Phase I/II trial of X-396 in patients (pts) with ALK+ non-small cell lung cancer (NSCLC): Correlation with plasma and tissue genotyping and response to therapy (tx)

Abstract

Background: X-396 is a novel, potent ALK small molecule TKI with additional activity against MET, ABL, Axl, EPHA2, LTK, ROS1 and SLK. We report on data from pts that includes detection/monitoring of ALK fusions by plasma next-generation sequencing (NGS). Methods: Pts with advanced solid tumors and ECOG PS 0-1 were tx'd with X-396 225 mg qd on a continuous 28-day schedule. In expansion phase, required to have measurable ALK+ NSCLC. Asymptomatic brain metastases allowed. Tissue confirmed centrally via FISH or IHC. Targeted NGS of cfDNA was performed retrospectively at baseline and on study and compared with tissue results. Results: As of April 15, 71 pts (35 men, 36 women) enrolled. Median age 54 (20-79) yrs, 66% had ECOG PS 1. 37 ALK+ NSCLC pts tx'd at doses ≥ 200 mg evaluable for response; partial response (PR) achieved in 21 pts (76%), stable disease (SD) in 8 (22%). In crizotinib-naïve pts (n = 8), responses in 7 (88%). In 20 pts with prior crizotinib but no other ALK TKI, 12 (60%) had PR, 7 (35%) SD. Tissue via FISH (F) and Plasma genotyping (P) available on 42 pts: RR for 25 F + P+ pts 52%, 6 F-P- pts 0%, 11 F + P- pts 55%. Concordance between F and P was 74%. Tissue via NGS (N) and P genotyping available on 13 pts with 27 mutations and fusions identified; RR for 18 T + P+ pts 78%, 4 T-P+ pts 100%, 5 T + P- pts 75%. 2 samples were T-P-. Concordance between N and P was 74%. Responses were seen in pts with L1196M, G1296M, G1202R, and T1151M resistant mutations. Serial sequencing demonstrated decrease in ALK in responding pts and increase at time of progression. CNS responses observed in crizotinib naïve and resistant pts. Median duration of tx in the 37 evaluable ALK+ pts is 23.6 wks, longest being 139+ wks. Most common drug-related AEs (>20% of pts) included rash (48%), nausea (28%), fatigue (25%), vomiting (23%). Most AEs were Grade (G) 1-2. Most common G3 tx-related AE was rash (8 pts). No G3 related GI AEs or liver enzyme elevations reported. Conclusions: X-396 is well-tolerated and induces responses in crizotinib-naïve & resistant ALK+ NSCLC pts, and pts with CNS lesions. Plasma sequencing may be used to select pts for tx and monitor for response and development of acquired resistance.