ALTA-1L (ALK in lung cancer trial of BrigAtinib in 1st Line): A randomized, phase 3 trial of brigatinib (BRG) versus crizotinib (CRZ) in tyrosine kinase inhibitor (TKI)–naive, advanced anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC)

Abstract

Background: The investigational oral ALK inhibitor BRG has potent preclinical activity against rearranged ALK and mutants resistant to CRZ. In a phase 1/2 study, BRG showed promising clinical activity, both systemically and in the brain, in ALK+ NSCLC patients ( pts), including those with prior CRZ therapy and those who were CRZ-naive. Based on the results of an ongoing pivotal randomized phase 2 trial exploring 2 regimens of BRG (90 mg once daily and 180 mg once daily with a 7-d lead-in at 90 mg), which demonstrated substantial efficacy in pts with CRZ-resistant ALK+ NSCLC and an acceptable safety profile, the ALTA-1L trial was designed to evaluate the efficacy and safety of BRG vs CRZ in pts with advanced ALK+ NSCLC naive to ALK-targeted therapy. Trial design: The ALTA-1L trial (NCT02737501) is a multicenter, randomized, open-label, phase 3 trial. Eligible pts (≥18 years) must have locally advanced or metastatic ALK+ NSCLC without prior TKI therapy. Pts may have received up to 1 regimen of systemic anticancer therapy in the advanced setting. Approximately 270 pts will be randomized 1:1 to receive BRG (180 mg once daily with a 7-d lead-in at 90 mg) or CRZ (250 mg twice daily). Pts will be stratified by brain metastases at baseline (present vs absent) and history of prior chemotherapy (yes vs no). The primary endpoint of this study is progression-free survival (PFS) assessed by a blinded independent review committee (BIRC). The primary analysis will be performed after 198 events are observed, with 2 interim analyses planned after approximately 50% and 75% of the total expected events. Secondary endpoints include objective response rate (ORR), duration of response, overall survival, intracranial ORR and intracranial PFS, safety and tolerability, and pt-reported outcomes. Pts randomized to CRZ are permitted to cross over to BRG (180 mg once daily with a 7-d lead-in at 90 mg) after BIRC-assessed progression. The trial was initiated in April 2016 with 150 planned sites in North America, Europe, and the Asia-Pacific region.