Brigatinib (AP26113) is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. It inhibits autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib has effectively inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
At clinically achievable concentrations (≤ 500 nM), brigatinib inhibited the in vitro viability of cells expressing EML4-ALK and 17 mutant forms associated with resistance to ALK inhibitors including crizotinib, as well as EGFR-Del (E746-A750), ROS1-L2026M, FLT3-F691L, and FLT3-D835Y. Brigatinib exhibited in vivo anti-tumor activity against 4 mutant forms of EML4-ALK, including G1202R and L1196M mutants identified in NSCLC tumors in patients who have progressed on crizotinib. Brigatinib also reduced tumor burden and prolonged survival in mice implanted intracranially with an ALK-driven tumor cell line.