As reported in the Journal of Clinical Oncology by D. Ross Camidge, MD, PhD, and colleagues, a second prespecified interim analysis of the pivotal phase III ALTA-1L trial has shown maintained progression-free survival benefit with brigatinib vs crizotinib in ALK inhibitor–naive patients with ALK-positive advanced non–small cell lung cancer (NSCLC).
Findings in the first interim analysis of the trial supported the May 2020 U.S. Food and Drug Administration approval of brigatinib for the treatment of adult patients with ALK-positive metastatic NSCLC.
“Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and quality of life over crizotinib, making it a promising first-line treatment [for] ALK-positive NSCLC.”— D. Ross Camidge, MD, PhD, and colleagues
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Study Details
In the open-label trial, 275 patients were randomly assigned between April 2016 and August 2017 to receive brigatinib at 180 mg once daily after a 7-day lead-in at 90 mg once daily (n = 137) or crizotinib at 250 mg twice daily (n = 138). The primary endpoint was progression-free survival as assessed by blinded independent review committee. The first interim analysis of progression-free survival was performed after 99 events had occurred, with a median brigatinib group follow-up of 11.0 months. The second interim analysis was performed after occurrence of 150 events.
Key Findings
After a median follow-up of 24.9 months in the brigatinib group, blinded independent review committee–assessed median progression-free survival was 24.0 months in the brigatinib group vs 11.0 months in the crizotinib group (hazard ratio [HR] = 0.49, P < .0001), with estimated 2-year rates of 48% vs 26%. The benefit of brigatinib was consistent across subgroups.
Pharmacokinetic analysis indicated that brigatinib daily area under the plasma concentration time curve was not a predictor of blinded independent review committee–assessed progression-free survival.
On investigator assessment, median progression-free survival was 29.4 months vs 9.2 months (HR = 0.43, 95% confidence interval [CI] =0.31–0.61), with estimated 2-year rates of 56% vs 24%.
The blinded independent review committee–assessed objective response rate was 74% vs 62%, with a median duration of response of not reached vs 13.8 months.
The overall survival probability at 2 years was 76% vs 74% (HR = 0.92, P = .771).
Among 61 patients in the crizotinib group (44% of group) who crossed over to brigatinib, median blinded independent review committee–assessed progression-free survival was 15.6 months (at a median follow-up of 14.4 months). In analysis adjusting for crossover effect, the hazard ratio for overall survival was 0.70 (95% CI = 0.39–1.26).
Among 96 patients with blinded independent review committee–identified baseline brain metastases, committee-assessed intracranial progression-free survival at 2 years was 48% vs 15%. Among 41 patients with measurable lesions, intracranial response rate was 78% vs 26%.
On assessment with the EORTC QLQ-C30 questionnaire, the brigatinib group had delayed median time to worsening of global health status/quality of life scores (HR = 0.70, P = .049).
No new safety concerns were identified.
The investigators concluded: “Brigatinib represents a once-daily ALK inhibitor with superior efficacy, tolerability, and quality of life over crizotinib, making it a promising first-line treatment [for] ALK-positive NSCLC.”
Dr. Camidge, of the University of Colorado Cancer Center, Anschutz Cancer Pavilion, Aurora, is the corresponding author for the Journal of Clinical Oncology article.
Disclosure: The study was supported by ARIAD Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited. For full disclosures of the study authors, visit ascopubs.org.
