{"entity":{"id":"paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019","kind":"paper","name":"ALK resistance mutations and efficacy of lorlatinib in advanced anaplastic lymphoma kinase-positive non-small-cell lung cancer","aka":[],"tldr":"In patients whose cancer had already outgrown a second ALK drug, the third-generation drug worked in seven out of ten of those whose tumour carried a resistance mutation and in fewer than three out of ten of those whose tumour did not.","summary":"Baseline plasma and tumour tissue samples were collected from 198 patients with ALK-positive non-small-cell lung cancer in the registrational phase 2 study of lorlatinib. Plasma DNA was analysed for ALK mutations with a commercial assay and tumour tissue DNA with an ALK mutation-focused next-generation sequencing assay. About a quarter of patients had ALK mutations detected by plasma or tissue genotyping. In patients with crizotinib-resistant disease, lorlatinib efficacy was comparable with and without ALK mutations. In patients who had failed one or more second-generation inhibitors, objective response was higher with ALK mutations, 62% against 32% by plasma and 69% against 27% by tissue, and progression-free survival was similar by plasma genotyping (7.3 against 5.5 months, hazard ratio 0.81) but significantly longer by tissue genotyping (11.0 against 5.4 months, hazard ratio 0.47).","asOf":"2026-09-25","links":[{"label":"Shaw et al., J Clin Oncol 2019: ALK resistance mutations and the efficacy of lorlatinib in 198 patients","url":"https://doi.org/10.1200/JCO.18.02236"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/30892989/"}],"tags":[],"related":["alk-fusion"],"cancers":["nsclc"],"sections":[],"technologies":["kinase-inhibitors","liquid-biopsy","cgp"],"targets":["alk","ros1"],"drugs":["lorlatinib","crizotinib","guardant360-cdx"],"companies":[],"institutions":["mgh"],"pathways":["resistance-routes-map","rtk-activation"],"terms":["resistance","gene-fusion","ctdna"],"trials":[],"people":["alice-shaw"],"bottlenecks":[],"keyPapers":[],"journals":["jco"],"dependsOn":[],"notes":[],"journal":"Journal of Clinical Oncology","year":2019,"doi":"10.1200/JCO.18.02236","pmid":"30892989","authors":"Shaw AT, Solomon BJ, Besse B, et al.","paperType":"rct","findings":["About a quarter of previously treated patients carried a detectable ALK resistance mutation.","After a second-generation inhibitor, response was 69% with an ALK mutation on tissue against 27% without.","Progression-free survival 11.0 against 5.4 months by tissue genotyping, hazard ratio 0.47.","After crizotinib alone, mutation status made no difference."],"whatItMeans":"It turned the laboratory prediction into a clinical rule: after a second-generation ALK inhibitor, genotype the tumour, and treat the absence of an ALK mutation as evidence that the cancer has stopped depending on ALK.","caveats":["A single-arm registrational study, so the comparison is between subgroups rather than between treatments.","Tissue and plasma disagreed, and the tissue result separated the groups more sharply.","Not all patients had both sample types."],"changedPractice":true,"participants":198},"route":"/key-papers/paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019/","neighbours":{"biomarker":[{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","route":"/biomarkers/alk-fusion/"},{"id":"alk-resistance-mutation","kind":"biomarker","name":"ALK kinase-domain resistance mutation (G1202R and the rest)","route":"/biomarkers/alk-resistance-mutation/"}],"cancer":[{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"}],"technology":[{"id":"cgp","kind":"technology","name":"Comprehensive genomic profiling","route":"/technologies/cgp/"},{"id":"liquid-biopsy","kind":"technology","name":"Liquid biopsy (ctDNA)","route":"/technologies/liquid-biopsy/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"},{"id":"ros1","kind":"target","name":"ROS1","route":"/targets/ros1/"}],"drug":[{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"guardant360-cdx","kind":"drug","name":"Guardant360 CDx","route":"/drugs/guardant360-cdx/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"}],"institution":[{"id":"mgh","kind":"institution","name":"Massachusetts General Hospital Cancer Center","route":"/institutions/mgh/"}],"pathway":[{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"},{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"term":[{"id":"ctdna","kind":"term","name":"Circulating tumour DNA (ctDNA)","route":"/terms/ctdna/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"gene-fusion","kind":"term","name":"Gene fusion","route":"/terms/gene-fusion/"}],"person":[{"id":"alice-shaw","kind":"person","name":"Alice T. Shaw","route":"/people/alice-shaw/"}],"journal":[{"id":"jco","kind":"journal","name":"Journal of Clinical Oncology","route":"/journals/jco/"}]}}