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

IF 12.8 Q1 MEDICINE, RESEARCH & EXPERIMENTAL Med Pub Date : 2024-10-03 DOI:10.1016/j.medj.2024.09.002

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

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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.

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佐来替尼一线治疗表皮生长因子受体突变非小细胞肺癌伴中枢神经系统转移：3期EVEREST试验。

背景：佐瑞福替尼（AZD3759）是一种表皮生长因子受体-酪氨酸激酶抑制剂（EGFR-TKI），具有很强的血脑屏障穿透能力，在中枢神经系统（CNS）转移患者的1期和2期研究中显示出良好的颅内和全身抗肿瘤活性：在这项EVEREST 3期试验（ClinicalTrials.gov：NCT03653546）中，EGFR致敏突变、晚期治疗无效的非小细胞肺癌（NSCLC）和未接受放射治疗的无症状或无症状中枢神经系统转移患者被随机（1:1）分配到佐非替尼或第一代EGFR-TKI（吉非替尼或厄洛替尼；对照组）。根据RECIST1.1.研究结果，主要终点是由盲法独立中央审查（BICR）评估的无进展生存期（PFS）：共有439名患者接受了随机治疗（佐瑞非替尼n=220；对照组n=219）。大多数患者存在表皮生长因子受体（EGFR）L858R突变（55%）或大于3个中枢神经系统病变（54%）。与对照组相比，佐瑞非替尼的中位生存期明显更长（9.6个月对6.9个月；危险比[HR]，0.719；95%置信区间[CI]，0.580-0.893；P = 0.0024）。与对照组相比，佐瑞非替尼明显延长了颅内PFS（根据修改后的RECIST1.1计算的BICR：HR，0.467；95% CI，0.352-0.619；研究者根据 RANO-BM：HR，0.627；95% CI，0.466-0.844）。总生存期（OS）尚不成熟；在随后接受第三代EGFR-TKIs治疗的患者中，估计中位OS为佐来替尼37.3个月，对照组31.8个月（HR，0.833；95% CI，0.524-1.283）。安全性与之前报道的佐非替尼数据一致：结论：与第一代表皮生长因子受体-TKIs相比，佐来非替尼明显改善了全身和颅内的PFS；不良反应是可控的。佐力非替尼和第三代表皮生长因子受体-TKIs的联合应用显示出延长患者生存期的潜力。研究结果支持佐来替尼作为EGFR突变NSCLC中枢神经系统转移患者的一种新型、经过充分验证的一线选择：本研究由阿尔法生物制药（江苏）有限公司资助。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Med MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

17.70

自引率

0.60%

发文量

102

期刊介绍： Med is a flagship medical journal published monthly by Cell Press, the global publisher of trusted and authoritative science journals including Cell, Cancer Cell, and Cell Reports Medicine. Our mission is to advance clinical research and practice by providing a communication forum for the publication of clinical trial results, innovative observations from longitudinal cohorts, and pioneering discoveries about disease mechanisms. The journal also encourages thought-leadership discussions among biomedical researchers, physicians, and other health scientists and stakeholders. Our goal is to improve health worldwide sustainably and ethically. Med publishes rigorously vetted original research and cutting-edge review and perspective articles on critical health issues globally and regionally. Our research section covers clinical case reports, first-in-human studies, large-scale clinical trials, population-based studies, as well as translational research work with the potential to change the course of medical research and improve clinical practice.