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 progressed 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 efficacy 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 analyses 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 ratio: 0.48 [95% confidence interval: 0.32–0.71]). Treatment-related adverse events in more than 30% of patients (brigatinib, 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.
Bibliographical noteFunding Information:
The authors thank the patients, their families, and their caregivers; the ALTA-3 investigators and their team members at each study site; and colleagues from Takeda Pharmaceutical Company Limited. Medical writing support for the development of this manuscript, under the direction of the authors, was provided by Lauren Gallagher, RPh, PhD, and Lela Creutz, PhD, of Peloton Advantage, LLC, an OPEN Health company, and funded by Takeda Development Center Americas, Inc. , Lexington, Massachusetts, and complied with the Good Publication Practice guidelines (DeTora LM, et al. Ann Intern Med. 2022;175:1298-1304). This study was sponsored by Takeda Development Center Americas, Inc., Lexington, Massachusetts.
© 2023 International Association for the Study of Lung Cancer
- Anaplastic lymphoma kinase
- Non–small cell lung cancer
- Tyrosine kinase inhibitor