Abstract CT088: Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non-small cell lung cancer (NSCLC)
Authors: Lovly Christine M. , Infante Jeffrey R. , Blumenschein George R. , Reckamp Karen , Wakelee Heather , Carter Corey A. , Waqar Saiama N. , Neal Joel , Gockerman Jon P. , Dukart Gary , Harrow Kimberly , Liang Chris , Gibbons James J. , Horn Leora 
Published: July 2016

Abstract
Background: 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. It has demonstrated significant anti-tumor activity in both ALK TKI-naive and crizotinib-resistant models of ALK fusion-positive NSCLC.
Methods: In this multicenter phase I/II study, patients (pts) with advanced solid tumors were enrolled in the phase I dose escalation portion of the study and given X-396 on a continuous 28-day schedule (NCT01625234). Doses from 25 up to 250 mg once daily were evaluated and 225mg was selected for further evaluation in the phase II expansion. Patients in this phase were required to have ALK+ NSCLC and measurable disease. Cohorts included pts who were 1) ALK TKI-naïve, 2) pts who progressed on prior crizotinib and had not received a 2nd generation ALK TKI, 3) pts who progressed on a 2nd generation ALK TKI (may also have received crizotinib), 4) pts with untreated or recurrent central nervous system (CNS) metastases, and 5) pts with leptomeningeal disease. All pts were assessed for adverse events (AEs) using CTCAE version 4.03, response to therapy was assessed using RECIST 1.1.
Results: As of the December 09, 2015 data cutoff, 57 pts (31 men, 26 women) have been enrolled. Median age is 56 (20-79) years, the majority of patients had ECOG performance status 1 (67%). The most common drug-related AEs included rash (49%), nausea (28%), vomiting (25%), and fatigue (23%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (7 pts), fatigue (1 pt), decreased appetite (1 pt), dehydration (1 pt), pruritus (1 pt), and face edema (1 pt). In particular, no G3 treatment-related gastrointestinal toxicity or liver enzyme elevation has been reported. To date, 27 ALK+ NSCLC pts treated at doses ? 200 mg are evaluable for response; partial response (PR) was achieved in 19 pts (70%) and stable disease (SD) in 2 pts (7%). In the crizotinib-naïve pts (n = 8), responses were observed in 7 pts (88%). In the 12 pts with prior crizotinib but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. CNS responses have been observed in both crizotinib naïve and crizotinib resistant pts. The median duration of treatment in the 27 evaluable ALK+ pts is 16+ weeks, with the longest being 128+ weeks.
Conclusion: X-396 is well-tolerated and induces responses in both crizotinib-naïve and crizotinib-resistant ALK+ NSCLC pts, as well as patients with CNS lesions. Enrollment is ongoing in the expansion cohorts.
Citation Format: Christine M. Lovly, Jeffrey R. Infante, George R. Blumenschein, Karen Reckamp, Heather Wakelee, Corey A. Carter, Saiama N. Waqar, Joel Neal, Jon P. Gockerman, Gary Dukart, Kimberly Harrow, Chris Liang, James J. Gibbons, Leora Horn. Phase I/II trial of X-396, a novel anaplastic lymphoma kinase (ALK) inhibitor, in patients with ALK+ non-small cell lung cancer (NSCLC). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT088.