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.
Patients with advanced ALK+ NSCLC that progressed on crizotinib were randomized 1:1 to brigatinib 180 mg once daily (7-day lead-in, 90 mg) or alectinib 600 mg twice daily, aiming to test superiority. The primary endpoint was blinded independent review committee (BIRC)-assessed progression-free survival (PFS). Interim analysis for efficacy and futility was planned at approximately 70% of 164 expected PFS events.
The population (N=248; brigatinib, n=125; alectinib, n=123) was notable for long median duration of prior crizotinib (16.0-16.8 months) and low rate of ALK fusion in baseline circulating tumor DNA (ctDNA; 78/232 [34%]). Median BIRC-assessed PFS was 19.3 months with brigatinib and 19.2 months with alectinib (hazard ratio: 0.97 [95% confidence interval [CI]: 0.66-1.42]; p=0.8672]). The study met futility criterion. Overall survival was immature (41 events [17%]). Exploratory analyses pooled across treatment groups demonstrated 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% CI: 0.32-0.71]). Treatment-related adverse events in >30% of patients (brigatinib/alectinib) were elevated blood creatine phosphokinase (70%/29%), aspartate aminotransferase (53%/38%), and alanine aminotransferase (40%/36%).
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.

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