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Clinical Trial
. 2025 Jan 10;6(1):100513.
doi: 10.1016/j.medj.2024.09.002. Epub 2024 Oct 9.

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial

Qing Zhou  1 , Yan Yu  2 , Ligang Xing  3 , Ying Cheng  4 , Ying Wang  5 , Yueyin Pan  6 , Yun Fan  7 , Jianhua Shi  8 , Guojun Zhang  9 , Jiuwei Cui  10 , Jianying Zhou  11 , Yong Song  12 , Wu Zhuang  13 , Zhiyong Ma  14 , Yanping Hu  15 , Gaofeng Li  16 , Xiaorong Dong  17 , Jifeng Feng  18 , Shun Lu  19 , Jingxun Wu  20 , Juan Li  21 , Longzhen Zhang  22 , Dong Wang  23 , Xinhua Xu  24 , Tsung-Ying Yang  25 , Nong Yang  26 , Yubiao Guo  27 , Jun Zhao  28 , Yu Yao  29 , Diansheng Zhong  30 , Bing Xia  31 , Cheng-Ta Yang  32 , Bo Zhu  33 , Ping Sun  34 , Byoung Yong Shim  35 , Yuan Chen  36 , Zhen Wang  37 , Myung-Ju Ahn  38 , Jie Wang  39 , Yi-Long Wu  40
Affiliations
Clinical Trial

First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial

Qing Zhou et al. Med. .

Abstract

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.

Keywords: CNS metastases; EGFR mutation; EGFR-TKI; L858R; Translation to patients; blood-brain barrier penetration; exon 19Del; non-small cell lung cancer.

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Conflict of interest statement

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.

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