Intracranial efficacy of systemic therapies for patients with ALK-positive non-small cell lung cancer in patients with brain metastases: a systematic review and meta-analysis

Lung cancer remains the leading cause of cancer-related mortality worldwide. Among patients with advanced non-small cell lung cancer (NSCLC), ALK-positive disease accounts for roughly 5% of cases We conducted a systematic search of PubMed, Embase, Cochrane, Web of Science, and ClinicalTrials.gov for randomized controlled trials comparing first-line ALK inhibitors with crizotinib or platinum-based chemotherapy and reporting intracranial outcomes. Eight trials (2,250 patients) met inclusion criteria. Median age ranged from 49 to 61 years, and baseline CNS metastases were present in 25.9% to 42% of participants. Second- and third -generation ALK TKIs showed a trend toward improved intracranial objective response rate (icORR) among patients with baseline brain metastases(RR 1.92, 95% CI: 0.58-6.44; p = 0.21). Lorlatinib, a third-generation ALK inhibitor, demonstrated a superior icORR in patients with measurable intracranial disease (RR 3.57, 95% CI: 1.29-9.86) and also showed higher intracranial complete response rates (RR 4.04, 95% CI 1.85-8.81). The safety profile was comparable between second- and third-generation ALK TKIs, with alectinib reporting fewer grade ≥3 adverse events (RR 0.72, 95% CI 0.58-0.88). These findings support the use of second- and third-generation ALK TKIs, particularly lorlatinib, as preferred first-line options for patients presenting with brain metastases at diagnosis.