Cns Activity Of Ensartinib In Alk-Positive Non-Small Cell Lung Cancer Patients

Background: Ensartinib (X-396) is a novel, potent anaplastic lymphoma kinase (ALK) small molecule tyrosine kinase inhibitor (TKI) with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. In animal studies, brain concentration of ensartinib in mice given at the therapeutic dose was 4 times higher than the IC50 for growth inhibition of ALK positive cells in vitro. Ensartinib was significantly more effective than crizotinib at inhibiting the intracranial growth of the SH-SY5Y neuroblastoma model harboring the F1174L mutation. We subsequently evaluated the CNS activity of ensartinib in patients with ALK positive non-small cell lung cancer (NSCLC). Methods: In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled and given ensartinib orally on a continuous 28-day schedule (NCT01625234). Doses from 25 mg up to 250 mg once daily were evaluated and 225 mg was selected for further evaluation in the phase II expansion. We report on patients enrolled with CNS metastases (with or without systemic disease) who were ALK TKI naive or had received prior crizotinib or a second generation ALK TKI. Patients with untreated asymptomatic CNS metastases were allowed to enroll. All pts were assessed for adverse events using CTCAE version 4.03, and response to therapy was assessed using RECIST 1.1. Patients with only CNS disease had to have at least one measurable target lesion ≥ 3 mm in diameter. Results: As of the December 13, 2016 data cutoff, 26 pts with ALK+ NSCLC and baseline CNS metastases have been treated at ≥ 200 mg. Of the 26 pts, 13 pts had baseline target lesions (8 of which also had non-target lesions) and 13 pts had baseline non-target lesions only. Median age is 52 (21-72) years and the majority of patients had ECOG performance status of 1 (69%). CNS responses have been observed in both ALK TKI naive pts and pts that received prior crizotinib. In the 13 pts with baseline target CNS lesions, intracranial response was achieved in 9 pts (69%), including 1 CR, and 4 pts (31%) had SD, a 100% disease control rate. In the 13 pts with non-target baseline lesions only, 1 CR was achieved and 8 pts had SD. All 3 (100%) ALK TKI naive pts with baseline target lesions achieved CR or PR, and 5/8 pts (62%) that received prior crizotinib only and had baseline target lesions responded. The median duration of intracranial response in the 10 pts who responded (9 with target lesions, 1 with non-target lesions only) is 5.8+ months, with the longest duration being 24 months. Conclusions: Our clinical findings support the preclinical results that the use of ensartinib at doses generally well-tolerated in the clinic may result in favorable therapeutic outcomes in pts with ALK+ NSCLC with baseline CNS metastases. The ongoing phase III eXalt3 study will assess CNS response rate and time to CNS progression in pts receiving first-line ensartinib vs crizotinib (NCT02767804 and NCT01625234). Citation Format: Leora Horn, Karen L. Reckamp, Sandip Patel, George Blumenschein, Joel W. Neal, Barbara Gitlitz, Saiama Waqar, Geoffrey Oxnard, Christina Brzezniak, Gary Dukart, Fenlai Tan, Kimberly Harrow, Chris Liang, James Gibbons, Heather A. Wakelee. CNS activity of ensartinib in ALK-positive non-small cell lung cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT151. doi:10.1158/1538-7445.AM2017-CT151