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. ALTA-1L was initiated in April 2016; 150 sites are planned in North America, Europe, and the Asia-Pacific region. 97 pts were enrolled as of February 6, 2017. Clinical trial information: NCT02737501