{"entity":{"id":"lorlatinib","kind":"drug","name":"Lorlatinib","aka":[],"tldr":"An ALK inhibitor with the longest disease control ever recorded for a targeted lung cancer pill: 60% progression-free at five years.","summary":"Lorlatinib is a macrocyclic third-generation ALK and ROS1 inhibitor designed to cover resistance mutations including G1202R and to cross the blood-brain barrier, taken as 100 mg once daily. In CROWN it achieved a 5-year progression-free survival of 60% versus 8% for crizotinib, with near-complete protection against brain progression. It was approved in 2018 after prior ALK inhibitors and in 2021 for first-line ALK-positive NSCLC. Its distinctive toxicities are metabolic and neurological: raised cholesterol and triglycerides, weight gain, oedema, neuropathy and cognitive or mood effects, which need active management. Its position against alectinib and newer agents such as neladalkib remains open. For a newcomer: the ALK pill with the most durable results, balanced against side effects that touch thinking and mood.","status":"approved","asOf":"2026-09-04","wikipedia":"https://en.wikipedia.org/wiki/Lorlatinib","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Lorlatinib"},{"label":"NICE TA628: lorlatinib for previously treated ALK-positive advanced non-small-cell lung cancer","url":"https://www.nice.org.uk/guidance/ta628"},{"label":"NICE TA1103: lorlatinib for ALK-positive advanced non-small-cell lung cancer not treated with an ALK inhibitor","url":"https://www.nice.org.uk/guidance/ta1103"}],"tags":[],"related":["alk-fusion"],"cancers":["nsclc","secondary-brain-tumours","neuroblastoma-high-risk","alk-positive-nsclc","lung-cancer"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["alk"],"drugs":[],"companies":["pfizer"],"institutions":[],"pathways":[],"terms":[],"trials":["nct05297890","crown"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"brand":"Lorbrena","modality":"Small-molecule kinase inhibitor (ALK/ROS1)","mechanism":"Macrocyclic third-generation ALK/ROS1 TKI covering G1202R.","approvals":[{"region":"US","year":2018,"indication":"ALK+ NSCLC after prior ALK TKI"},{"region":"US","year":2021,"indication":"First-line ALK+ NSCLC"},{"region":"England (NICE)","year":2020,"indication":"ALK-positive advanced non-small-cell lung cancer progressing after alectinib or ceritinib as the first ALK inhibitor, or after crizotinib and at least one other ALK inhibitor","note":"TA628, published 13 May 2020, subject to the commercial arrangement."},{"region":"England (NICE)","year":2025,"indication":"ALK-positive advanced non-small-cell lung cancer not previously treated with an ALK inhibitor","note":"TA1103, published 21 October 2025 (CROWN); must be funded in England within 90 days of publication."}],"mechanismSteps":["Oral drug is absorbed and reaches the tumour","Binds the ATP pocket (or allosteric site) of ALK (and ROS1), including G1202R resistance mutations","Phosphorylation of downstream substrates stops","Macrocycle enters the brain and blocks ALK fusion signalling","Oncogene-addicted cells arrest and undergo apoptosis"],"dosing":{"route":"Oral","schedule":"100 mg once daily","modifications":"Reduce to 75 then 50 mg for CNS effects, hyperlipidaemia, AV block","monitoring":"Lipids at baseline and monthly; ECG; mood and cognition; LFTs","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications"},"toxicity":[{"event":"Hypercholesterolaemia","note":"CROWN: ~70% any grade, ~20% grade 3-4"},{"event":"Hypertriglyceridaemia"},{"event":"Oedema"},{"event":"Weight gain"},{"event":"Peripheral neuropathy"},{"event":"Cognitive and mood effects"},{"event":"Hypertension"}],"access":[{"country":"US","reimbursement":"Medicare Part D (oral); commercial plans per formulary, often with prior authorisation","assistance":"https://www.pfizeroncologytogether.com","source":"https://www.cms.gov/medicare/payment/part-b-drugs/asp-pricing-files","asOf":"2026-09-06"},{"country":"UK","reimbursement":"NICE: recommended first-line for ALK+ NSCLC (TA909)","source":"https://www.nice.org.uk/guidance/published?ngt=Technology%20appraisal%20guidance","asOf":"2026-09-06"}],"regulatoryEvents":[{"date":"2018-11-02","type":"accelerated-approval","region":"US","note":"ALK+ NSCLC after prior ALK TKIs (accelerated)","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","indication":"ALK-positive metastatic NSCLC that has progressed on: • Crizotinib and at least one other ALK inhibitor for metastatic disease; or • Alectinib as the first ALK inhibitor therapy for metastatic disease; or • Ceritinib as the first ALK inhibitor therapy for metastatic disease"},{"date":"2021-03-03","type":"conversion","region":"US","note":"First-line ALK+ NSCLC (CROWN); full approval","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/oncology-cancer-hematologic-malignancies-approval-notifications","indication":"ALK-positive metastatic NSCLC that has progressed on: • Crizotinib and at least one other ALK inhibitor for metastatic disease; or • Alectinib as the first ALK inhibitor therapy for metastatic disease; or • Ceritinib as the first ALK inhibitor therapy for metastatic disease"}]},"route":"/drugs/lorlatinib/","neighbours":{"biomarker":[{"id":"alk-fusion","kind":"biomarker","name":"ALK fusion (ALK-positive)","route":"/biomarkers/alk-fusion/"}],"cancer":[{"id":"alk-positive-nsclc","kind":"cancer","name":"ALK-positive non-small-cell lung cancer","route":"/cancers/alk-positive-nsclc/"},{"id":"secondary-brain-tumours","kind":"cancer","name":"Brain metastases (secondary brain tumours)","route":"/cancers/secondary-brain-tumours/"},{"id":"neuroblastoma-high-risk","kind":"cancer","name":"High-risk neuroblastoma","route":"/cancers/neuroblastoma-high-risk/"},{"id":"inflammatory-myofibroblastic-tumour","kind":"cancer","name":"Inflammatory myofibroblastic tumour (IMT)","route":"/cancers/inflammatory-myofibroblastic-tumour/"},{"id":"lung-cancer","kind":"cancer","name":"Lung cancer (all types)","route":"/cancers/lung-cancer/"},{"id":"neuroblastoma","kind":"cancer","name":"Neuroblastoma (paediatric)","route":"/cancers/neuroblastoma/"},{"id":"nsclc","kind":"cancer","name":"Non-small-cell lung cancer","route":"/cancers/nsclc/"},{"id":"paediatric-high-grade-glioma","kind":"cancer","name":"Paediatric high-grade glioma (excluding diffuse midline glioma)","route":"/cancers/paediatric-high-grade-glioma/"}],"technology":[{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"alk","kind":"target","name":"ALK","route":"/targets/alk/"}],"company":[{"id":"pfizer","kind":"company","name":"Pfizer (incl. Seagen)","route":"/companies/pfizer/"}],"trial":[{"id":"nct05297890","kind":"trial","name":"A Study of Lorlatinib in Subjects With ROS1-Positive Non-Small Cell Lung Cancer","route":"/trials/nct05297890/"},{"id":"anbl1531","kind":"trial","name":"COG ANBL1531","route":"/trials/anbl1531/"},{"id":"crown","kind":"trial","name":"CROWN","route":"/trials/crown/"},{"id":"nct06858410","kind":"trial","name":"Lorlatinib Compared with Concurrent/ Sequential Chemoradiotherapy in Stage III ALK Positive Lung Adenocarcinoma","route":"/trials/nct06858410/"}],"drug":[{"id":"neladalkib","kind":"drug","name":"Neladalkib","route":"/drugs/neladalkib/"}],"pairing":[{"id":"targeted-before-io-nsclc","kind":"pairing","name":"Sequence: targeted therapy before immunotherapy in driver-positive NSCLC","route":"/pairings/targeted-before-io-nsclc/"}],"term":[{"id":"graded-prognostic-assessment","kind":"term","name":"Graded Prognostic Assessment (GPA) for brain metastases","route":"/terms/graded-prognostic-assessment/"},{"id":"kinase","kind":"term","name":"Kinase","route":"/terms/kinase/"},{"id":"lung-uk-drug-access","kind":"term","name":"Lung cancer drugs in England: what NICE has recommended","route":"/terms/lung-uk-drug-access/"},{"id":"mycn-amplification","kind":"term","name":"MYCN amplification","route":"/terms/mycn-amplification/"},{"id":"segmental-chromosomal-aberrations","kind":"term","name":"Segmental chromosomal aberrations and ploidy (neuroblastoma)","route":"/terms/segmental-chromosomal-aberrations/"}],"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-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-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/"}],"pathway":[{"id":"drug-efflux-pumps","kind":"pathway","name":"Drug efflux pumps (ABC transporters)","route":"/pathways/drug-efflux-pumps/"},{"id":"nsclc-signalling","kind":"pathway","name":"Non-small cell lung cancer (KEGG map)","route":"/pathways/nsclc-signalling/"},{"id":"organ-tropism-seed-soil","kind":"pathway","name":"Organ tropism: seed and soil","route":"/pathways/organ-tropism-seed-soil/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"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/"},{"id":"blood-brain-barrier-metastasis","kind":"pathway","name":"The blood-brain barrier & brain metastasis","route":"/pathways/blood-brain-barrier-metastasis/"}],"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":"kim-dong-wan","kind":"person","name":"Dong-Wan Kim","route":"/people/kim-dong-wan/"},{"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":"yael-mosse","kind":"person","name":"Yael P. Mossé","route":"/people/yael-mosse/"}],"idea":[{"id":"idea-tr1-brain-mets-default-included","kind":"idea","name":"Brain metastases included by default in every solid-tumour trial","route":"/ideas/idea-tr1-brain-mets-default-included/"},{"id":"idea-bio2-paediatric-first-development","kind":"idea","name":"Develop drugs in children first when the target is a children's target","route":"/ideas/idea-bio2-paediatric-first-development/"},{"id":"idea-bio2-brain-met-prevention-trials","kind":"idea","name":"Prevention trials aimed only at brain metastasis","route":"/ideas/idea-bio2-brain-met-prevention-trials/"},{"id":"idea-bio1-first-strike-second-strike","kind":"idea","name":"Switch drugs at maximum response, not at relapse","route":"/ideas/idea-bio1-first-strike-second-strike/"}],"institution":[{"id":"chop","kind":"institution","name":"Children's Hospital of Philadelphia","route":"/institutions/chop/"},{"id":"shanghai-chest-hospital","kind":"institution","name":"Shanghai Chest Hospital","route":"/institutions/shanghai-chest-hospital/"},{"id":"colorado-cancer-center","kind":"institution","name":"University of Colorado Cancer Center","route":"/institutions/colorado-cancer-center/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}