{"entity":{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","aka":[],"tldr":"A BTK blocker that works after the older ones stop, because it grips a different part of the enzyme. Fully approved for CLL in December 2025.","summary":"Binds BTK reversibly and is active against C481 mutations. BRUIN CLL-321 (n=238, post-covalent BTKi): PFS 11.2 vs 8.7 months vs idelalisib-rituximab or bendamustine-rituximab (HR 0.58), leading to traditional approval on 3 December 2025 after the December 2023 accelerated approval. Also approved in MCL (2023). Frontline trials (BRUIN CLL-313 vs bendamustine-rituximab, CLL-314 vs ibrutinib) and combination with venetoclax (CLL-322) are reading out 2026-27. Resistance via T474I and L528W confers cross-resistance to some covalent inhibitors.","status":"approved","asOf":"2026-09-07","wikipedia":"https://en.wikipedia.org/wiki/Pirtobrutinib","links":[{"label":"FDA label (DailyMed)","url":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Pirtobrutinib"},{"label":"Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib","url":"https://doi.org/10.1056/NEJMoa1400029"},{"label":"Mato et al., N Engl J Med 2023: pirtobrutinib after a covalent BTK inhibitor (BRUIN, 317 patients)","url":"https://doi.org/10.1056/NEJMoa2300696"},{"label":"Blombery et al., Blood Adv 2022: enrichment of BTK Leu528Trp on zanubrutinib and cross-resistance to pirtobrutinib","url":"https://doi.org/10.1182/bloodadvances.2022008325"}],"tags":[],"related":[],"cancers":["cll","dlbcl","cll-relapsed","richter-transformation-cll"],"sections":[],"technologies":["kinase-inhibitors"],"targets":["btk"],"drugs":[],"companies":["eli-lilly"],"institutions":[],"pathways":[],"terms":["richter-transformation"],"trials":["bruin-cll-321","nct07162181","nct06973187","nct06588478","nct05023980","nct05254743","nct04965493","nct04662255"],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":["Lymphoma biology: a non-covalent inhibitor exists because of one amino acid. Covalent BTK inhibitors bind cysteine 481, and the C481S substitution leaves the kinase working while making the inhibition reversible (Woyach 2014); pirtobrutinib does not need that cysteine and gave an overall response of 73.3% in 247 patients who had already had a covalent inhibitor (Mato 2023). It is not a universal answer: the kinase-dead L528W substitution, enriched after zanubrutinib at 7 of 13 progressing patients against 1 of 24 after ibrutinib, confers cross-resistance and was enriched further under pirtobrutinib (Blombery 2022)."],"brand":"Jaypirca","modality":"Small-molecule non-covalent (reversible) BTK inhibitor","mechanism":"Non-covalent, highly selective BTK inhibitor occupying the ATP site independent of C481, with a long half-life for continuous occupancy.","approvals":[{"region":"US","year":2023,"indication":"Relapsed MCL after BTK inhibitor (accelerated, January); CLL/SLL after BTK and BCL-2 inhibitors (accelerated, December)"},{"region":"US","year":2025,"indication":"Relapsed/refractory CLL/SLL after a covalent BTK inhibitor (traditional approval, BRUIN CLL-321)"}],"mechanismSteps":["Pirtobrutinib binds the BTK ATP pocket reversibly and tightly","Works whether or not C481 is mutated","BCR signalling is blocked; CLL cells lose survival cues","Once-daily dosing maintains >90% occupancy through the dosing interval"],"dosing":{"route":"Oral","schedule":"200 mg once daily continuously","monitoring":"Infections, bleeding, cytopenias, atrial fibrillation (low), second primary malignancies","source":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Jaypirca"},"toxicity":[{"event":"Fatigue","anyGradePct":29,"source":"https://dailymed.nlm.nih.gov/dailymed/search.cfm?labeltype=all&query=Jaypirca"},{"event":"Neutropenia","grade3PlusPct":16},{"event":"Atrial fibrillation","anyGradePct":3.7},{"event":"Bruising","anyGradePct":24}],"access":[],"regulatoryEvents":[{"date":"2023-01-27","type":"accelerated-approval","region":"US","note":"Accelerated approval on a surrogate endpoint; the confirmatory requirement was still open 3.6 years later, when the FDA's table was read.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-relapsed-or-refractory-mantle-cell-lymphoma","indication":"Adult patients with relapsed or refractory mantle cel lymphoma (MCL) after at least two lines of systemic therapy, including a BTK inhibitor."},{"date":"2023-12-01","type":"accelerated-approval","region":"US","note":"CLL/SLL accelerated approval","indication":"Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor"},{"date":"2025-12-02","type":"conversion","region":"US","note":"Confirmed: the accelerated approval of 2023 converted to traditional approval 2.0 years after it was granted.","source":"https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic","indication":"Adult patients with chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) who have received at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor"},{"date":"2025-12-03","type":"approval","region":"US","note":"Traditional approval; label broadened to any prior covalent BTKi","source":"https://ascopost.com/news/december-2025/fda-grants-traditional-approval-to-pirtobrutinib-for-cllsll/"}]},"route":"/drugs/pirtobrutinib/","neighbours":{"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"mantle-cell-lymphoma","kind":"cancer","name":"Mantle cell lymphoma","route":"/cancers/mantle-cell-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":"waldenstrom","kind":"cancer","name":"Waldenström macroglobulinaemia","route":"/cancers/waldenstrom/"}],"technology":[{"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/"}],"company":[{"id":"eli-lilly","kind":"company","name":"Eli Lilly (incl. Loxo)","route":"/companies/eli-lilly/"}],"term":[{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"mipi","kind":"term","name":"MIPI (Mantle Cell Lymphoma International Prognostic Index)","route":"/terms/mipi/"},{"id":"richter-transformation","kind":"term","name":"Richter transformation","route":"/terms/richter-transformation/"}],"trial":[{"id":"nct06588478","kind":"trial","name":"A Study Evaluating the Efficacy and Safety of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","route":"/trials/nct06588478/"},{"id":"nct05023980","kind":"trial","name":"A Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)","route":"/trials/nct05023980/"},{"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":"nct06973187","kind":"trial","name":"A Study to Evaluate the Safety and Efficacy of Tacabrutideg (BGB-16673) Compared to Pirtobrutinib in Adults With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma","route":"/trials/nct06973187/"},{"id":"nct04965493","kind":"trial","name":"A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)","route":"/trials/nct04965493/"},{"id":"bruin-cll-321","kind":"trial","name":"BRUIN CLL-321","route":"/trials/bruin-cll-321/"},{"id":"cadance-304","kind":"trial","name":"CaDAnCe-304","route":"/trials/cadance-304/"},{"id":"nct06252675","kind":"trial","name":"Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma","route":"/trials/nct06252675/"},{"id":"nct07162181","kind":"trial","name":"Long-Term Safety of Pirtobrutinib in Participants With Previously Treated Types of Blood Cancers","route":"/trials/nct07162181/"},{"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/"}],"biomarker":[{"id":"btk-c481s","kind":"biomarker","name":"BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors","route":"/biomarkers/btk-c481s/"}],"bottleneck":[{"id":"b-resistance","kind":"bottleneck","name":"Acquired resistance to every therapy","route":"/bottlenecks/b-resistance/"}],"paper":[{"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/"}],"pathway":[{"id":"resistance-routes-map","kind":"pathway","name":"Resistance routes: how a blocked pathway comes back","route":"/pathways/resistance-routes-map/"}],"roadmap":[{"id":"targeted-therapy-roadmap","kind":"roadmap","name":"Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall","route":"/roadmaps/targeted-therapy-roadmap/"}]}}