Preliminary Clinical and Molecular Analysis Results From a Single-Arm Phase 2 Trial of Brigatinib in Patients With Disease Progression After Next-Generation ALK Tyrosine Kinase Inhibitors in Advanced ALK+ NSCLC

Introduction: Brigatinib is a potent next-generation ALK tyrosine kinase inhibitor (TKI) with activity against ALK resistance mutations and central nervous system activity. We prospectively studied the activity and safety of brigatinib in patients with disease progression after other next-generation ALK TKIs. Methods: Patients with stage IIIB or IV ALK+ NSCLC and progressive disease after next-generation ALK TKIs were eligible. Patients were required to undergo tumor biopsy less than or equal to 60 days before enrollment, and circulating tumor DNA was collected at baseline. Brigatinib treatment was 90 mg daily for 7 days and then escalated to 180 mg daily. Primary end point was objective response rate, and two-stage design was used. Results: Between March 2017 and November 2018, a total of 20 patients were treated in stage 1; median age was 55 years (range: 32–71), median number of previous therapies was three (range: 1–6), median number of previous ALK TKIs was two (range: 1–4), and 11 had central nervous system disease at baseline. The objective response rate was 40% (95% confidence interval [CI]: 19%–62%), and the duration of response was 5.3 months (95% CI: 3.6–nonassessable). With follow-up of 22 months, the median progression-free survival was 7.0 months (95% CI: 4.6–10.1). Grade 3 or 4 adverse events were consistent with those of previous studies. Conclusions: Brigatinib has activity in ALK+ NSCLC after previous next-generation ALK TKIs. Further study in patients with disease progression on next-generation ALK TKI is warranted.