Brigatinib versus crizotinib in anaplastic lymphoma kinase (ALK) inhibitor-naive advanced alk-positive non-small cell lung cancer: final results of the Phase 3 ALTA-1L trial

Abstract

Introduction: In the phase 3 ALTA-1L study of brigatinib in anaplastic lymphoma kinase (ALK) inhibitor-naive advanced ALK+ NSCLC, brigatinib demonstrated superior progression-free survival (PFS) versus crizotinib in 2 planned interim analyses. We report final efficacy, safety, and exploratory results. Methods: Patients were randomized to brigatinib 180 mg once daily (7-day lead-in at 90 mg once daily) or crizotinib 250 mg twice daily. Primary endpoint was blinded independent review committee (BIRC)-assessed PFS. Genetic alterations in plasma cell-free DNA were assessed in relation to clinical efficacy. Results: 275 patients were enrolled (brigatinib, n = 137; crizotinib, n = 138). At study end, (brigatinib median follow-up: 40.4 months), 3-year PFS by BIRC was 43% (brigatinib) versus 19% (crizotinib; median, 24.0 vs 11.1 months; HR: 0.48; 95% CI: 0.35-0.66). Median overall survival (OS) was not reached in either group (HR: 0.81; 95% CI: 0.53-1.22). Post hoc analyses suggested an OS benefit for brigatinib in patients with baseline brain metastases (HR: 0.43; 95% CI: 0.21-0.89). Detectable baseline EML4-ALK fusion variant 3 and TP53 mutation in plasma were associated with poor PFS. Brigatinib demonstrated efficacy superior to crizotinib regardless of EML4-ALK variant and TP53 mutation. Emerging secondary ALK mutations were rare in patients progressing on brigatinib. No new safety signals were observed. Conclusions: At ALTA-1L final analysis, with longer follow-up brigatinib continued to demonstrate superior efficacy and tolerability versus crizotinib in patients with or without poor prognostic biomarkers. The suggested survival benefit with brigatinib in patients with brain metastases warrants future study.