Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non–small-cell lung cancer: a multicenter study using targeted next-generation sequencing. (October 2021)

• Record Type: Journal Article
• Authors: Lin, Yen-Ting; Chiang, Chi-Lu; Hung, Jen-Yu; Lee, Mei-Hsuan; Su, Wu-Chou; Wu, Shang-Yin; Wei, Yu-Feng; Lee, Kang-Yun; Tseng, Yen-Han; Su, Jian; Chung, Hsin-Pei; Lin, Chih-Bin; Ku, Wen-Hui; Chiang, Tsai-Shin; Chiu, Chao-Hua; Shih, Jin-Yuan
• Is Part Of: European journal of cancer. Volume 156(2021)
• Page Start: 1
• Page End: 11
• Publication Date: 2021-10
• Subjects: ALK TKI resistance -- Drug resistance -- Rebiopsy -- Liquid biopsy -- Compound mutations -- Drug sensitivity; Cancer -- Periodicals; Neoplasms -- Periodicals; Cancer -- Périodiques; Cancer; Tumors; Electronic journals; Periodicals; Electronic journals; 616.994
• DOI: 10.1016/j.ejca.2021.06.043
• Languages: English
• ISSNs: 0959-8049

Abstract

Abstract: 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. Highlights: We analyzed cfDNA and rebiopsied tumors by NGS after ALK inhibitor resistance. ALK kinase domain mutations were found in less than one-third of patients. At rebiopsy, adding cfDNA NGS to tissue NGS may increase mutation detection rate. Compound mutations were found in crizotinib, ceritinib, and alectinib resistance. Lorlatinib was not effective against compound ALK mutations in this cohort.