Brigatinib in Crizotinib-Refractory ALK+ NSCLC: 2-Year Follow-up on Systemic and Intracranial Outcomes in the Phase 2 ALTA Trial
Abstract
Introduction: We present updated findings from a phase 2 randomized trial assessing the efficacy of brigatinib in patients with crizotinib-refractory anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC).
Methods: Patients were randomly assigned (1:1) to receive either oral brigatinib 90 mg daily (arm A) or 180 mg daily with a 7-day lead-in at 90 mg (arm B). Stratification was based on the presence of central nervous system (CNS) metastases and best response to crizotinib. The primary endpoint was the confirmed objective response rate, as assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary endpoints included progression-free survival (PFS), intracranial PFS (iPFS), and overall survival (OS), as evaluated by an independent review committee (IRC). Exploratory analyses focused on response to target lesions in the CNS versus ex-CNS and the relationship between the depth of response and PFS/OS.
Results: Of the 222 patients randomized (112 in arm A and 110 in arm B), 59 (27%) remained on brigatinib at the time of analysis, with median follow-up of 19.6 months for arm A and 24.3 months for arm B. At baseline, 71% of patients in arm A and 67% in arm B had brain lesions. Investigator-assessed confirmed objective response rates were 46% for arm A and 56% for arm B. Median IRC-assessed PFS was 9.2 months (95% CI: 7.4-12.8) for arm A, compared to 16.7 months (95% CI: 11.6-21.4) for arm B. Median OS was 29.5 months (18.2 months to not reached) for arm A, and 34.1 months (27.7 months to not reached) for arm B. Among patients with measurable baseline brain lesions, IRC-confirmed intracranial objective response rates were 50% (13 of 26) for arm A and 67% (12 of 18) for arm B, with median durations of intracranial response of 9.4 months and 16.6 months, respectively. IRC-assessed iPFS was 12.8 months for arm A and 18.4 months for arm B. Across both arms, median IRC-assessed PFS ranged from 1.9 months (for patients with no target lesion shrinkage) to 15.6 months (for those with 76%-100% shrinkage). No new safety concerns were noted with extended follow-up.
Conclusions: Brigatinib (180 mg once daily with lead-in) continues to show significant PFS benefits, prolonged iPFS, and durable intracranial response in crizotinib-refractory patients. The depth of response may serve as a valuable endpoint in future studies of targeted therapies.