Zorifertinib

Zhou Q, et al. Med, 2025, 6(1), 100513.

In the phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), the efficacy of zorifertinib (AZD3759), a high-blood-brain barrier penetrating EGFR-tyrosine kinase inhibitor (TKI), was rigorously assessed as a first-line therapy in patients with advanced EGFR-mutant non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. Patients harboring EGFR-sensitizing mutations and untreated CNS metastases were randomized in a 1:1 ratio to receive either zorifertinib or a first-generation EGFR-TKI (gefitinib or erlotinib). Blinded independent central review (BICR) was utilized to evaluate the primary endpoint of progression-free survival (PFS) according to RECIST1.1 criteria. Importantly, zorifertinib demonstrated a significant median PFS improvement (9.6 months vs. 6.9 months; HR 0.719; p = 0.0024) and enhanced intracranial PFS (HR 0.467 by modified RECIST1.1; HR 0.627 by RANO-BM), underscoring its potent activity against CNS lesions. Adverse events were consistent with previous studies and were manageable. This trial's rigorous experimental design and endpoint assessments highlight zorifertinib's promising therapeutic profile as a first-line option for CNS-metastatic EGFR-mutant NSCLC.