Abstract 579: Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study
Authors: Zhao Hongyun , Ma Yuxiang , Zhang Yang , Hong Shaodong , Fang Wenfeng , Yang Yunpeng , Huang Jianjin , Zhao Jing , Huang Yan , Ding Lieming , Mao Li , Selvaggi Giovanni , Zhang Li 
Published: September 2020

Abstract
Background: Ensartinib (X-396) is a novel ALK inhibitor with high activity against a broad range of crizotinib-resistant ALK mutations (such as G1269A, F1174, C1156Y, and T1151) and CNS metastases. This Phase I study (NCT02959619) determined the maximum tolerated dose (MTD) and recommended Phase II dose (RP2D), investigated the safety and PK, and explored the clinical efficiency for the compound as monotherapy in Chinese ALK+ NSCLC patients.
Methods: Patients with advanced ALK+ NSCLC were treated with oral ensartinib (150, 200, 225, or 250 mg once daily) using a conventional 3+3 dose escalation design. The dose-escalation evaluated patients in 28-day cycles. In the dose-expansion phase, ensartinib was given at the recommended dose to further explore PK and clinical efficacy. Treatment was continued until disease progression, or unacceptable toxicity.
Results: Between March, 2017 and August, 2018, 48 patients were enrolled. 43 patients were locally detected ALK positive by FISH or IHC (VANTANA), 5 patients harbored with ROS1 fusion. In 43 ALK positive patients, 32 patients were ALK TKI-naïve while 11 patients progressed on prior molecular targeted therapy (including 10 crizotinib-treatment and 2 ceritinib- or alectinib-treatment). Two DLTs were observed in the 250 mg dose cohort (grade 3 rash). All patients experienced at least one treatment-related adverse event, in which 19 (39.6%) had grade 3 or higher events with skin rash (16.7%) as the most common one. Ensartinib was moderately absorbed (median time to max concentration: 3.00-4.00 h) and slowly eliminated (mean half-life: 21.0-30.2 h). In multiple dose administration, a steady-state concentration of ensartinib was reached after 8-15 days. The geometric mean AUC0-tau and Cmax of ensartinib at 225 mg were 6950 h*ng/mL and 435 ng/mL, respectively. The ratio of drug concentration in cerebrospinal fluid (CSF) to that in plasma was 1.31-2.05% in 6 patients treated with ensartinib. Objective tumor responses were observed across all dose cohorts. In 46 evaluable patients, the objective response rates (ORR) and disease control rates (DCR) were 71.7% (1 CR and 32 PR) and 84.8% (6 SD), respectively. In ALK positive patients, the ORR and DCR were 80.5% (33/41) and 87.8% (36/41). The ORRs and DCRs at ≥225mg were 68.6% (24/35) and 85.7% (30/35), respectively. The confirmed ORR was 90.0% (27/30) in ALK TKI-naive patients compared to 54.5% (6/11) in ALK TKI-resistant patients. The ORR and DCR in 16 patients with baseline brain metastases were 75% and 75%, respectively. At data cut-off (07-Nov-2019), the median PFS for all 46 evaluable patients was 17.1 months (95% CI 6.3-27.9), and was 20.4 months (95% CI 13.2-27.6) for ALK positive patients, 8.6 months (95% CI 0-24.8) for ROS1 fusion patients. The median PFS was 24.5 months (95% CI 17.4-31.6) and 4.2 months (95% CI 0-8.9) for ALK TKI-naive and ALK TKI-resistant patients, respectively.
Conclusions: Ensartinib was well tolerated in Chinese ALK-positive NSCLC patients with high antitumor activity. RP2D was established at 225 mg QD. Ensartinib could penetrate the blood-brain barrier with a CSF/plasma concentration ratio of 1.65%, supporting its remarkable intracranial efficacy. A global randomized phase 3 trial of ensartinib versus crizotinib in NSCLC patients who have not previously been treated with ALK TKIs is underway (NCT02767804).
Citation Format: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Wenfeng Fang, Yunpeng Yang, Jianjin Huang, Jing Zhao, Yan Huang, Lieming Ding, Li Mao, Giovanni Selvaggi, Li Zhang. Ensartinib (X-396), a novel ALK TKI, in Chinese ALK-positive non-small cell lung cancer: A phase I, dose-escalation and expansion study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 579.