Data from Molecular Mechanisms of Resistance to First- and Second-Generation ALK Inhibitors in <i>ALK</i>-Rearranged Lung Cancer

Abstract

<div>Abstract<p>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 <i>ALK</i> 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 <i>ALK</i> resistance mutations and that the frequency of one mutation, <i>ALK</i><sup>G1202R</sup>, 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 <i>ALK</i> resistance mutations is highly predictive for sensitivity to lorlatinib, whereas those cell lines without <i>ALK</i> mutations are resistant.</p><p><b>Significance:</b> Secondary <i>ALK</i> 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. <i>Cancer Discov; 6(10); 1118–33. ©2016 AACR</i>.</p><p><i>See related commentary by Qiao and Lovly, p. 1084</i>.</p><p><i>This article is highlighted in the In This Issue feature, p. 1069</i></p></div>