Zhou Qing, Yu Yan, Xing Ligang, Cheng Ying, Wang Ying, Pan Yueyin, Fan Yun, Shi Jianhua, Zhang Guojun, Cui Jiuwei, Zhou Jianying, Song Yong, Zhuang Wu, Ma Zhiyong, Hu Yanping, Li Gaofeng, Dong Xiaorong, Feng Jifeng, Lu Shun, Wu Jingxun, Li Juan, Zhang Longzhen, Wang Dong, Xu Xinhua, Yang Tsung-Ying, Yang Nong, Guo Yubiao, Zhao Jun, Yao Yu, Zhong Diansheng, Xia Bing, Yang Cheng-Ta, Zhu Bo, Sun Ping, Shim Byoung Yong, Chen Yuan, Wang Zhen, Ahn Myung-Ju, Wang Jie, Wu Yi-Long
Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong 510080, China.
Department of Thoracic Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150081, China.
Med. 2025 Jan 10;6(1):100513. doi: 10.1016/j.medj.2024.09.002. Epub 2024 Oct 9.
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.
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.
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.
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.
This work was funded by Alpha Biopharma (Jiangsu) Co., Ltd., China.
佐利替尼（AZD3759）是一种具有高血脑屏障穿透能力的表皮生长因子受体酪氨酸激酶抑制剂（EGFR-TKI），在中枢神经系统（CNS）转移患者的1期和2期研究中显示出有前景的颅内和全身抗肿瘤活性。
在这项3期EVEREST试验（ClinicalTrials.gov：NCT03653546）中，具有EGFR敏感突变、初治的晚期非小细胞肺癌（NSCLC）且有未接受过放疗的有症状或无症状CNS转移的患者被随机（1:1）分为佐利替尼组或第一代EGFR-TKI（吉非替尼或厄洛替尼；对照组）。主要终点是根据RECIST1.1由盲态独立中央审查（BICR）评估的无进展生存期（PFS）。
总体而言，439例患者被随机分组（佐利替尼组n = 220；对照组n = 219）。大多数患者具有EGFR L858R突变（55%）或>3个CNS病灶（54%）。与对照组相比，佐利替尼的中位PFS显著更长（9.6个月对6.9个月；风险比[HR]，0.719；95%置信区间[CI]，0.580 - 0.893；p = 0.0024）。与对照组相比，佐利替尼显著延长了颅内PFS（根据改良RECIST1.1由BICR评估：HR，0.467；95% CI，0.352 - 0.619；根据RANO-BM由研究者评估：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-TKI治疗的患者中，佐利替尼组的估计中位OS为37.3个月，对照组为31.8个月（HR，0.833；95% CI，0.524 - 1.283）。安全性特征与先前报道的佐利替尼数据一致。
与第一代EGFR-TKI相比，佐利替尼显著改善了全身和颅内PFS；不良事件可控。序贯使用佐利替尼和第三代EGFR-TKI显示出延长患者生存期的潜力。结果支持佐利替尼作为EGFR突变NSCLC的CNS转移患者的一种新型、经过充分验证的一线治疗选择。
本研究由中国江苏阿尔法生物药业有限公司资助。
