Brigatinib, a next-generation ALK inhibitor, has robust efficacy in patients with ALK-positive NSCLC that is refractory to crizotinib. The efficacy of brigatinib, as compared with crizotinib, in patients with advanced ALK-positive NSCLC who have not previously received an ALK inhibitor is unclear.

The Phase 3, open-label ALTA-1L study (NCT02737501), randomly assigned in a 1:1 fashion 275 ALK inhibitor-naïve patients with ALK-rearranged advanced NSCLC to either receive brigatinib 180 mg once daily or crizotinib 250 mg twice daily. Brigatinib was initiated at 90 mg per day in the first seven days.

The primary efficacy endpoint was the progression-free survival PFS) by a blinded independent central review (BIRC). The secondary endpoints included the objective response rate (ORR) and intracranial response. A planned interim analysis was scheduled when approximately 50% of 198 expected primary efficacy events (disease progression or death) had occurred.

After 99 events, at the first interim analysis, the median follow-up was 11.0 months for the brigatinib group (N=137) and 9.3 months for the crizotinib group (N=138). The estimated 12-month PFS-rate with brigatinib was 67% (95% CI, 56-75) vs 43% (95% CI, 32-53) with crizotinib (HR=0.49; 95% CI, 0.33-0.74; p<0.001). The ORR by BIRC measured 71% (95% CI, 62-78) and 60% (95% CI, 51-68) for brigatinib and crizotinib, respectively. The confirmed intracranial response rate in patients with measurable lesions was 78% (95% CI, 52-94) with brigatinib and 29% (95% CI, 11-52) with crizotinib.

Safety

No new safety concerns were reported. Common adverse events (AEs) of any grade in ≥20% of patients treated with brigatinib were diarrhoea (49%), increased blood creatinine kinase levels (39%), nausea (26%), cough (25%), and hypertension (23%). Common Grade 3/4 AEs in ≥10% of patients treated with brigatinib were increased blood creatinine kinase levels (16%), increased lipase levels (13%), hypertension (10%).

Seven patients (5%) in both the brigatinib and crizotinib group had AEs leading to death within 30 days after receiving the last dose of study medication, but none were deemed related to the study treatment by the investigators.

Grade 3 or 4 interstitial lung disease (ILD) or pneumonitis occurred in 4 (3%) of brigatinib-treated patients and 1 (1%) of crizotinib-treated patients. Thirty-five patients crossed over from crizotinib to brigatinib and one patient (3%) developed ILD or pneumonitis. Dose reductions for any AE occurred in 29% of brigatinib-treated patients and 21% of crizotinib-treated patients. Finally, 12% of patients receiving brigatinib and 9% of patients receiving crizotinib discontinued the treatment due to AEs.