{"entity":{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","aka":[],"tldr":"The pill that ended chemotherapy for most CLL. It blocks the survival signal B cells depend on, and it was the first drug to beat chemoimmunotherapy in nearly every CLL setting.","summary":"Approved 2014 (relapsed CLL, RESONATE), 2016 (frontline, RESONATE-2), and with venetoclax as fixed-duration therapy (GLOW, CAPTIVATE; EU 2022). Also mantle cell lymphoma (withdrawn in the US 2023), Waldenström, marginal zone (withdrawn), and chronic GVHD. Off-target inhibition of EGFR, TEC, and CSK causes atrial fibrillation (~10-16%), hypertension, bleeding, and arthralgia; head-to-head trials (ELEVATE-RR, ALPINE) showed acalabrutinib and zanubrutinib are better tolerated, and zanubrutinib more effective, so ibrutinib is now second choice where alternatives exist.","status":"approved","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Ibrutinib","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Ibrutinib"},{"label":"Tempero et al., RESOLVE (Annals of Oncology 2021)","url":"https://doi.org/10.1016/j.annonc.2021.01.070"},{"label":"Davis et al., Nature 2010: chronic active B-cell receptor signalling in diffuse large B-cell lymphoma","url":"https://doi.org/10.1038/nature08638"},{"label":"Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib","url":"https://doi.org/10.1056/NEJMoa1400029"}],"tags":[],"related":[],"cancers":["cll","dlbcl","pancreatic","metastatic-pdac"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["btk"],"drugs":[],"companies":["abbvie","johnson-johnson"],"institutions":[],"pathways":[],"terms":[],"trials":["resonate","captivate","glow","alpine","nct01804686","nct03960840","nct05283720","nct03379428","nct02477696","nct04509700","nct05254743","nct05963074","nct04494503","nct04662255","resolve"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Pancreatic cancer: RESOLVE (424 randomised) found no overall survival benefit (9.7 against 10.8 months) and shorter progression-free survival (5.3 against 6.0 months) when ibrutinib was added to nab-paclitaxel and gemcitabine.","Lymphoma biology: the drug exists because knocking down BTK killed activated B-cell-like lymphoma cells with wild-type CARD11 and left other lymphomas alone, which is what identified chronic active B-cell receptor signalling as a pathogenetic mechanism (Davis 2010). Resistance is on-target in most patients, through BTK C481S, and bypass in a minority, through gain-of-function PLCG2 changes below the kinase that no BTK inhibitor can reach (Woyach 2014)."],"brand":"Imbruvica","modality":"Small-molecule covalent BTK inhibitor (first generation)","mechanism":"Covalent binding to cysteine 481 in the BTK active site irreversibly blocks BCR signalling; also inhibits ITK, TEC, EGFR (off-target).","approvals":[{"region":"US","year":2013,"indication":"Relapsed mantle cell lymphoma (accelerated); first BTK inhibitor"},{"region":"US","year":2014,"indication":"Relapsed CLL (RESONATE); del(17p) CLL"},{"region":"US","year":2016,"indication":"First-line CLL (RESONATE-2)"},{"region":"EU","year":2014,"indication":"Relapsed mantle cell lymphoma; CLL after one prior therapy or with del(17p)/TP53 mutation"},{"region":"EU","year":2022,"indication":"Fixed-duration ibrutinib + venetoclax, first-line CLL (GLOW, CAPTIVATE)"}],"mechanismSteps":["B-cell receptor engagement activates BTK in the CLL cell","Ibrutinib binds C481 covalently and permanently inactivates that BTK molecule","PLCγ2, NF-κB, and chemokine signalling stop; cells lose adhesion","CLL cells are flushed from lymph nodes into blood (transient lymphocytosis) and die over months","Continuous daily dosing is required because new BTK is synthesised"],"dosing":{"route":"Oral","schedule":"420 mg once daily continuously until progression (CLL); 560 mg in MCL","monitoring":"Atrial fibrillation, hypertension, bleeding (hold around surgery), infections, cytopenias","source":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Imbruvica"},"toxicity":[{"event":"Atrial fibrillation","anyGradePct":16,"source":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Imbruvica","note":"Pooled long-term CLL data; 5% grade ≥3"},{"event":"Hypertension","anyGradePct":42,"note":"Cumulative over years"},{"event":"Major haemorrhage","anyGradePct":4},{"event":"Diarrhoea","anyGradePct":50},{"event":"Arthralgia","anyGradePct":30}],"access":[],"regulatoryEvents":[{"date":"2013-11-13","type":"accelerated-approval","region":"US","note":"Mantle cell lymphoma (accelerated); first BTK inhibitor","indication":"Adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy"},{"date":"2014-02-12","type":"accelerated-approval","region":"US","note":"Relapsed CLL","indication":"Chronic lymphocytic leukemia after at least one prior therapy"},{"date":"2014-07-28","type":"conversion","region":"US","note":"Confirmed: the accelerated approval of 2014 converted to traditional approval 0.5 years after it was granted.","indication":"Chronic lymphocytic leukemia after at least one prior therapy"},{"date":"2016-03-04","type":"approval","region":"US","note":"First-line CLL"},{"date":"2017-01-18","type":"accelerated-approval","region":"US","note":"Accelerated approval on a surrogate endpoint, with a confirmatory trial required.","indication":"Adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy"},{"date":"2023-04-06","type":"withdrawal","region":"US","note":"MCL and MZL indications voluntarily withdrawn after confirmatory trials missed"},{"date":"2023-05-18","type":"withdrawal","region":"US","note":"Withdrawn: the indication came off the label 9.5 years after its accelerated approval.","indication":"Adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy"},{"date":"2023-05-18","type":"withdrawal","region":"US","note":"Withdrawn: the indication came off the label 6.3 years after its accelerated approval.","indication":"Adult patients with marginal zone lymphoma (MZL) who require systemic therapy and have received at least one prior anti-CD20-based therapy"}]},"route":"/drugs/ibrutinib/","neighbours":{"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cll-treatment-naive","kind":"cancer","name":"Chronic lymphocytic leukaemia, first treatment","route":"/cancers/cll-treatment-naive/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"hairy-cell-leukemia","kind":"cancer","name":"Hairy cell leukaemia","route":"/cancers/hairy-cell-leukemia/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-lymphoma/"},{"id":"marginal-zone-lymphoma","kind":"cancer","name":"Marginal zone lymphoma","route":"/cancers/marginal-zone-lymphoma/"},{"id":"metastatic-pdac","kind":"cancer","name":"Metastatic pancreatic ductal adenocarcinoma","route":"/cancers/metastatic-pdac/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"primary-cns-lymphoma","kind":"cancer","name":"Primary CNS lymphoma","route":"/cancers/primary-cns-lymphoma/"},{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","route":"/cancers/cll-relapsed/"},{"id":"richter-transformation-cll","kind":"cancer","name":"Richter transformation of chronic lymphocytic leukaemia","route":"/cancers/richter-transformation-cll/"},{"id":"splenic-b-cell-lymphoma-leukaemia-prominent-nucleoli","kind":"cancer","name":"Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant)","route":"/cancers/splenic-b-cell-lymphoma-leukaemia-prominent-nucleoli/"},{"id":"t-cell-prolymphocytic-leukaemia","kind":"cancer","name":"T-cell prolymphocytic leukaemia","route":"/cancers/t-cell-prolymphocytic-leukaemia/"},{"id":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}],"technology":[{"id":"gvhd-belumosudil-axatilimab-ibrutinib","kind":"technology","name":"After ruxolitinib: belumosudil, axatilimab and ibrutinib in chronic GvHD","route":"/technologies/gvhd-belumosudil-axatilimab-ibrutinib/"},{"id":"gvhd-chronic-overview","kind":"technology","name":"Chronic graft-versus-host disease","route":"/technologies/gvhd-chronic-overview/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"target":[{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"hck","kind":"target","name":"HCK kinase","route":"/targets/hck/"},{"id":"itk","kind":"target","name":"ITK","route":"/targets/itk/"},{"id":"tec","kind":"target","name":"TEC","route":"/targets/tec/"}],"company":[{"id":"abbvie","kind":"company","name":"AbbVie (incl. ImmunoGen, Capstan)","route":"/companies/abbvie/"},{"id":"johnson-johnson","kind":"company","name":"Johnson & Johnson","route":"/companies/johnson-johnson/"}],"trial":[{"id":"nct01804686","kind":"trial","name":"A Long-term Extension Study of PCI-32765 (Ibrutinib)","route":"/trials/nct01804686/"},{"id":"nct04274738","kind":"trial","name":"A Study of Mavorixafor in Combination With Ibrutinib in Participants With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4","route":"/trials/nct04274738/"},{"id":"nct05254743","kind":"trial","name":"A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)","route":"/trials/nct05254743/"},{"id":"nct05963074","kind":"trial","name":"A Study to Customize Ibrutinib Treatment Regimens for Participants With Previously Untreated Chronic Lymphocytic Leukemia","route":"/trials/nct05963074/"},{"id":"nct05283720","kind":"trial","name":"A Study to Evaluate Adverse Events and Change in Disease Activity of Subcutaneous (SC) Epcoritamab in Combination With Oral and Intravenous Anti-Neopl","route":"/trials/nct05283720/"},{"id":"alpine","kind":"trial","name":"ALPINE","route":"/trials/alpine/"},{"id":"aspen-wm","kind":"trial","name":"ASPEN (Waldenström macroglobulinaemia)","route":"/trials/aspen-wm/"},{"id":"bellwave-011","kind":"trial","name":"BELLWAVE-011","route":"/trials/bellwave-011/"},{"id":"nct03328078","kind":"trial","name":"CA-4948-101: Open-Label, Dose Escalation and Expansion Trial of Emavusertib (CA-4948) in Relapsed or Refractory Primary Central Nervous System Lymphoma (R/R PCNSL)","route":"/trials/nct03328078/"},{"id":"captivate","kind":"trial","name":"CAPTIVATE","route":"/trials/captivate/"},{"id":"cll12","kind":"trial","name":"CLL12","route":"/trials/cll12/"},{"id":"cll13-gaia","kind":"trial","name":"CLL13 / GAIA","route":"/trials/cll13-gaia/"},{"id":"enrich","kind":"trial","name":"ENRICH","route":"/trials/enrich/"},{"id":"glow","kind":"trial","name":"GLOW","route":"/trials/glow/"},{"id":"nct03960840","kind":"trial","name":"Phase I/II Study of Rapcabtagene Autoleucel in CLL, 3L+ DLBCL, r/r ALL and 1L HR LBCL","route":"/trials/nct03960840/"},{"id":"resolve","kind":"trial","name":"RESOLVE","route":"/trials/resolve/"},{"id":"resonate","kind":"trial","name":"RESONATE","route":"/trials/resonate/"},{"id":"resonate-2","kind":"trial","name":"RESONATE-2","route":"/trials/resonate-2/"},{"id":"nct04509700","kind":"trial","name":"Rollover Study to Provide Continued Treatment for Participants With B-Cell Malignancies Previously Enrolled in Studies of Parsaclisib (INCB050465)","route":"/trials/nct04509700/"},{"id":"shine","kind":"trial","name":"SHINE","route":"/trials/shine/"},{"id":"nct02477696","kind":"trial","name":"Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL)","route":"/trials/nct02477696/"},{"id":"nct04494503","kind":"trial","name":"Study of APG2575 Single Agent and Combination Therapy in Patients With Relapsed/Refractory CLL/SLL","route":"/trials/nct04494503/"},{"id":"nct04662255","kind":"trial","name":"Study of BTK Inhibitor LOXO-305 Versus Approved BTK Inhibitor Drugs in Patients With Mantle Cell Lymphoma (MCL)","route":"/trials/nct04662255/"},{"id":"sympatico","kind":"trial","name":"SYMPATICO","route":"/trials/sympatico/"},{"id":"nct03379428","kind":"trial","name":"Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer","route":"/trials/nct03379428/"},{"id":"triangle","kind":"trial","name":"TRIANGLE","route":"/trials/triangle/"}],"pairing":[{"id":"btki-plus-venetoclax-fixed-duration","kind":"pairing","name":"BTK inhibitor + venetoclax, fixed duration","route":"/pairings/btki-plus-venetoclax-fixed-duration/"},{"id":"btki-ibrutinib-cardiac-caution","kind":"pairing","name":"Caution: ibrutinib in patients with cardiac risk","route":"/pairings/btki-ibrutinib-cardiac-caution/"}],"term":[{"id":"lymphoma-tx-uk-versus-us","kind":"term","name":"British and American lymphoma practice: where they differ, and why","route":"/terms/lymphoma-tx-uk-versus-us/"},{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"cardiotoxicity","kind":"term","name":"Cardiotoxicity (LVEF decline, cardiomyopathy)","route":"/terms/cardiotoxicity/"},{"id":"cll-ipi","kind":"term","name":"CLL-IPI (chronic lymphocytic leukaemia prognostic index)","route":"/terms/cll-ipi/"},{"id":"fixed-duration","kind":"term","name":"Fixed-duration vs continuous therapy","route":"/terms/fixed-duration/"},{"id":"gvhd","kind":"term","name":"Graft-versus-host disease (GVHD) and graft-versus-leukaemia","route":"/terms/gvhd/"},{"id":"inflation-reduction-act","kind":"term","name":"Inflation Reduction Act 2022: Medicare drug price negotiation","route":"/terms/inflation-reduction-act/"},{"id":"mipi","kind":"term","name":"MIPI (Mantle Cell Lymphoma International Prognostic Index)","route":"/terms/mipi/"},{"id":"myd88-l265p","kind":"term","name":"MYD88 L265P and CXCR4 mutations","route":"/terms/myd88-l265p/"},{"id":"pancreatic-failed-programmes","kind":"term","name":"Pancreatic cancer: the failed and stopped programmes and why","route":"/terms/pancreatic-failed-programmes/"},{"id":"cyclin-d1-t11-14","kind":"term","name":"t(11;14), cyclin D1 and SOX11","route":"/terms/cyclin-d1-t11-14/"},{"id":"tki-term","kind":"term","name":"Tyrosine kinase inhibitor (TKI)","route":"/terms/tki-term/"},{"id":"lymphoma-tx-uk-access","kind":"term","name":"What the NHS in England funds for lymphoma, appraisal by appraisal","route":"/terms/lymphoma-tx-uk-access/"}],"biomarker":[{"id":"btk-c481s","kind":"biomarker","name":"BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors","route":"/biomarkers/btk-c481s/"},{"id":"cd79b-itam-mutation","kind":"biomarker","name":"CD79B ITAM mutation","route":"/biomarkers/cd79b-itam-mutation/"}],"paper":[{"id":"paper-cll12-ibrutinib-early-stage-langerbeins-jco-2025","kind":"paper","name":"CLL12: ibrutinib in early-stage chronic lymphocytic leukaemia, a randomised placebo-controlled phase 3 trial","route":"/key-papers/paper-cll12-ibrutinib-early-stage-langerbeins-jco-2025/"},{"id":"paper-elevate-tn-acalabrutinib-lancet-2020","kind":"paper","name":"ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL","route":"/key-papers/paper-elevate-tn-acalabrutinib-lancet-2020/"},{"id":"paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025","kind":"paper","name":"Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial","route":"/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/"},{"id":"paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022","kind":"paper","name":"Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma","route":"/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/"},{"id":"paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019","kind":"paper","name":"Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)","route":"/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/"},{"id":"paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024","kind":"paper","name":"TRIANGLE: ibrutinib with immunochemotherapy with or without autologous transplant versus immunochemotherapy and transplant in untreated mantle cell lymphoma","route":"/key-papers/paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024/"},{"id":"paper-zuma-2-brexu-cel-mantle-cell-nejm-2020","kind":"paper","name":"ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors","route":"/key-papers/paper-zuma-2-brexu-cel-mantle-cell-nejm-2020/"}],"roadmap":[{"id":"lymphoma-roadmap","kind":"roadmap","name":"Lymphoma roadmap: from a jaw tumour in Uganda and the first human cancer virus to gene-expression subtypes, PET-adapted chemotherapy, CAR-T cells, bispecific antibodies and the genetics-directed trials now recruiting","route":"/roadmaps/lymphoma-roadmap/"}],"idea":[{"id":"lymphoma-ev-fixed-duration-chemotherapy-free-first-line","kind":"idea","name":"Fixed-duration, chemotherapy-free first-line treatment for the indolent lymphomas","route":"/ideas/lymphoma-ev-fixed-duration-chemotherapy-free-first-line/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"inflammation-nfkb","kind":"pathway","name":"Inflammation & NF-κB","route":"/pathways/inflammation-nfkb/"}],"bottleneck":[{"id":"b-drug-pricing","kind":"bottleneck","name":"Prices and value","route":"/bottlenecks/b-drug-pricing/"}],"institution":[{"id":"osu-james","kind":"institution","name":"The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute","route":"/institutions/osu-james/"}],"drug":[{"id":"mavorixafor","kind":"drug","name":"Mavorixafor","route":"/drugs/mavorixafor/"}]}}