Zhou Q, Yu Y, Xing L, Cheng Y, Wang Y, Pan Y, Fan Y, Shi J, Zhang G, Cui J, Zhou J, Song Y, Zhuang W, Ma Z, Hu Y, Li G, Dong X, Feng J, Lu S, Wu J, Li J, Zhang L, Wang D, Xu X, Yang TY, Yang N, Guo Y, Zhao J, Yao Y, Zhong D, Xia B, Yang CT, Zhu B, Sun P, Shim BY, Chen Y, Wang Z, Ahn MJ, Wang J, and Wu YL
Background: Zorifertinib (AZD3759), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) with high blood-brain barrier penetration capability, demonstrated promising intracranial and systemic antitumor activity in phase 1 and 2 studies in central nervous system (CNS)-metastatic patients., Methods: In this phase 3 EVEREST trial (ClinicalTrials.gov: NCT03653546), patients with EGFR-sensitizing mutations, advanced treatment-naive non-small cell lung cancer (NSCLC), and non-irradiated symptomatic or asymptomatic CNS metastases were randomized (1:1) to zorifertinib or first-generation EGFR-TKI (gefitinib or erlotinib; control). The primary endpoint was blinded independent central review (BICR)-assessed progression-free survival (PFS) per RECIST1.1., Findings: Overall, 439 patients were randomized (zorifertinib n = 220; control n = 219). Most patients had the EGFR L858R mutation (55%) or >3 CNS lesions (54%). Median PFS was significantly longer with zorifertinib versus control (9.6 versus 6.9 months; hazard ratio [HR], 0.719; 95% confidence interval [CI], 0.580-0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95% CI, 0.352-0.619; investigator per RANO-BM: HR, 0.627; 95% CI, 0.466-0.844). Overall survival (OS) was immature; the estimated median OS was 37.3 months with zorifertinib and 31.8 months with control (HR, 0.833; 95% CI, 0.524-1.283) in patients subsequently treated with third-generation EGFR-TKIs. Safety profiles were consistent with previously reported data for zorifertinib., Conclusions: Zorifertinib significantly improved systemic and intracranial PFS versus first-generation EGFR-TKIs; adverse events were manageable. Sequential use of zorifertinib and third-generation EGFR-TKIs showed the potential to prolong patients' survival. The results favor zorifertinib as a novel, well-validated first-line option for CNS-metastatic patients with EGFR-mutant NSCLC., Funding: This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China., Competing Interests: Declaration of interests Q.Z. declares lecture and presentation fees from AstraZeneca, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi. S.L. declares grants or contracts from AstraZeneca, Hutchison, BMS, Hengrui, BeiGene, Roche, and Hansoh; consulting fees from AstraZeneca, Pfizer, Boehringer Ingelheim, Hutchison Medipharma, Simcere, Zai Lab, GenomiCare, Yuhan, prlME Oncology, Menarini, InventisBio, and Roche; lecture and presentation fees from AstraZeneca, Roche, Hansoh, and Hengrui Therapeutics; participation on a data safety monitoring board or advisory board for Roche, Regeneron, AstraZeneca, and Xcovery Holdings; and a leadership or fiduciary role in the Chinese Lung Cancer Associate and CSCO. Z. Wang is an employee of Alpha Biopharma (Jiangsu) and declares no stock ownership in the company. M.-J.A. declares consulting fees from AstraZeneca, Amgen, Merck, Takeda, BMS, ONO, Roche, Daiichi-Sankyo, Janssen, Alpha Pharmaceuticals, Yuhan, Arcus Biosciences, Eutilex, and VORONOI and lecture and presentation fees from AstraZeneca, Amgen, Merck, Takeda, BMS, ONO, Roche, Daiichi-Sankyo, Janssen, and Yuhan. Y.-L.W. declares consulting services for AstraZeneca, Boehringer Ingelheim, Novartis, and Takeda; lecture and presentation fees from AstraZeneca, BeiGene, Boehringer Ingelheim, BMS, Eli Lilly, MSD, Pfizer, Roche, and Sanofi; and grants or contracts from AstraZeneca, Boehringer Ingelheim, BMS, Hengrui, and Roche., (Copyright © 2024 Elsevier Inc. All rights reserved.)