INTRODUCTION: The second-generation anaplastic lymphoma kinase (ALK) inhibitor 
alectinib recently showed superior efficacy compared to the first-generation ALK 
inhibitor crizotinib in advanced ALK-rearranged NSCLC, establishing alectinib as 
the new standard first-line therapy. Brigatinib, another second-generation ALK 
inhibitor, has shown substantial activity in patients with crizotinib-refractory 
ALK-positive NSCLC; however, its activity in the alectinib-refractory setting is 
unknown.
METHODS: A multicenter, retrospective study was performed at three institutions. 
Patients were eligible if they had advanced, alectinib-refractory ALK-positive 
NSCLC and were treated with brigatinib. Medical records were reviewed to 
determine clinical outcomes.
RESULTS: Twenty-two patients were eligible for this study. Confirmed objective 
responses to brigatinib were observed in 3 of 18 patients (17%) with measurable 
disease. Nine patients (50%) had stable disease on brigatinib. The median 
progression-free survival was 4.4 months (95% confidence interval [CI]: 1.8-5.6 
months) with a median duration of treatment of 5.7 months (95% CI: 1.8-6.2 
months). Among 9 patients in this study who underwent 
post-alectinib/pre-brigatinib biopsies, 5 had an ALK I1171X or V1180L resistance 
mutation; of these, 1 had a confirmed partial response and 3 had stable disease 
on brigatinib. One patient had an ALK G1202R mutation in a 
post-alectinib/pre-brigatinib biopsy, and had progressive disease as the best 
overall response to brigatinib.
CONCLUSIONS: Brigatinib has limited clinical activity in alectinib-refractory 
ALK-positive NSCLC. Additional studies are needed to establish biomarkers of 
response to brigatinib and to identify effective therapeutic options for 
alectinib-resistant ALK-positive NSCLC patients.