Design of ALTA-1L (ALK in lung cancer trial of brigatinib in first-line), a randomized phase 3 trial of brigatinib (BRG) versus crizotinib (CRZ) in tyrosine kinase inhibitor (TKI)-naive patients (pts) with advanced anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC)

Background:BRG is an investigational, next‐generation ALK inhibitor with potent preclinical activity against rearranged ALK and CRZ‐resistant mutants. In an ongoing phase 1/2 trial, BRG has shown promising intracranial and whole‐body activity in ALK+ NSCLC pts with or without prior CRZ therapy (Lancet Oncol. 2016;17:1683‐96). In an ongoing pivotal randomized phase 2 trial (ALTA) evaluating 2 BRG regimens (90 mg qd and 180 mg qd with a 7‐d lead‐in at 90 mg), BRG has shown substantial objective response rates (ORRs) and robust progression‐free survival (PFS) in pts with CRZ‐resistant ALK+ NSCLC, particularly at 180 mg (with lead‐in), and acceptable safety (J Thorac Oncol. 2017;12:S612‐3). Based on these results, the ALTA‐1L trial was designed to assess the efficacy and safety of BRG vs CRZ in pts with advanced ALK+ NSCLC naive to TKI therapy (including ALK inhibitors).Methods:ALTA‐1L (NCT02737501) is an open‐label, multicenter, randomized phase 3 trial. Pts (≥18 y of age) are required to have locally advanced or metastatic ALK+ NSCLC, no prior TKI therapy, and ≤1 prior systemic anticancer regimen in the advanced setting. Approximately 270 pts will be stratified by presence of brain metastases at baseline and prior chemotherapy (yes/no) and randomized 1:1 to receive oral BRG (180 mg qd with a 7‐d lead‐in at 90 mg) or CRZ (250 mg bid). The primary endpoint is PFS per RECIST v1.1 assessed by a blinded independent review committee (BIRC); secondary endpoints include ORR, duration of response, overall survival, safety/tolerability, pt‐reported outcomes, and intracranial ORR/PFS. The primary endpoint will be analyzed with the Kaplan‐Meier method and a 2‐sided stratified log‐rank test after 198 events; 2 interim analyses are planned after approximately 50% and 75% of expected events. CRZ‐treated pts may cross over to BRG (180 mg [with lead‐in]) after BIRC‐assessed disease progression.