{"entity":{"id":"alk-resistance-mutation","kind":"biomarker","name":"ALK kinase-domain resistance mutation (G1202R and the rest)","aka":["ALK resistance mutation","G1202R","ALK G1202R","L1196M","ALK secondary mutation","solvent front mutation"],"tldr":"After a lung cancer stops responding to an ALK-blocking tablet, finding a change inside the ALK protein itself is good news: it means the cancer still depends on ALK, and a later-generation tablet is likely to work. Finding none means the opposite.","summary":"Each generation of ALK inhibitor selects its own set of secondary mutations in the ALK kinase domain. Across 103 repeat biopsies, crizotinib was followed by a diverse spectrum (L1196M, G1269A and others) in a minority of patients, while second-generation inhibitors (alectinib, brigatinib, ceritinib) were followed by mutations in the majority, with the solvent-front substitution G1202R rising significantly in frequency (Gainor 2016). The readout is predictive rather than descriptive: in the lorlatinib registration study, among patients who had failed one or more second-generation inhibitors, objective response was 69% with an ALK mutation on tissue genotyping against 27% without, and progression-free survival 11.0 against 5.4 months (hazard ratio 0.47); after crizotinib alone, mutation status made no difference (Shaw 2019). Compound mutations can reverse the ordering entirely: C1156Y with L1198F confers resistance to lorlatinib and restores sensitivity to crizotinib (Shaw 2016).","asOf":"2026-09-25","links":[{"label":"Gainor et al., Cancer Discov 2016: 103 repeat biopsies and the resistance mutations of first- and second-generation ALK inhibitors","url":"https://doi.org/10.1158/2159-8290.CD-16-0596"},{"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":"Shaw et al., N Engl J Med 2016: resensitisation to crizotinib by the lorlatinib resistance mutation ALK L1198F","url":"https://doi.org/10.1056/NEJMoa1508887"}],"tags":["biomarker","resistance"],"related":["alk-fusion"],"cancers":["nsclc"],"sections":[],"technologies":["cgp","liquid-biopsy","kinase-inhibitors"],"targets":["alk"],"drugs":[],"companies":[],"institutions":[],"pathways":["resistance-routes-map","rtk-activation","clonal-evolution"],"terms":["resistance","cross-resistance","gene-fusion","biopsy"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-gainor-alk-resistance-mutations-cancer-discov-2016","paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019","paper-shaw-alk-l1198f-resensitisation-nejm-2016"],"journals":[],"dependsOn":[],"notes":[],"target":"alk","measurement":"sequencing-variant","scoringRule":{"text":"Presence of a secondary missense substitution in the ALK kinase domain on tumour tissue or plasma sequencing taken at progression, reported with the specific residue and with the inhibitors already received, since the spectrum differs by generation.","quote":"each ALK inhibitor is associated with a distinct spectrum of ALK resistance mutations and that the frequency of one mutation, ALK G1202R, increases significantly after treatment with second-generation agents","source":"https://doi.org/10.1158/2159-8290.CD-16-0596","sourceLabel":"Gainor et al., Cancer Discovery 2016"},"thresholds":[],"definedBy":{"label":"Shaw et al., J Clin Oncol 2019: ALK resistance mutations and the efficacy of lorlatinib","url":"https://doi.org/10.1200/JCO.18.02236"},"tests":[],"assays":[],"companionDiagnostics":[],"forPatient":"A repeat biopsy or blood test when a treatment stops working is not a formality here. Finding a change in the ALK protein usually means another tablet in the same family will work; finding none usually means it is time for a different kind of treatment."},"route":"/biomarkers/alk-resistance-mutation/","neighbours":{"biomarker":[{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","route":"/biomarkers/alk-fusion/"}],"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/"}],"pathway":[{"id":"clonal-evolution","kind":"pathway","name":"Clonal evolution & minimal residual disease","route":"/pathways/clonal-evolution/"},{"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":"biopsy","kind":"term","name":"Biopsy","route":"/terms/biopsy/"},{"id":"cross-resistance","kind":"term","name":"Cross-resistance","route":"/terms/cross-resistance/"},{"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/"}],"paper":[{"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","route":"/key-papers/paper-shaw-alk-resistance-mutations-lorlatinib-jco-2019/"},{"id":"paper-gainor-alk-resistance-mutations-cancer-discov-2016","kind":"paper","name":"Molecular mechanisms of resistance to first- and second-generation ALK inhibitors in ALK-rearranged lung cancer","route":"/key-papers/paper-gainor-alk-resistance-mutations-cancer-discov-2016/"},{"id":"paper-shaw-alk-l1198f-resensitisation-nejm-2016","kind":"paper","name":"Resensitization to crizotinib by the lorlatinib ALK resistance mutation L1198F","route":"/key-papers/paper-shaw-alk-l1198f-resensitisation-nejm-2016/"}]}}