Brivanib Alaninate (DB11865): A Comprehensive Monograph on a Dual VEGFR/FGFR Inhibitor from Discovery to Clinical Discontinuation

Executive Summary

Brivanib alaninate (BMS-582664) is an orally bioavailable, investigational small molecule designed as a targeted therapy for solid tumors. It is the L-alanine ester prodrug of its active moiety, brivanib (BMS-540215), a potent, ATP-competitive dual inhibitor of Vascular Endothelial Growth Factor Receptor 2 (VEGFR-2) and Fibroblast Growth Factor Receptor 1 (FGFR-1).[1] The development of brivanib alaninate was predicated on a strong scientific rationale, particularly for the treatment of advanced Hepatocellular Carcinoma (HCC), a malignancy where both the VEGF and FGF signaling pathways are known to be critical drivers of tumor angiogenesis, proliferation, and survival. The central hypothesis was that simultaneous inhibition of both pathways could provide a more robust and durable antitumor effect and potentially overcome the adaptive resistance mechanisms that limit the efficacy of therapies targeting only the VEGF pathway.[4]

Developed by Bristol-Myers Squibb, brivanib alaninate underwent an extensive global clinical development program that enrolled over 4,000 patients across a range of malignancies, including colorectal, cervical, and endometrial cancers, with a primary strategic focus on advanced HCC.[7] Despite promising preclinical data and encouraging results from Phase II studies, the compound's trajectory was ultimately defined by the negative outcomes of two pivotal, large-scale Phase III trials in HCC.