# Ibrutinib

Source: https://onco.cc/drugs/ibrutinib/  
OnCo record `ibrutinib` (Treatment). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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 Also mantle cell lymphoma (withdrawn in the US 2023), Waldenström, marginal zone (withdrawn), and chronic GVHD.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.

## Fields

- Kind: Treatment
- Status: approved
- Last checked: 2026-09-07
- 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: US 2013: Relapsed mantle cell lymphoma (accelerated); first BTK inhibitor; US 2014: Relapsed CLL (RESONATE); del(17p) CLL; US 2016: First-line CLL (RESONATE-2); EU 2014: Relapsed mantle cell lymphoma; CLL after one prior therapy or with del(17p)/TP53 mutation; EU 2022: Fixed-duration ibrutinib + venetoclax, first-line CLL (GLOW, CAPTIVATE)
- Dosing: Oral; 420 mg once daily continuously until progression (CLL); 560 mg in MCL

## 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).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Ibrutinib
- FDA label (DailyMed): https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Ibrutinib
- Tempero et al., RESOLVE (Annals of Oncology 2021): https://doi.org/10.1016/j.annonc.2021.01.070
- Davis et al., Nature 2010: chronic active B-cell receptor signalling in diffuse large B-cell lymphoma: https://doi.org/10.1038/nature08638
- Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib: https://doi.org/10.1056/NEJMoa1400029

## Connected records

- cancers: [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Chronic lymphocytic leukaemia, first treatment](https://onco.cc/cancers/cll-treatment-naive/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Hairy cell leukaemia](https://onco.cc/cancers/hairy-cell-leukemia/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-lymphoma/), [Marginal zone lymphoma](https://onco.cc/cancers/marginal-zone-lymphoma/), [Metastatic pancreatic ductal adenocarcinoma](https://onco.cc/cancers/metastatic-pdac/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Primary CNS lymphoma](https://onco.cc/cancers/primary-cns-lymphoma/), [Relapsed or refractory chronic lymphocytic leukaemia](https://onco.cc/cancers/cll-relapsed/), [Richter transformation of chronic lymphocytic leukaemia](https://onco.cc/cancers/richter-transformation-cll/), [Splenic B-cell lymphoma/leukaemia with prominent nucleoli (formerly B-cell prolymphocytic leukaemia and hairy cell leukaemia variant)](https://onco.cc/cancers/splenic-b-cell-lymphoma-leukaemia-prominent-nucleoli/), [T-cell prolymphocytic leukaemia](https://onco.cc/cancers/t-cell-prolymphocytic-leukaemia/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- technologies: [After ruxolitinib: belumosudil, axatilimab and ibrutinib in chronic GvHD](https://onco.cc/technologies/gvhd-belumosudil-axatilimab-ibrutinib/), [Chronic graft-versus-host disease](https://onco.cc/technologies/gvhd-chronic-overview/), [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [HCK kinase](https://onco.cc/targets/hck/), [ITK](https://onco.cc/targets/itk/), [TEC](https://onco.cc/targets/tec/)
- companies: [AbbVie (incl. ImmunoGen, Capstan)](https://onco.cc/companies/abbvie/), [Johnson & Johnson](https://onco.cc/companies/johnson-johnson/)
- trials: [A Long-term Extension Study of PCI-32765 (Ibrutinib)](https://onco.cc/trials/nct01804686/), [A Study of Mavorixafor in Combination With Ibrutinib in Participants With Waldenstrom's Macroglobulinemia (WM) Whose Tumors Express Mutations in MYD88 and CXCR4](https://onco.cc/trials/nct04274738/), [A Study of Pirtobrutinib (LOXO-305) Versus Ibrutinib in Participants With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)](https://onco.cc/trials/nct05254743/), [A Study to Customize Ibrutinib Treatment Regimens for Participants With Previously Untreated Chronic Lymphocytic Leukemia](https://onco.cc/trials/nct05963074/), [A Study to Evaluate Adverse Events and Change in Disease Activity of Subcutaneous (SC) Epcoritamab in Combination With Oral and Intravenous Anti-Neopl](https://onco.cc/trials/nct05283720/), [ALPINE](https://onco.cc/trials/alpine/), [ASPEN (Waldenström macroglobulinaemia)](https://onco.cc/trials/aspen-wm/), [BELLWAVE-011](https://onco.cc/trials/bellwave-011/), [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)](https://onco.cc/trials/nct03328078/), [CAPTIVATE](https://onco.cc/trials/captivate/), [CLL12](https://onco.cc/trials/cll12/), [CLL13 / GAIA](https://onco.cc/trials/cll13-gaia/), [ENRICH](https://onco.cc/trials/enrich/), [GLOW](https://onco.cc/trials/glow/), [Phase I/II Study of Rapcabtagene Autoleucel in CLL, 3L+ DLBCL, r/r ALL and 1L HR LBCL](https://onco.cc/trials/nct03960840/), [RESOLVE](https://onco.cc/trials/resolve/), [RESONATE](https://onco.cc/trials/resonate/), [RESONATE-2](https://onco.cc/trials/resonate-2/), [Rollover Study to Provide Continued Treatment for Participants With B-Cell Malignancies Previously Enrolled in Studies of Parsaclisib (INCB050465)](https://onco.cc/trials/nct04509700/), [SHINE](https://onco.cc/trials/shine/), [Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL)](https://onco.cc/trials/nct02477696/), [Study of APG2575 Single Agent and Combination Therapy in Patients With Relapsed/Refractory CLL/SLL](https://onco.cc/trials/nct04494503/), [Study of BTK Inhibitor LOXO-305 Versus Approved BTK Inhibitor Drugs in Patients With Mantle Cell Lymphoma (MCL)](https://onco.cc/trials/nct04662255/), [SYMPATICO](https://onco.cc/trials/sympatico/), [Trial of Ibrutinib Plus Trastuzumab in HER2-amplified Metastatic Breast Cancer](https://onco.cc/trials/nct03379428/), [TRIANGLE](https://onco.cc/trials/triangle/)
- pairings: [BTK inhibitor + venetoclax, fixed duration](https://onco.cc/pairings/btki-plus-venetoclax-fixed-duration/), [Caution: ibrutinib in patients with cardiac risk](https://onco.cc/pairings/btki-ibrutinib-cardiac-caution/)
- terms: [British and American lymphoma practice: where they differ, and why](https://onco.cc/terms/lymphoma-tx-uk-versus-us/), [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [Cardiotoxicity (LVEF decline, cardiomyopathy)](https://onco.cc/terms/cardiotoxicity/), [CLL-IPI (chronic lymphocytic leukaemia prognostic index)](https://onco.cc/terms/cll-ipi/), [Fixed-duration vs continuous therapy](https://onco.cc/terms/fixed-duration/), [Graft-versus-host disease (GVHD) and graft-versus-leukaemia](https://onco.cc/terms/gvhd/), [Inflation Reduction Act 2022: Medicare drug price negotiation](https://onco.cc/terms/inflation-reduction-act/), [MIPI (Mantle Cell Lymphoma International Prognostic Index)](https://onco.cc/terms/mipi/), [MYD88 L265P and CXCR4 mutations](https://onco.cc/terms/myd88-l265p/), [Pancreatic cancer: the failed and stopped programmes and why](https://onco.cc/terms/pancreatic-failed-programmes/), [t(11;14), cyclin D1 and SOX11](https://onco.cc/terms/cyclin-d1-t11-14/), [Tyrosine kinase inhibitor (TKI)](https://onco.cc/terms/tki-term/), [What the NHS in England funds for lymphoma, appraisal by appraisal](https://onco.cc/terms/lymphoma-tx-uk-access/)
- biomarkers: [BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors](https://onco.cc/biomarkers/btk-c481s/), [CD79B ITAM mutation](https://onco.cc/biomarkers/cd79b-itam-mutation/)
- key papers: [CLL12: ibrutinib in early-stage chronic lymphocytic leukaemia, a randomised placebo-controlled phase 3 trial](https://onco.cc/key-papers/paper-cll12-ibrutinib-early-stage-langerbeins-jco-2025/), [ELEVATE-TN: acalabrutinib, alone or with obinutuzumab, against chemo-immunotherapy in untreated CLL](https://onco.cc/key-papers/paper-elevate-tn-acalabrutinib-lancet-2020/), [Ibrutinib and rituximab versus immunochemotherapy in patients with previously untreated mantle cell lymphoma (ENRICH): a randomised, open-label, phase 2/3 superiority trial](https://onco.cc/key-papers/paper-enrich-ibrutinib-rituximab-mantle-cell-lancet-2025/), [Ibrutinib plus bendamustine and rituximab in untreated mantle-cell lymphoma](https://onco.cc/key-papers/paper-shine-ibrutinib-bendamustine-rituximab-mantle-cell-nejm-2022/), [Randomized phase III trial of ibrutinib and R-CHOP in non-germinal centre B-cell diffuse large B-cell lymphoma (PHOENIX)](https://onco.cc/key-papers/paper-phoenix-ibrutinib-r-chop-non-gcb-dlbcl-jco-2019/), [TRIANGLE: ibrutinib with immunochemotherapy with or without autologous transplant versus immunochemotherapy and transplant in untreated mantle cell lymphoma](https://onco.cc/key-papers/paper-triangle-ibrutinib-mantle-cell-lymphoma-dreyling-lancet-2024/), [ZUMA-2: brexu-cel CAR-T for mantle cell lymphoma that has failed BTK inhibitors](https://onco.cc/key-papers/paper-zuma-2-brexu-cel-mantle-cell-nejm-2020/)
- roadmaps: [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](https://onco.cc/roadmaps/lymphoma-roadmap/)
- ideas: [Fixed-duration, chemotherapy-free first-line treatment for the indolent lymphomas](https://onco.cc/ideas/lymphoma-ev-fixed-duration-chemotherapy-free-first-line/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Inflammation & NF-κB](https://onco.cc/pathways/inflammation-nfkb/)
- bottlenecks: [Prices and value](https://onco.cc/bottlenecks/b-drug-pricing/)
- institutions: [The Ohio State University Comprehensive Cancer Center, James Cancer Hospital and Solove Research Institute](https://onco.cc/institutions/osu-james/)
- drugs: [Mavorixafor](https://onco.cc/drugs/mavorixafor/)

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