Purpose Most crizotinib-treated patients with anaplastic lymphoma kinase gene ( 
ALK)-rearranged non-small-cell lung cancer (ALK-positive NSCLC) eventually 
experience disease progression. We evaluated two regimens of brigatinib, an 
investigational next-generation ALK inhibitor, in crizotinib-refractory 
ALK-positive NSCLC. Patients and Methods Patients were stratified by brain 
metastases and best response to crizotinib. They were randomly assigned (1:1) to 
oral brigatinib 90 mg once daily (arm A) or 180 mg once daily with a 7-day 
lead-in at 90 mg (180 mg once daily [with lead-in]; arm B). 
Investigator-assessed confirmed objective response rate (ORR) was the primary 
end point. Results Of 222 patients enrolled (arm A: n = 112, 109 treated; arm B: 
n = 110, 110 treated), 154 (69%) had baseline brain metastases and 164 of 222 
(74%) had received prior chemotherapy. With 8.0-month median follow-up, 
investigator-assessed confirmed ORR was 45% (97.5% CI, 34% to 56%) in arm A and 
54% (97.5% CI, 43% to 65%) in arm B. Investigator-assessed median 
progression-free survival was 9.2 months (95% CI, 7.4 to 15.6) and 12.9 months 
(95% CI, 11.1 to not reached) in arms A and B, respectively. Independent review 
committee-assessed intracranial ORR in patients with measurable brain metastases 
at baseline was 42% (11 of 26 patients) in arm A and 67% (12 of 18 patients) in 
arm B. Common treatment-emergent adverse events were nausea (arm A/B, 33%/40%), 
diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 
18%/34%), and were mainly grades 1 to 2. A subset of pulmonary adverse events 
with early onset (median onset: day 2) occurred in 14 of 219 treated patients 
(all grades, 6%; grade ≥ 3, 3%); none occurred after escalation to 180 mg in arm 
B. Seven of 14 patients were successfully retreated with brigatinib. Conclusion 
Brigatinib yielded substantial whole-body and intracranial responses as well as 
robust progression-free survival; 180 mg (with lead-in) showed consistently 
better efficacy than 90 mg, with acceptable safety.