Despite the advances in new targeted therapies in ALK positive population, most 
patients progress under ALK inhibitors within first 2 years; being the brain the 
most frequent site of relapse. ALK mutations, in ~30% of patients, are the main 
known mechanism of resistance. Classically, second-generation ALK inhibitors 
have been the standard of care in the crizotinib-resistant population; however, 
each ALK inhibitor has a different spectrum of sensitivity to ALK mutations, 
complicating the optimal treatment strategy for the resistant population. 
Brigatinib (AP26113) is a novel highly selective and potent inhibitor of ALK and 
ROS1 with a high degree of selectivity. In vitro, brigatinib not only inhibited 
ALK with 12-fold higher potency compared to crizotinib, but also inhibited 
IGF-1R, FLT3 and EGFR mutants, with some activity against the EGFRT790M 
resistance mutation. In xenograft models, brigatinib overcomes resistance to ALK 
inhibitors, including the ALK G1202R mutation, which is resistant to first- and 
second-generation inhibitors. The efficacy of brigatinib in 
crizotinib-resistant, ALK-positive patients has been demonstrated in two early 
studies, which led to its approval in this setting, and it is currently being 
investigated as the first-line therapy versus crizotinib in tyrosine kinase 
inhibitor-naïve patients. Brigatinib demonstrates not only promising whole-body 
activity, but also an impressive improvement of intracranial outcomes in terms 
of both objective response rate and progression-free survival in the 
crizotinib-resistant population, with optimal efficacy at 180 mg (following a 90 
mg run-in for 7 days) and good tolerance. These data confirm brigatinib as an 
excellent therapeutic strategy after crizotinib failure, particularly in the 
setting of central nervous system involvement. In this review, we summarize the 
two main clinical studies reported to date with brigatinib in ALK-positive 
advanced NSCLC patients, in particular, in the crizotinib-resistant population. 
We also address the mechanism of action for development of resistance and the 
challenging issues of optimal implementation for sequences of administration for 
ALK inhibitors.