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

Qing Zhou; Yan Yu; Ligang Xing; Ying Cheng; Ying Wang; Yueyin Pan; Yun Fan; Jianhua Shi; Guojun Zhang; Jiuwei Cui; Jianying Zhou; Yong Song; Wu Zhuang; Zhiyong Ma; Yanping Hu; Gaofeng Li; Xiaorong Dong; Jifeng Feng; Shun Lu; Jingxun Wu; Juan Li; Longzhen Zhang; Dong Wang; Xinhua Xu; Tsung Ying Yang; Nong Yang; Yubiao Guo; Jun Zhao; Yu Yao; Diansheng Zhong; Bing Xia; Cheng Ta Yang; Bo Zhu; Ping Sun; Byoung Yong Shim; Yuan Chen; Zhen Wang; Myung Ju Ahn; Jie Wang; Yi Long Wu

doi:10.1016/j.medj.2024.09.002

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

Qing Zhou
, Yan Yu
, Ligang Xing
, Ying Cheng
, Ying Wang
, Yueyin Pan
, Yun Fan
, Jianhua Shi
, Guojun Zhang
, Jiuwei Cui
, Jianying Zhou
, Yong Song
, Wu Zhuang
, Zhiyong Ma
, Yanping Hu
, Gaofeng Li
, Xiaorong Dong
, Jifeng Feng
, Shun Lu
, Jingxun Wu

Juan Li, Longzhen Zhang, Dong Wang, Xinhua Xu, Tsung Ying Yang, Nong Yang, Yubiao Guo, Jun Zhao, Yu Yao, Diansheng Zhong, Bing Xia, Cheng Ta Yang, Bo Zhu, Ping Sun, Byoung Yong Shim, Yuan Chen, Zhen Wang, Myung Ju Ahn, Jie Wang, Yi Long Wu

Department of Internal Medicine

Guangdong Academy of Medical Sciences
Harbin Medical University
Shandong First Medical University & Shandong Academy of Medical Sciences
Jilin Cancer Hospital
Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital
University of Science and Technology of China
Chinese Academy of Sciences
Linyi Cancer Hospital
the First Affiliated Hospital of Zhengzhou University
Jilin University
The First Affiliated Hospital, Zhejiang University School of Medicine
Nanjing University
Fujian Medical University
Zhengzhou University
Huazhong University of Science and Technology
The Third Affiliated Hospital of Kunming Medical University
Jiangsu Institute of Cancer Institute & Hospital
Shanghai Jiao Tong University
The First Affiliated Hospital of Xiamen University
Sichuan Cancer Hospital and Institute
Xuzhou Medical University
Army Medical Center of the People's Liberation Army of China
China Three Gorges University
Veterans General Hospital-Taichung Taiwan
Central South University
Sun Yat-Sen University
Peking University
Xi’an Jiaotong University
Tianjin Medical University
Zhejiang University
Chang Gung Memorial Hospital
Army Medical University
Yantai Yuhuangding Hospital
The Catholic University of Korea
Ltd.
Chinese Academy of Medical Sciences

Research output: Contribution to journal › Article › peer-review

30 Scopus citations

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.

Original language	English
Article number	100513
Journal	Med
Volume	6
Issue number	1
DOIs	https://doi.org/10.1016/j.medj.2024.09.002
State	Published - 10 Jan 2025

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

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

Access to Document

10.1016/j.medj.2024.09.002

Cite this

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, Y. L. (2025). First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial. Med, 6(1), Article 100513. https://doi.org/10.1016/j.medj.2024.09.002

@article{e81de952904e440eb716bd1b6137d787,

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

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{\textendash}0.893; p = 0.0024). Zorifertinib significantly prolonged intracranial PFS versus control (BICR per modified RECIST1.1: HR, 0.467; 95\% CI, 0.352{\textendash}0.619; investigator per RANO-BM: HR, 0.627; 95\% CI, 0.466{\textendash}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{\textendash}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{\textquoteright} 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",

author = "Qing Zhou and Yan Yu and Ligang Xing and Ying Cheng and Ying Wang and Yueyin Pan and Yun Fan and Jianhua Shi and Guojun Zhang and Jiuwei Cui and Jianying Zhou and Yong Song and Wu Zhuang and Zhiyong Ma and Yanping Hu and Gaofeng Li and Xiaorong Dong and Jifeng Feng and Shun Lu and Jingxun Wu and Juan Li and Longzhen Zhang and Dong Wang and Xinhua Xu and Yang, \{Tsung Ying\} and Nong Yang and Yubiao Guo and Jun Zhao and Yu Yao and Diansheng Zhong and Bing Xia and Yang, \{Cheng Ta\} and Bo Zhu and Ping Sun and Shim, \{Byoung Yong\} and Yuan Chen and Zhen Wang and Ahn, \{Myung Ju\} and Jie Wang and Wu, \{Yi Long\}",

note = "Publisher Copyright: {\textcopyright} 2024 Elsevier Inc.",

year = "2025",

month = jan,

day = "10",

doi = "10.1016/j.medj.2024.09.002",

language = "English",

volume = "6",

journal = "Med",

issn = "2666-6359",

publisher = "Cell Press",

number = "1",

}

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 & Wu, YL 2025, 'First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases: The phase 3 EVEREST trial', Med, vol. 6, no. 1, 100513. https://doi.org/10.1016/j.medj.2024.09.002

TY - JOUR

T1 - First-line zorifertinib for EGFR-mutant non-small cell lung cancer with central nervous system metastases

T2 - The phase 3 EVEREST trial

AU - Zhou, Qing

AU - Yu, Yan

AU - Xing, Ligang

AU - Cheng, Ying

AU - Wang, Ying

AU - Pan, Yueyin

AU - Fan, Yun

AU - Shi, Jianhua

AU - Zhang, Guojun

AU - Cui, Jiuwei

AU - Zhou, Jianying

AU - Song, Yong

AU - Zhuang, Wu

AU - Ma, Zhiyong

AU - Hu, Yanping

AU - Li, Gaofeng

AU - Dong, Xiaorong

AU - Feng, Jifeng

AU - Lu, Shun

AU - Wu, Jingxun

AU - Li, Juan

AU - Zhang, Longzhen

AU - Wang, Dong

AU - Xu, Xinhua

AU - Yang, Tsung Ying

AU - Yang, Nong

AU - Guo, Yubiao

AU - Zhao, Jun

AU - Yao, Yu

AU - Zhong, Diansheng

AU - Xia, Bing

AU - Yang, Cheng Ta

AU - Zhu, Bo

AU - Sun, Ping

AU - Shim, Byoung Yong

AU - Chen, Yuan

AU - Wang, Zhen

AU - Ahn, Myung Ju

AU - Wang, Jie

AU - Wu, Yi Long

PY - 2025/1/10

Y1 - 2025/1/10

N2 - 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.

AB - 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.

KW - CNS metastases

KW - EGFR mutation

KW - EGFR-TKI

KW - L858R

KW - Translation to patients

KW - blood-brain barrier penetration

KW - exon 19Del

KW - non-small cell lung cancer

UR - https://www.scopus.com/pages/publications/85207753798

U2 - 10.1016/j.medj.2024.09.002

DO - 10.1016/j.medj.2024.09.002

M3 - Article

C2 - 39389055

AN - SCOPUS:85207753798

SN - 2666-6359

VL - 6

JO - Med

JF - Med

IS - 1

M1 - 100513

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

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