{"entity":{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","aka":["ALK-rearranged lung cancer","ALK fusion NSCLC","EML4-ALK lung cancer","ALK+ NSCLC"],"tldr":"ALK-positive lung cancer is driven by a fused ALK gene and is treated with a pill from the start. The newest inhibitors keep the disease under control for years, with lorlatinib holding six in ten patients progression-free at five years, and two years of alectinib after surgery cuts recurrence by three quarters.","summary":"The EML4-ALK fusion was found in lung cancer in Japan in 2007, and crizotinib, a MET inhibitor that happened to block ALK, was approved four years later on the strength of response rates around 60 percent, one of the fastest paths from discovery to approval in oncology. PROFILE 1014 (2014) showed crizotinib beat chemotherapy first line, but most patients progressed within a year, frequently in the brain, which crizotinib penetrates poorly. Ceritinib, alectinib and brigatinib were developed against crizotinib-resistant disease and then moved to the front.\n\nALEX (2017) showed alectinib beat crizotinib first line, with median progression-free survival of 34.8 versus 10.9 months, brain progression cut from 41 to 9 percent at one year and five-year survival of 62.5 versus 45.5 percent. ALTA-1L (2018) showed the same for brigatinib (24.0 versus 11.1 months), and CROWN (2020) for lorlatinib, a third-generation inhibitor designed to cover every known resistance mutation and to enter the brain: at five years 60 percent of lorlatinib patients were progression-free against 8 percent with crizotinib (hazard ratio 0.19), a result without precedent in metastatic lung cancer, though lorlatinib's cognitive, mood, weight and lipid effects need active management. Resistance to second-generation drugs is dominated by the G1202R solvent-front mutation, which lorlatinib covers; resistance to lorlatinib produces compound mutations that neladalkib (NVL-655, ALKOVE-1) is designed to overcome. Oligoprogression is often treated with local radiotherapy while the inhibitor continues.\n\nIn resected stage IB to IIIA disease ALINA (2024) showed that two years of adjuvant alectinib cut recurrence by 76 percent compared with platinum chemotherapy (hazard ratio 0.24), and it was approved in April 2024. Checkpoint inhibitors are ineffective in ALK-positive disease and carry excess liver toxicity with ALK inhibitors. Open questions are the sequence of inhibitors, whether ALK-positive cancers can be cured with prolonged therapy, and how long adjuvant treatment should last.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Anaplastic_lymphoma_kinase"},{"label":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}],"tags":["subtype-page","lung"],"related":["egfr-mutant-nsclc","ros1-positive-nsclc","ret-fusion-nsclc","ntrk-fusion-nsclc","met-altered-nsclc","kras-g12c-nsclc"],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","radiosurgery-srs","liquid-biopsy","cgp"],"targets":["alk"],"drugs":["alectinib","brigatinib","lorlatinib","crizotinib","ceritinib","ensartinib","iruplinalkib","neladalkib"],"companies":["roche-genentech","pfizer","takeda","novartis","nuvalent"],"institutions":[],"pathways":["nsclc-signalling","rtk-activation"],"terms":["gene-fusion","oncogene-addiction","gatekeeper-mutation","brain-metastases","oligoprogression","tki-term","resistance"],"trials":["alex","alta-1l","crown","alina","alkove-1"],"people":["solomon-benjamin","ross-camidge","solange-peters","tony-mok","ahn-myung-ju","wu-yi-long","justin-gainor"],"bottlenecks":[],"keyPapers":["paper-shaw-crown-lorlatinib-crizotinib-nejm-2020"],"journals":[],"dependsOn":[],"notes":[],"group":"lung","burden":"About 3 to 5 percent of non-small-cell lung cancers carry an ALK fusion, most often EML4-ALK; patients are on average a decade younger than other lung cancer patients and most have never smoked or smoked lightly. Brain metastases develop in over half over the course of the disease.","subtypes":["EML4-ALK fusion adenocarcinoma (variants 1, 2 and 3 differ in resistance patterns)","ALK-positive adenocarcinoma with brain metastases at diagnosis","Crizotinib-resistant ALK-positive disease (second-generation inhibitors)","G1202R solvent-front resistance (lorlatinib)","Compound ALK mutations after lorlatinib (neladalkib)"],"biomarkers":["ALK fusion by immunohistochemistry, fluorescence in situ hybridisation or RNA sequencing","ALK resistance mutations at progression (G1202R, compound mutations) by tissue or plasma sequencing","EML4-ALK variant (prognostic, research)","TP53 co-mutation (worse outcome)","Brain MRI at diagnosis and during follow-up","Lipids, weight and mood on lorlatinib"],"standardOfCare":[{"setting":"Advanced, first line","approach":"Alectinib (ALEX), brigatinib (ALTA-1L) or lorlatinib (CROWN); lorlatinib gives the longest control and the best brain protection, with dose adjustment for cognitive, mood and metabolic effects.","refs":["alectinib","alex","brigatinib","alta-1l","lorlatinib","crown","brain-metastases"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after a second-generation inhibitor","approach":"Lorlatinib, guided where possible by the resistance mutation; local radiotherapy for oligoprogression; platinum-pemetrexed once inhibitors are exhausted.","refs":["lorlatinib","oligoprogression","sbrt","pemetrexed","carboplatin","gatekeeper-mutation"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Advanced, after lorlatinib","approach":"Neladalkib in trials (ALKOVE-1); chemotherapy; clinical trial.","refs":["neladalkib","alkove-1","pemetrexed"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Resected stage IB to IIIA","approach":"Surgery then two years of adjuvant alectinib (ALINA) in place of platinum chemotherapy.","refs":["alectinib","alina","neoadjuvant-adjuvant"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}},{"setting":"Brain metastases","approach":"Next-generation inhibitors control most brain metastases without radiotherapy; stereotactic radiosurgery for large or symptomatic lesions; whole-brain radiotherapy avoided.","refs":["lorlatinib","alectinib","radiosurgery-srs","brain-metastases","wbrt"],"guideline":{"version":"NCCN Guidelines: Non-Small Cell Lung Cancer","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1450"}}],"stateOfArt":["Lorlatinib first line: 60 percent progression-free at five years in CROWN, the longest control reported in any metastatic lung cancer trial.","Adjuvant alectinib (ALINA) replaces chemotherapy after resection.","Sequencing of inhibitors by resistance mutation, with neladalkib designed for compound mutations after lorlatinib.","Brain metastases managed largely with drugs rather than radiotherapy."],"history":[{"year":2007,"title":"EML4-ALK fusion discovered in lung cancer (Soda and Mano, Japan)","refs":["alk","gene-fusion"]},{"year":2011,"title":"Crizotinib approved four years after the fusion was found","refs":["crizotinib"]},{"year":2014,"title":"PROFILE 1014: crizotinib beats chemotherapy first line","refs":["crizotinib","solomon-benjamin"]},{"year":2017,"title":"ALEX: alectinib beats crizotinib first line with far less brain progression","refs":["alex","alectinib","solange-peters"]},{"year":2018,"title":"ALTA-1L: brigatinib beats crizotinib first line","refs":["alta-1l","brigatinib","ross-camidge"]},{"year":2020,"title":"CROWN: lorlatinib first line; five-year update in 2024 shows 60 percent progression-free","refs":["crown","lorlatinib","solomon-benjamin"]},{"year":2024,"title":"ALINA: two years of adjuvant alectinib cuts recurrence by 76 percent","refs":["alina","alectinib","wu-yi-long"]}],"pipeline":["neladalkib","alkove-1","iruplinalkib","ensartinib","idea-bio1-ctdna-adaptive-tki"],"openProblems":["Whether any sequence of inhibitors cures metastatic ALK-positive disease or only holds it is unknown.","Lorlatinib's cognitive, mood and metabolic effects are managed by dose reduction without trials of the optimal dose.","Resistance after lorlatinib is compound mutations and bypass pathways with no approved option.","The right duration of adjuvant alectinib is untested; recurrences after stopping are being watched."],"parent":"nsclc"},"route":"/cancers/alk-positive-nsclc/","neighbours":{"cancer":[{"id":"lung-adenocarcinoma","kind":"cancer","name":"Adenocarcinoma of the lung","route":"/cancers/lung-adenocarcinoma/"},{"id":"egfr-mutant-nsclc","kind":"cancer","name":"EGFR-mutated non-small-cell lung cancer","route":"/cancers/egfr-mutant-nsclc/"},{"id":"her2-mutant-nsclc","kind":"cancer","name":"HER2-mutant non-small-cell lung cancer","route":"/cancers/her2-mutant-nsclc/"},{"id":"kras-g12c-nsclc","kind":"cancer","name":"KRAS G12C-mutant non-small-cell lung cancer","route":"/cancers/kras-g12c-nsclc/"},{"id":"met-altered-nsclc","kind":"cancer","name":"MET exon 14 and MET-amplified non-small-cell lung cancer","route":"/cancers/met-altered-nsclc/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"ntrk-fusion-nsclc","kind":"cancer","name":"NTRK fusion-positive non-small-cell lung cancer","route":"/cancers/ntrk-fusion-nsclc/"},{"id":"pdl1-high-nsclc","kind":"cancer","name":"PD-L1-high non-small-cell lung cancer without a driver mutation","route":"/cancers/pdl1-high-nsclc/"},{"id":"resectable-nsclc","kind":"cancer","name":"Resectable stage I to III non-small-cell lung cancer","route":"/cancers/resectable-nsclc/"},{"id":"ret-fusion-nsclc","kind":"cancer","name":"RET fusion-positive non-small-cell lung cancer","route":"/cancers/ret-fusion-nsclc/"},{"id":"ros1-positive-nsclc","kind":"cancer","name":"ROS1-positive non-small-cell lung cancer","route":"/cancers/ros1-positive-nsclc/"},{"id":"stage-iii-unresectable-nsclc","kind":"cancer","name":"Unresectable stage III non-small-cell lung cancer","route":"/cancers/stage-iii-unresectable-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":"sbrt","kind":"technology","name":"SBRT / SABR (stereotactic radiotherapy)","route":"/technologies/sbrt/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"},{"id":"radiosurgery-srs","kind":"technology","name":"Stereotactic radiosurgery (Gamma Knife, CyberKnife, linac SRS)","route":"/technologies/radiosurgery-srs/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"}],"drug":[{"id":"alectinib","kind":"drug","name":"Alectinib","route":"/drugs/alectinib/"},{"id":"brigatinib","kind":"drug","name":"Brigatinib","route":"/drugs/brigatinib/"},{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"ceritinib","kind":"drug","name":"Ceritinib","route":"/drugs/ceritinib/"},{"id":"crizotinib","kind":"drug","name":"Crizotinib","route":"/drugs/crizotinib/"},{"id":"ensartinib","kind":"drug","name":"Ensartinib","route":"/drugs/ensartinib/"},{"id":"iruplinalkib","kind":"drug","name":"Iruplinalkib","route":"/drugs/iruplinalkib/"},{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","route":"/drugs/lorlatinib/"},{"id":"neladalkib","kind":"drug","name":"Neladalkib","route":"/drugs/neladalkib/"},{"id":"pemetrexed","kind":"drug","name":"Pemetrexed","route":"/drugs/pemetrexed/"}],"company":[{"id":"novartis","kind":"company","name":"Novartis","route":"/companies/novartis/"},{"id":"nuvalent","kind":"company","name":"Nuvalent","route":"/companies/nuvalent/"},{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/"},{"id":"roche-genentech","kind":"company","name":"Roche / Genentech","route":"/companies/roche-genentech/"},{"id":"takeda","kind":"company","name":"Takeda","route":"/companies/takeda/"}],"pathway":[{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"rtk-activation","kind":"pathway","name":"Receptor tyrosine kinase activation","route":"/pathways/rtk-activation/"}],"term":[{"id":"brain-metastases","kind":"term","name":"Brain metastases (intracranial disease)","route":"/terms/brain-metastases/"},{"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/"},{"id":"never-smoker-lung-cancer","kind":"term","name":"Lung cancer in never-smokers","route":"/terms/never-smoker-lung-cancer/"},{"id":"neoadjuvant-adjuvant","kind":"term","name":"Neoadjuvant / adjuvant / perioperative","route":"/terms/neoadjuvant-adjuvant/"},{"id":"oligoprogression","kind":"term","name":"Oligoprogression","route":"/terms/oligoprogression/"},{"id":"gatekeeper-mutation","kind":"term","name":"On-target resistance mutations (gatekeeper, solvent-front, compound)","route":"/terms/gatekeeper-mutation/"},{"id":"oncogene-addiction","kind":"term","name":"Oncogene addiction","route":"/terms/oncogene-addiction/"},{"id":"tki-term","kind":"term","name":"Tyrosine kinase inhibitor (TKI)","route":"/terms/tki-term/"},{"id":"wbrt","kind":"term","name":"Whole-brain radiotherapy (WBRT)","route":"/terms/wbrt/"}],"trial":[{"id":"nct07491497","kind":"trial","name":"A Phase 1/2 Study of TRI-611 in ALK-Positive NSCLC","route":"/trials/nct07491497/"},{"id":"nct05186506","kind":"trial","name":"A Study Comparing Ensatinib Versus Platinum-Based Chemotherapy as Adjuvant Treatment for Stage II-IIIA ALK -Positive Non-Small Cell Lung Cancer","route":"/trials/nct05186506/"},{"id":"nct04641754","kind":"trial","name":"A Study Evaluates the Safety and Efficacy of WX-0593 in ALK -Positive, or ROS1-positive Non-small Cell Lung Cancer","route":"/trials/nct04641754/"},{"id":"nct06254599","kind":"trial","name":"A Study Of SY-3505 Versus Crizotinib In First Line Treatment Of Patients With ALK-Positive NSCLC","route":"/trials/nct06254599/"},{"id":"nct04772287","kind":"trial","name":"Adjuvant Toripalimab Plus Chemotherapy for EGFR/ALK Mutation Negative Stage II-IIIB(N2) NSCLC (LungMate-008)","route":"/trials/nct04772287/"},{"id":"nct06780839","kind":"trial","name":"Adjuvant Treatment of ALK-positive Non-small Cell Lung Cancer with Ensartinib Guided by MRD","route":"/trials/nct06780839/"},{"id":"alesia","kind":"trial","name":"ALESIA","route":"/trials/alesia/"},{"id":"alex","kind":"trial","name":"ALEX","route":"/trials/alex/"},{"id":"alina","kind":"trial","name":"ALINA","route":"/trials/alina/"},{"id":"alkove-1","kind":"trial","name":"ALKOVE-1","route":"/trials/alkove-1/"},{"id":"alta","kind":"trial","name":"ALTA","route":"/trials/alta/"},{"id":"alta-1l","kind":"trial","name":"ALTA-1L","route":"/trials/alta-1l/"},{"id":"nct01828099","kind":"trial","name":"ASCEND-4","route":"/trials/nct01828099/"},{"id":"nct02568267","kind":"trial","name":"Basket Study of Entrectinib (RXDX-101) for the Treatment of Patients With Solid Tumors Harboring NTRK 1/2/3 (Trk A/B/C), ROS1, or ALK Gene Rearrangeme","route":"/trials/nct02568267/"},{"id":"crown","kind":"trial","name":"CROWN","route":"/trials/crown/"},{"id":"nct05987644","kind":"trial","name":"Delayed or Upfront Brain RAdiotherapy in Treatment naïve Lung Cancer Patients With Asymptomatic or Minimally Symptomatic Brain Metastases and ALK rEarrangements","route":"/trials/nct05987644/"},{"id":"nct07361484","kind":"trial","name":"Docetaxel Plus Plinabulin vs Docetaxel Plus Placebo in Advanced/Metastatic Non-Squamous NSCLC After PD-1/PD-L1 Therapy and Platinum Chemotherapy (DUBLIN-4)","route":"/trials/nct07361484/"},{"id":"nct02767804","kind":"trial","name":"eXalt3","route":"/trials/nct02767804/"},{"id":"j-alex","kind":"trial","name":"J-ALEX","route":"/trials/j-alex/"},{"id":"nct01828112","kind":"trial","name":"LDK378 Versus Chemotherapy in ALK Rearranged (ALK Positive) Patients Previously Treated With Chemotherapy (Platinum Doublet) and Crizotinib","route":"/trials/nct01828112/"},{"id":"nct06858410","kind":"trial","name":"Lorlatinib Compared with Concurrent/ Sequential Chemoradiotherapy in Stage III ALK Positive Lung Adenocarcinoma","route":"/trials/nct06858410/"},{"id":"nct06765109","kind":"trial","name":"Neladalkib (NVL-655) for TKI-naive Patients With Advanced ALK-Positive NSCLC","route":"/trials/nct06765109/"},{"id":"nct05765877","kind":"trial","name":"Neoadjuvant WX-0593 in Resectable ALK-positive or ROS1-positive Non-small Cell Lung Cancer","route":"/trials/nct05765877/"},{"id":"nct05950139","kind":"trial","name":"Peptide Vaccine To Prevent Acquired Resistance In Patients With Advanced ALK+ NSCLC","route":"/trials/nct05950139/"},{"id":"profile-1014","kind":"trial","name":"PROFILE 1014","route":"/trials/profile-1014/"},{"id":"nct04632758","kind":"trial","name":"Study Comparing WX-0593 to Crizotinib in ALK Positive Non-Small Cell Lung Cancer (NSCLC) Patients","route":"/trials/nct04632758/"},{"id":"nct06569420","kind":"trial","name":"Study Of Comparing SAF-189s With Crizotinib In First Line ALK-Positive Advanced and Metastatic NSCLC","route":"/trials/nct06569420/"},{"id":"nct05955391","kind":"trial","name":"TGRX-326 Chinese Phase II for Advanced Non-small Cell Lung Cancer (NSCLC)","route":"/trials/nct05955391/"},{"id":"nsclc-3","kind":"trial","name":"TGRX-326 Chinese Phase III for Advanced Non-small Cell Lung Cancer (NSCLC)","route":"/trials/nsclc-3/"},{"id":"nct06951399","kind":"trial","name":"Tracking T-Cell Responses to Evaluate Pembrolizumab Effectiveness in Advanced Non-Small Cell Lung Cancer","route":"/trials/nct06951399/"}],"person":[{"id":"solomon-benjamin","kind":"person","name":"Benjamin Solomon","route":"/people/solomon-benjamin/"},{"id":"ross-camidge","kind":"person","name":"D. Ross Camidge","route":"/people/ross-camidge/"},{"id":"justin-gainor","kind":"person","name":"Justin F. Gainor","route":"/people/justin-gainor/"},{"id":"ahn-myung-ju","kind":"person","name":"Myung-Ju Ahn","route":"/people/ahn-myung-ju/"},{"id":"sanjay-popat","kind":"person","name":"Sanjay Popat","route":"/people/sanjay-popat/"},{"id":"solange-peters","kind":"person","name":"Solange Peters","route":"/people/solange-peters/"},{"id":"tony-mok","kind":"person","name":"Tony S. K. Mok","route":"/people/tony-mok/"},{"id":"wu-yi-long","kind":"person","name":"Yi-Long Wu","route":"/people/wu-yi-long/"}],"paper":[{"id":"paper-wu-alina-adjuvant-alectinib-nejm-2024","kind":"paper","name":"Alectinib in resected ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-wu-alina-adjuvant-alectinib-nejm-2024/"},{"id":"paper-peters-alex-alectinib-crizotinib-nejm-2017","kind":"paper","name":"Alectinib versus crizotinib in untreated ALK-positive non-small-cell lung cancer","route":"/key-papers/paper-peters-alex-alectinib-crizotinib-nejm-2017/"},{"id":"paper-kwak-crizotinib-alk-nsclc-nejm-2010","kind":"paper","name":"Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer","route":"/key-papers/paper-kwak-crizotinib-alk-nsclc-nejm-2010/"},{"id":"paper-alta-jco-2017","kind":"paper","name":"Brigatinib in patients with crizotinib-refractory ALK-positive non-small-cell lung cancer: a randomized, multicenter phase II trial (ALTA)","route":"/key-papers/paper-alta-jco-2017/"},{"id":"paper-ascend-4-lancet-2017","kind":"paper","name":"First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study","route":"/key-papers/paper-ascend-4-lancet-2017/"},{"id":"paper-shaw-crown-lorlatinib-crizotinib-nejm-2020","kind":"paper","name":"First-line lorlatinib or crizotinib in advanced ALK-positive lung cancer","route":"/key-papers/paper-shaw-crown-lorlatinib-crizotinib-nejm-2020/"},{"id":"paper-soda-eml4-alk-fusion-nature-2007","kind":"paper","name":"Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer","route":"/key-papers/paper-soda-eml4-alk-fusion-nature-2007/"}],"idea":[{"id":"idea-bio1-ctdna-adaptive-tki","kind":"idea","name":"ctDNA-guided dose holidays for lung cancer targeted therapy","route":"/ideas/idea-bio1-ctdna-adaptive-tki/"},{"id":"idea-lung-resistance-directed-sequencing-at-every-progression","kind":"idea","name":"Make resistance a diagnosis: sequence at every progression and choose the next line from what the tumour became","route":"/ideas/idea-lung-resistance-directed-sequencing-at-every-progression/"},{"id":"idea-lung-brain-metastasis-prevention-as-a-primary-endpoint","kind":"idea","name":"Measure brain metastasis prevention as a primary endpoint, not as a secondary one","route":"/ideas/idea-lung-brain-metastasis-prevention-as-a-primary-endpoint/"}]}}