Objective: To evaluate the relative efficacy and safety of brigatinib compared with other ALK inhibitors for the first-line treatment of ALK-positive non-small cell lung cancer (NSCLC) patients.

Methods: A systematic review with eligible randomized controlled trials (RCT) was conducted from Jan 2010 to Oct 2021. Outcomes evaluated by indirect treatment comparison (ITC) using Bucher method included progression free survival (PFS), overall survival (OS), objective response rate (ORR), and safety.

Results: 10 RCTs assessing crizotinib, ceritinib, alectinib, brigatinib, ensartinib, and lorlatinib were included and included 2,831 patients.

• Brigatinib significantly prolonged independent review committee assessed PFS compared with crizotinib (HR=0.48, 95% CI: 0.35 to 0.66) and ceritinib (HR=0.41, 95% CI: 0.26, 0.65); and had a comparable PFS compared with alectinib and ensartinib. Subgroup analysis of brain metastases patients and Asian patients yielded similar results to the above.
• Brigatinib significantly reduced the risk of death compared with crizotinib (HR=0.50, 95% CI: 0.28, 0.87) after adjusting for treatment crossover in crizotinib arm. No significant differences were observed in OS between brigatinib and other next generation ALK-inhibitors: alectinib, ensartinib, and lorlatinib.
• Brigatinib was associated with better ORR than crizotinib (OR=1.73, 95% CI: 1.04, 2.88), and comparable with other ALK-inhibitors.
• For patients with any brain metastases at baseline, brigatinib had significantly superior effects in intracranial ORR than crizotinib (OR=11.75, 95% CI: 4.19, 32.91) and ceritinib (OR=31.5, 95% CI: 6.02, 164.73).
• The incidence of grade ≥3 AEs of brigatinib is comparable to ceritinib, ensartinib and lorlatinib. Brigatinib also significantly delayed time to worsening in the EORTC QLQ-C30 GHS/QOL than crizotinib (HR=0.69; 95% CI: 0.49, 0.98)

Conclusion: Brigatinib was superior to crizotinib and ceritinib in PFS and intracranial ORR, and had comparable efficacy and safety profile with other 2^nd generation ALK-inhibitors in first-line treatments for patients with ALK-positive NSCLC.