Stepping in the right direction but still some ways to go

Over the last few years we have witnessed substantial advances in systemic treatment of non-small cell lung cancer (NSCLC) patients harboring anaplastic lymphoma kinase gene rearrangements (ALK+ NSCLC).Multiple ALK inhibitors (ALKi) have been approved (alectinib, lorlatinib, brigatinib, ceritinib, crizotinib).Despite the survival benefit of all of these drugs, all patients with ALK+ NSCLC will inevitably progress at some point during their treatment.Given the increased number of therapeutic options, understanding the resistance mechanism appears to be increasingly important.Recently, Shaw et al. (1) published the results of an ALK resistance mutation analysis, performed on either cellfree plasma DNA (cfDNA) or tissue DNA (tDNA) assays, in the NCT01970865 trial.In the phase II portion of the study, 228 NSCLC patients with ALK rearrangements were enrolled in one of several expansion cohorts defined by prior treatments, and were treated with lorlatinib (2).Primary endpoint of the study was to assess the overall and intracranial efficacy of lorlatinib.The results have led to the approval of lorlatinib in the United States and Japan, as well as a positive recommendation by the EMA, for previously treated, advanced ALK+ NSCLC.The secondary endpoint was to assess predictive markers of response to lorlatinib in tDNA and cfDNA.Among all the patients, 45 (24%) had one or more ALK mutations detected in cfDNA 41 (21%) had no detectable mutations in cfDNA.Among the 191 archival and de novo tumour samples, 40 (24%) harbored more than 1 ALK mutation.Within the de novo specimens, 76 (78%) were adequate for NGS analysis of which 36 (47%) were found to have one or more ALK mutations.No difference seen