MMDA-26 INTRACRANIAL OUTCOMES WITH NEXT-GENERATION ALK INHIBITORS VERSUS CRIZOTINIB IN FIRST-LINE ALK-POSITIVE NON-SMALL CELL LUNG CANCER: A META-ANALYSIS OF PHASE III RANDOMIZED TRIALS
Raghda Mateen, Aditya Anand, Harshit NarulaAbstract
Background
Anaplastic lymphoma kinase (ALK)–rearranged non-small cell lung cancer (NSCLC) is associated with a high incidence of central nervous system (CNS) metastases, which substantially contribute to morbidity and disease progression. Next-generation ALK inhibitors demonstrate improved CNS penetration compared with crizotinib; however, intracranial outcomes are inconsistently reported across trials.
Methods
A PRISMA-compliant systematic search (January 2026) of PubMed and Embase identified phase III randomized controlled trials comparing next-generation ALK inhibitors with crizotinib in treatment-naïve adults with ALK-positive advanced NSCLC. Primary outcomes included progression-free survival (PFS) and intracranial time-to-event outcomes. Secondary outcomes included overall survival (OS) and response-based endpoints. Hazard ratios (HRs) were pooled using random-effects models, with a common-effect model applied for intracranial CNS progression due to limited contributing studies. Heterogeneity was assessed using the I² statistic.
Results
Eight phase III randomized trials were included. Compared with crizotinib, next-generation ALK inhibitors significantly improved PFS (pooled HR 0.41; 95% CI 0.34–0.49; I² = 28.2%). A modest improvement in OS was observed (pooled HR 0.83; 95% CI 0.75–0.91; I² = 0.0%). Among trials reporting intracranial outcomes, next-generation agents were associated with a reduced risk of CNS progression (pooled HR 0.11; 95% CI 0.07–0.17), although heterogeneity was substantial (I² = 79.8%). Response-based and time-to-treatment endpoints generally favored next-generation inhibitors, with higher rates of grade ≥3 adverse events in some studies.
Conclusion
Next-generation ALK inhibitors are associated with improved systemic and intracranial disease control compared with crizotinib in first-line ALK-positive NSCLC. However, variability in intracranial endpoint reporting and substantial heterogeneity limit cross-trial comparisons. Standardized CNS-specific time-to-event endpoints are needed to better define intracranial efficacy and inform treatment selection.