# Pirtobrutinib

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

## TL;DR

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.

## Fields

- Kind: Treatment
- Status: approved
- Last checked: 2026-09-07
- 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: US 2023: Relapsed MCL after BTK inhibitor (accelerated, January); CLL/SLL after BTK and BCL-2 inhibitors (accelerated, December); US 2025: Relapsed/refractory CLL/SLL after a covalent BTK inhibitor (traditional approval, BRUIN CLL-321)
- Dosing: Oral; 200 mg once daily continuously
- Toxicity (grade 3+): Neutropenia 16%

## 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).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Pirtobrutinib
- FDA label (DailyMed): https://dailymed.nlm.nih.gov/dailymed/search.cfm?query=Pirtobrutinib
- Woyach et al., N Engl J Med 2014: BTK C481S and PLCG2 resistance mutations under ibrutinib: https://doi.org/10.1056/NEJMoa1400029
- Mato et al., N Engl J Med 2023: pirtobrutinib after a covalent BTK inhibitor (BRUIN, 317 patients): https://doi.org/10.1056/NEJMoa2300696
- Blombery et al., Blood Adv 2022: enrichment of BTK Leu528Trp on zanubrutinib and cross-resistance to pirtobrutinib: https://doi.org/10.1182/bloodadvances.2022008325

## Connected records

- cancers: [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Mantle cell lymphoma](https://onco.cc/cancers/mantle-cell-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/), [Waldenström macroglobulinaemia](https://onco.cc/cancers/waldenstrom/)
- technologies: [Small-molecule kinase inhibitors](https://onco.cc/technologies/kinase-inhibitors/)
- targets: [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/)
- companies: [Eli Lilly (incl. Loxo)](https://onco.cc/companies/eli-lilly/)
- terms: [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [MIPI (Mantle Cell Lymphoma International Prognostic Index)](https://onco.cc/terms/mipi/), [Richter transformation](https://onco.cc/terms/richter-transformation/)
- trials: [A Study Evaluating the Efficacy and Safety of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma](https://onco.cc/trials/nct06588478/), [A Study of Pirtobrutinib (LOXO-305) Versus Bendamustine Plus Rituximab (BR) in Untreated Patients With Chronic Lymphocytic Leukemia (CLL)/Small Lymphocytic Lymphoma (SLL)](https://onco.cc/trials/nct05023980/), [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 Evaluate the Safety and Efficacy of Tacabrutideg (BGB-16673) Compared to Pirtobrutinib in Adults With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma](https://onco.cc/trials/nct06973187/), [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)](https://onco.cc/trials/nct04965493/), [BRUIN CLL-321](https://onco.cc/trials/bruin-cll-321/), [CaDAnCe-304](https://onco.cc/trials/cadance-304/), [Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma](https://onco.cc/trials/nct06252675/), [Long-Term Safety of Pirtobrutinib in Participants With Previously Treated Types of Blood Cancers](https://onco.cc/trials/nct07162181/), [Study of BTK Inhibitor LOXO-305 Versus Approved BTK Inhibitor Drugs in Patients With Mantle Cell Lymphoma (MCL)](https://onco.cc/trials/nct04662255/)
- biomarkers: [BTK resistance mutations: C481S, and L528W and T474I after the non-covalent inhibitors](https://onco.cc/biomarkers/btk-c481s/)
- bottlenecks: [Acquired resistance to every therapy](https://onco.cc/bottlenecks/b-resistance/)
- key papers: [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/)
- pathways: [Resistance routes: how a blocked pathway comes back](https://onco.cc/pathways/resistance-routes-map/)
- roadmaps: [Targeted therapy roadmap: imatinib → designed for resistance → the undruggable drivers fall](https://onco.cc/roadmaps/targeted-therapy-roadmap/)

---
JSON: https://onco.cc/api/v1/entities/pirtobrutinib.json