Plasma Genotyping of Patients Enrolled on the Expansion Phase I/II Trial of X-396 in Patients (pts) with ALK+ Non-Small Cell Lung Cancer (NSCLC).

9056 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. We report data on ALK TKI-naive and crizotinib (C)-resistant NSCLC pts treated with X-396. Methods: In this multicenter expansion study, pts with ALK+ NSCLC were treated with X-396 225 mg daily on a 28-day schedule. Pts had measurable disease, ECOG PS 0-1, untreated brain metastases (CNS) and leptomeningeal disease were allowed. NGS on plasma samples was performed at baseline and on study and compared with central tissue results (FISH/IHC). All pts were assessed for response to therapy using RECIST 1.1, adverse events (AEs) using CTCAE version 4.03 were recorded. Results: 60 pts (53% female) have been enrolled. Median age 56 (20-79) years, 67% ECOG PS 1. Of 30 ALK+ NSCLC pts evaluable for response; partial response (PR) was achieved in 19 pts (60%) and stable disease (SD) in 2 pts (7%). In the C-naïve pts (n = 8), PRs were observed in 7 pts (88%). In the 12 pts with prior C but no other ALK TKI, 10 pts (83%) achieved PR and 1 (8%) SD. Median duration of response was 24 - 128 wks. In the 8 pts who had received two or more prior ALK TKIs, there was 1 PR, 3 SD (50% DCR) with response duration of 8-32 wks. CNS responses have been observed in both C naïve and C resistant pts. Plasma and tissue genotyping are available on 27 pts (26 ALK + and 1 ALK -) ALK was detected in plasma in 16 pts all had a response to therapy, two pts were tissue +ve and -ve on plasma testing and had PD, 9 plasma samples were inevaluable. Serial sequencing demonstrated a decrease in ALK in pts responding and an increase at the time of progression. The most common drug-related AEs ( ≥ 20% of pt s) included rash (48%), nausea (26%), vomiting (23%), and fatigue (21%). Most AEs were Grade (G) 1-2. The G3 treatment-related AEs were rash (8 pts), fatigue (1 pt), decreased appetite (1 pt), pruritus (1 pt), and face edema (1 pt). Conclusions: X-396 is well-tolerated and induces response in both C-naive and C-resistant ALK+ NSCLC pts, as well as pts with CNS disease. Plasma sequencing may be used to select pts for therapy and monitor for response and development of acquired resistance. Clinical trial information: NCT01625234.