) [88] .…”

Potential Molecular Targets and Drugs for Treatment of Hepatocellular Carcinoma

“…On the other hand, brivanib, which targets VEGFR, PDGFR and FGFR, also failed to prolong OS (Table 1) in a phase III trial conducted to investigate its efficacy as a first line therapy even though it had a more favorable toxicity profile than sorafenib [89,90]. Moreover, another phase III, randomized, placebo-controlled study investigated the efficacy of brivanib after sorafenib failure and the authors reported that, in comparison to placebo, brivanib resulted in a longer median TTP but insignificant increase in the OS (Table 1) [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107][108].…”