<i>ALK</i> Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer.

Abstract

Lorlatinib is a potent, brain-penetrant, third-generation anaplastic lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical activity in advanced ALK-positive non-small-cell lung cancer, including in patients who have failed prior ALK TKIs. Molecular determinants of response to lorlatinib have not been established, but preclinical data suggest that <i>ALK</i> resistance mutations may represent a biomarker of response in previously treated patients. Baseline plasma and tumor tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer from the registrational phase II study of lorlatinib. We analyzed plasma DNA for <i>ALK</i> mutations using Guardant360. Tumor tissue DNA was analyzed using an <i>ALK</i> mutation-focused next-generation sequencing assay. Objective response rate, duration of response, and progression-free survival were evaluated according to <i>ALK</i> mutation status. Approximately one quarter of patients had <i>ALK</i> mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, the efficacy of lorlatinib was comparable among patients with and without <i>ALK</i> mutations using plasma or tissue genotyping. In contrast, in patients who had failed 1 or more second-generation ALK TKIs, objective response rate was higher among patients with <i>ALK</i> mutations (62% <i>v</i> 32% [plasma]; 69% <i>v</i> 27% [tissue]). Progression-free survival was similar in patients with and without <i>ALK</i> mutations on the basis of plasma genotyping (median, 7.3 months <i>v</i> 5.5 months; hazard ratio, 0.81) but significantly longer in patients with <i>ALK</i> mutations identified by tissue genotyping (median, 11.0 months <i>v</i> 5.4 months; hazard ratio, 0.47). In patients who have failed 1 or more second-generation ALK TKIs, lorlatinib shows greater efficacy in patients with <i>ALK</i> mutations compared with patients without <i>ALK</i> mutations. Tumor genotyping for <i>ALK</i> mutations after failure of a second-generation TKI may identify patients who are more likely to derive clinical benefit from lorlatinib.