Brivanib has had a massive investment and was tested for treatment of patients with hepatocellular cancer in 25 different clinical trials and all trials have failed including four Phase 3 trials, the last in 2017 (clinicaltrials.gov). In general, the drug is well tolerated, but is failing trials for its poor efficacy, especially when compared to Sorafenib, the only approved drug on the market for this disease. The patient response to the drug is variable with some participants having a positive response and others with no effect.
The drug targets are 7 receptors in the tyrosine kinase family, three Vascular Endothelial Growth Factor Receptors 1-3 (VEGFR) and four Fibroblast Growth Factor Receptors 1-4 (FGFR). We took a closer look at one target VEGFR2 as an example. The structure for structure for Brivanib complexed with a receptor was not available but there is a structure with another ATP analog, AAL993 that binds VEGFR2 (PDB: 5EW3). The contact residues for the drug with the binding site are: V848, A866, V867, K868, I892, E885, I888, L889, V898, V914, V916, E917, C919, L1019, L1035, I1044, D1046, F1047.
There are no mutations in VEGFR2 for hepatocellular cancer and only 17 VEGFR2 variants for other disorders in ClinVar, the main public disease-variant database. However, there are 713 missense variants observed in ~250,000 people (GnomAD) ranging from singletons to 22% allele frequency; 74 variants are in the drug binding site region. There are about 1,500 missense variants observed in cancers (COSMIC), with approximately 100 in this binding site region.