Abstract CT044: Efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC) and ALK kinase domain mutations
Authors: Shaw Alice T. , Martini Jean-François , Besse Benjamin , Bauer Todd M. , Lin Chia-Chi , Soo Ross A. , Riely Gregory J. , Ou Sai-Hong Ignatius , Clancy Jill S. , Li Sherry , Thurm Holger , Satouchi Miyako , Camidge D. Ross , Kao Steven , Chiari Rita , Gadgeel Shirish , Felip Enriqueta , Solomon Benjamin J. 
Published: August 2018

Abstract
BACKGROUND: Lorlatinib is a selective, potent, brain-penetrant, 3rd-generation ALK/ROS1 TKI preclinically active against most known resistance mutations. In a Ph I/II study, lorlatinib showed robust clinical activity in ALK+ advanced NSCLC pts, most of whom had CNS metastases (mets) and were pre-treated.1 To identify molecular correlates of response, we performed molecular profiling of circulating free DNA (cfDNA) and tumor tissue in pts who were previously treated with ALK tyrosine kinase inhibitor (TKI) therapy and who received the recommended Ph II dose of lorlatinib.
METHODS: Samples were analyzed from pts enrolled in one of four pre-treated ALK+ expansion cohorts: EXP2 (prior crizotinib only), EXP3 (prior crizotinib + chemotherapy [CT] or any 1 other ALK TKI ± CT), EXP4 (2 prior ALK TKI ± CT) and EXP5 (3 prior ALK TKI ± CT) from the ongoing Ph II study (NCT01970865). Baseline plasma and tumor tissue (archival or de novo biopsy) samples were collected in this study from 190 and 188 pts, respectively. Plasma DNA was analyzed for ALK mutations using digital sequencing (Guardant360, Guardant Health, Inc., Redwood City, CA, USA); tumor tissue DNA was analyzed with an ALK-mutation focused next generation sequencing (NGS) panel (Molecular MD, Portland, OR, USA).
RESULTS: Out of 190 plasma samples from pts in EXP2-5, 139 (73%) did not harbor any detectable ALK kinase domain mutations (including 38 that did not have detectable cfDNA), 45 (24%) did with as many as 8 mutations detected in a single sample, and 6 (3%) were not analyzable. A total of 75 ALK mutations (consisting of 27 unique ALK mutations) were detected, with the ALK G1202R mutation being the most frequent (25%), followed by F1174 (15%), L1196M (15%), G1269A (11%), and I1171 mutations (8%). Responses were observed in 29/45 pts (64%) whose samples harbored ≥1 ALK kinase domain mutation. Among pts without a detectable ALK mutation in cfDNA, 58/139 (42%) responded to lorlatinib. While ALK G1202R was not detected in EXP2 samples, this mutation was seen frequently in patients who had received 2 (EXP4; 9/17 pts with ≥1 ALK mutation detected in cfDNA) or 3 (EXP5; 8/14 pts) prior ALK TKIs. ALK G1202R mutations were found in plasma samples from 19 pts; 11 of these pts (58%) experienced a response with durations of response ranging from 1.4+ to 14.5+ months (+ denotes pts still on study with ongoing responses). Additional NGS analysis of tumor tissues is ongoing.
CONCLUSION: Lorlatinib exhibited antitumor activity across a variety of ALK kinase domain resistance mutations, including the difficult-to-treat ALK G1202R mutation. Responses to lorlatinib were also seen in pts resistant to prior ALK TKIs and without detectable ALK kinase domain mutations in plasma.
REFERENCES: 1. Solomon BJ, et al. 18th WCLC 2017; Abstract OA 05.06
Citation Format: Alice T. Shaw, Jean-François Martini, Benjamin Besse, Todd M. Bauer, Chia-Chi Lin, Ross A. Soo, Gregory J. Riely, Sai-Hong Ignatius Ou, Jill S. Clancy, Sherry Li, Holger Thurm, Miyako Satouchi, D. Ross Camidge, Steven Kao, Rita Chiari, Shirish Gadgeel, Enriqueta Felip, Benjamin J. Solomon. Efficacy of lorlatinib in patients (pts) with advanced ALK-positive non-small cell lung cancer (NSCLC) and ALK kinase domain mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr CT044.