Efficacy, safety and dose selection of AZD3759 in patients with untreated EGFR-mutated non-small-cell lung cancer and central nervous system metastases in China (CTONG1702-Arm 8): a multi-center, single-arm, phase 2 trial
Si‐Yang Maggie Liu, Xiaorong Dong, Zhen Wang, Yingying Du, Jiuwei Cui, Qian Chu, Bing-Fei Xu, Ming-Ying Zheng, Jia‐Yi Deng, Chang Lu, Xue‐Wu Wei, Yang-Si Li, Mei-Mei Zheng, Mingyi Yang, Jie Huang, Anna Li, Xiaoyan Bai, Yue‐Li Sun, Chong‐Rui Xu, Bin-Chao Wang, Hua‐Jun Chen, Jin‐Ji Yang, Hong‐Hong Yan, Wen‐Zhao Zhong, Qing Zhou, Yi‐Long Wu
Abstract
Background Central nervous system (CNS) metastases is inevitable for epidermal growth factor receptor ( EGFR )-mutant non-small cell lung cancer (NSCLC). AZD3759 is a novel EGFR-TKI with impressive CNS penetration. Methods We initiated a phase 2, multi-center, umbrella trial (CTONG1702, NCT03574402). The eighth arm assessed the efficacy and safety of AZD3759 in untreated EGFR -mutated NSCLC with CNS metastases. The primary objective was the objective response rate (ORR). Simon's minimax two-stage design was used to calculate the sample size. Dose optimal selection was performed using 200- and 300-mg bid cohorts. Findings Between Oct 18, 2018 and Sep 14, 2020, 30 patients received AZD3759 at 200 mg (n = 15) or 300 mg (n = 15) bid. At data cutoff (Dec 31, 2022), median follow-up was 35.4 months. The primary endpoint was reached, with a confirmed ORR of 70% (21/30) (200 mg, 80%; 300 mg, 60%). The median progression-free survival was 12.9 months (200 mg, 15.8 months; 300 mg, 10.7 months). Grade 3 or 4 treatment-related adverse events occurred in 73% (22/30) of the patients (200 mg: 60%; 300 mg: 87%). 59% (10/17) of the patients developed a T790M mutation at disease progression. The median overall survival was 33.7 months, and 34.1 months and 25.3 months in patient treated with or without osimertinib in a later-line setting, respectively. Interpretation AZD3759 showed promising efficacy and tolerable safety as a first-line therapy in EGFR -mutated NSCLC with CNS metastases. The 200-mg bid cohort had better clinical outcomes. Sequential use of AZD3759 and third-generation EGFR-TKIs represents a new option. Funding Chinese Thoracic Oncology Group (CTONG).