LAUSR

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.