Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing.

Introduction: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib are approved for advanced non-small-cell lung cancer (NSCLC) with ALK rearrangement. However, the mechanisms of resistance remain largely unclear.
Methods: This prospective multicenter study analyzed cell-free DNA (cfDNA) and/or cancer tissues of patients with NSCLC after progression on ALK TKI(s), using targeted next-generation sequencing. Patients' clinicopathologic characteristics and treatment outcomes were analyzed.
Results: Overall, 88 patients were enrolled; 31 cancer tissues and 90 cfDNA samples were analyzed. Five (16%) ALK mutations (L1196M ×2, I1171T, D1203N, G1269A/F1174L) and 3 possible bypass mutations (NRAS G12V, EGFR R108K, PIK3CA E545K) were found in 32 crizotinib-resistant cancers. Four (22%) ALK mutations (G1128A, G1202R, G1269A, I1171T/E1210K) and 3 possible bypass mutations (KIT D820E, MET E1012∗, EGFR P265_C291del) were found in 18 ceritinib-resistant cancers. Four (17%) ALK mutations (G1202R ×2, W1295C, G1202R/L1196M) and 1 possible bypass mutation (EGFR P753S) were found in 24 alectinib-resistant cancers. Two (11%) ALK mutations (G1202R/G1269A ×2) and 2 possible bypass mutations (BRAF V600E, MET D1246N) were found in 18 lorlatinib-resistant cancers. In patients with simultaneous paired tissue and cfDNA samples (n = 20), mutations were identified in 9 (45%) and 6 (30%) cases, respectively; the concordance rate was 45%.
Conclusions: The mechanisms of ALK TKI resistance were heterogeneous; ALK mutations were found in less than one-third of patients. Compound ALK mutations, which may confer lorlatinib resistance, may occur in crizotinib, ceritinib, and alectinib-resistant lung cancers.
Competing Interests: Conflict of interest statement The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: YTL has received speaking honoraria from ACT Genomics, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Manudipharma, Merck Sharp & Dohme, Novartis, Pfizer, Roche, and TTY Biopharm; and travel expense from Pfizer. CLC has received speaking honoraria from Chugai Pharmaceutical, Novartis, and Pfizer. SYW has received speaking honoraria from Boehringer Ingelheim, Merck Sharp & Dohme, Merck KGaA, Novartis, and Sanofi; and travel expense from Bristol-Myers Squibb and TTY Biopharm. HPC has received speaking honoraria from AstraZeneca, Chugai Pharmaceutical, Novartis, and Pfizer. CHC has received honoraria from AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly, Merck Sharp & Dohme, Novartis, Ono Pharmaceutical, Pfizer, Roche, and Takeda. JYS has been an advisory board member for AstraZeneca, Roche, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, Bristol-Myers Squibb, Cstone Pharmaceuticals, Janssen Pharmaceutica, and Takeda. JYS has received speaking honoraria from AstraZeneca, Roche, Boehringer-Ingelheim, Eli Lilly, Pfizer, Novartis, Merck Sharp & Dohme, Ono Pharmaceutical, Chugai Pharmaceutical, and Bristol-Myers Squibb; and travel expense from Roche, Boehringer Ingelheim, Pfizer, Merck Sharp & Dohme, Chugai Pharmaceutical, and Bristol-Myers Squibb. The remaining authors declare no conflict of interest. Results from this study were presented, in part, at the 2020 Annual Congress of Taiwan Society of Pulmonary and Critical Care Medicine in Taipei, Taiwan, December 12, 2020.
(Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)