Supplementary Table S1. ALK inhibitors in clinical development. Supplementary Table S2. Summary of clinical characteristics of ALK-positive patients undergoing biopsies at the time of ALK inhibitor resistance. Supplementary Table S3. Paired, post-crizotinib and post second-generation ALK inhibitor biopsies. Supplementary Table S4. Treatment course of ALK-positive patients undergoing post-ceritinib biopsies. Supplementary Table S5. Treatment course of ALK-positive patients undergoing post-alectinib biopsies. Supplementary Table S6. Treatment course of ALK-positive patients undergoing post-brigatinib biopsies. Supplementary Table S7. Resistant biopsies with {greater than or equal to}2 resistance mutations. Supplementary Table S8. Mutations in ceritinib-resistant biopsies. Supplementary Table S9. Mutations in alectinib-resistant biopsies. Supplementary Table S10. Mutations in brigatinib-resistant biopsies. Supplementary Table S11. Single-nucleotide variants identified in patient-derived cell lines. Supplementary Table S12. EMT in ceritinib-resistant biopsies. Supplementary Table S13. Cells seeded for survival assays. Supplementary Table S14. Cells seeded for growth assays.
ARTICLE ABSTRACT
Advanced, anaplastic lymphoma kinase (ALK)–positive lung cancer is currently treated with the first-generation ALK inhibitor crizotinib followed by more potent, second-generation ALK inhibitors (e.g., ceritinib and alectinib) upon progression. Second-generation inhibitors are generally effective even in the absence of crizotinib-resistant ALK mutations, likely reflecting incomplete inhibition of ALK by crizotinib in many cases. Herein, we analyzed 103 repeat biopsies from ALK-positive patients progressing on various ALK inhibitors. We find that each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALKG1202R, increases significantly after treatment with second-generation agents. To investigate strategies to overcome resistance to second-generation ALK inhibitors, we examine the activity of the third-generation ALK inhibitor lorlatinib in a series of ceritinib-resistant, patient-derived cell lines, and observe that the presence of ALK resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without ALK mutations are resistant.Significance: Secondary ALK mutations are a common resistance mechanism to second-generation ALK inhibitors and predict for sensitivity to the third-generation ALK inhibitor lorlatinib. These findings highlight the importance of repeat biopsies and genotyping following disease progression on targeted therapies, particularly second-generation ALK inhibitors. Cancer Discov; 6(10); 1118–33. ©2016 AACR.See related commentary by Qiao and Lovly, p. 1084.This article is highlighted in the In This Issue feature, p. 1069