Envonalkib versus crizotinib for treatment-naive ALK-positive non-small cell lung cancer: a randomized, multicenter, open-label, phase III trial

• Published in: Signal transduction and targeted therapy Vol. 8; no. 1; p. 301
• Main Authors: Yang, Yunpeng, Min, Jie, Yang, Nong, Yu, Qitao, Cheng, Ying, Zhao, Yanqiu, Li, Manxiang, Chen, Hong, Ren, Shou’an, Zhou, Jianying, Zhuang, Wu, Qin, Xintian, Cao, Lejie, Yu, Yan, Zhang, Jian, He, Jianxing, Feng, Jifeng, Yu, Hao, Zhang, Li, Fang, Wenfeng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.08.2023; Nature Publishing Group
• Subjects: 692/4028/67/1612; 692/699/67; Antitumor agents; Brain Neoplasms - drug therapy; Brain Neoplasms - genetics; Cancer Research; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - genetics; Cell Biology; Central nervous system; Crizotinib - pharmacology; Crizotinib - therapeutic use; Humans; Internal Medicine; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - genetics; Medicine; Medicine & Public Health; Metastases; Non-small cell lung carcinoma; Oncology; Pathology; Protein Kinase Inhibitors - therapeutic use; Protein-tyrosine kinase; Small cell lung carcinoma
• ISSN: 2059-3635; 2095-9907; 2059-3635
• DOI: 10.1038/s41392-023-01538-w

Anaplastic lymphoma kinase (ALK) rearrangements are present in about 5–6% of non-small cell lung cancer (NSCLC) cases and associated with increased risks of central nervous system (CNS) involvement. Envonalkib, a novel ALK inhibitor, demonstrated promising anti-tumor activity and safety in advanced ALK-positive NSCLC in the first-in-human phase I study. This phase III trial (ClinicalTrials.gov NCT04009317) investigated the efficacy and safety of first-line envonalkib in advanced ALK-positive NSCLC cases. Totally 264 participants were randomized 1:1 to receive envonalkib ( n  = 131) or crizotinib ( n  = 133). Median independent review committee (IRC)-assessed progression-free survival (PFS) times were 24.87 (95% confidence interval [CI]: 15.64–30.36) and 11.60 (95% CI: 8.28–13.73) months in the envonalkib and crizotinib groups, respectively (hazard ratio [HR] = 0.47, 95% CI: 0.34–0.64, p  < 0.0001). IRC-assessed confirmed objective response rate (ORR) was higher (81.68% vs. 70.68%, p  = 0.056) and duration of response was longer (median, 25.79 [95% CI, 16.53–29.47] vs. 11.14 [95% CI, 9.23–16.59] months, p  = 0.0003) in the envonalkib group compared with the crizotinib group. In participants with baseline brain target lesions, IRC-assessed CNS-ORR was improved with envonalkib compared with crizotinib (78.95% vs. 23.81%). Overall survival (OS) data were immature, and median OS was not reached in either group (HR = 0.84, 95% CI: 0.48–1.47, p  = 0.5741). The 12-month OS rates were 90.6% (95% CI, 84.0%–94.5%) and 89.4% (95% CI, 82.8%–93.6%) in the envonalkib and crizotinib groups, respectively. Grade ≥3 treatment-related adverse events were observed in 55.73% and 42.86% of participants in the envonalkib and crizotinib groups, respectively. Envonalkib significantly improved PFS and delayed brain metastasis progression in advanced ALK-positive NSCLC.