Brigatinib Versus Alectinib in ALK-Positive NSCLC After Disease Progression on Crizotinib: Results of Phase 3 ALTA-3 Trial

Introduction: This open-label, phase 3 trial (ALTA-3; NCT03596866) compared efficacy and safety of brigatinib versus alectinib for ALK+ NSCLC after disease progression on crizotinib. Methods: Patients with advanced ALK+ NSCLC that pro-gressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-d lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary end point was blinded independent review committee-assessed progression-free survival (PFS). Interim analysis for effi-cacy and futility was planned at approximately 70% of 164 expected PFS events. Results: The population (N = 248; brigatinib, n = 125; alectinib, n = 123) was notable for long median duration of prior crizotinib (16.0-16.8 mo) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78 of 232 [34%]). Median blinded independent review committee-assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio = 0.97 [95% confidence interval: 0.66- 1.42], p = 0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory ana-lyses pooled across the treatment groups revealed median PFS of 11.1 versus 22.5 months in patients with versus without ctDNA-detectable ALK fusion at baseline (hazard ra-tio: 0.48 [95% confidence interval: 0.32-0.71]). Treatment -related adverse events in more than 30% of patients (brig-atinib, alectinib) were elevated levels of blood creatine phosphokinase (70%, 29%), aspartate aminotransferase (53%, 38%), and alanine aminotransferase (40%, 36%). Conclusions: Brigatinib was not superior to alectinib for PFS in crizotinib-pretreated ALK+ NSCLC. Safety was consistent with the well-established and unique profiles of each drug. The low proportion of patients with ctDNA-detectable ALK fusion may account for prolonged PFS with both drugs in ALTA-3. (c) 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons. org/licenses/by/4.0/).