Shaw AT, et al. - Researchers assessed if ALK resistance mutations may serve as a biomarker of response to lorlatinib in previously treated patients. From 198 patients with ALK-positive non–small-cell lung cancer baseline plasma and tumor tissue samples were gathered to assess ALK mutations, which were ultimately seen in about 25% of participants. Using plasma or tissue genotyping, the effectiveness of lorlatinib was similar between patients with and without ALK mutations in patients with crizotinib-resistant disease, while patients with ALK mutations saw a higher objective response rate in patients who had failed 1 or more second-generation ALK TKIs. Based on plasma genotyping, patients with and without ALK mutations had similar progression-free survival but it was significantly longer in patients with ALK mutations identified by tissue genotyping. Patients more likely to derive clinical benefit from lorlatinib may be found via tumor genotyping for ALK mutations after failure of a second-generation TKI.