VJToday

FDA approves pirtobrutinib for previously untreated chronic lymphocytic leukemia

On October 2, 2026, the U.S. Food and Drug Administration (FDA) approved pirtobrutinib for adult patients with previously untreated chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) with no known 17p deletion.1

The treatment landscape for CLL has evolved dramatically over the last decade, with the emergence of Bruton tyrosine kinase inhibitors (BTKis) and B-cell lymphoma 2 inhibitors (BCL2is).2 Currently, standard-of-care regimens include BTKi- and BCL2i-based combinations, while bendamustine plus rituximab (BendaR), a chemoimmunotherapy regimen, represents a traditional frontline treatment option.2

Pirtobrutinib is a potent, non-covalent BTKi that reversibly binds to the ATP-binding pocket of BTK, disrupting signalling pathways essential for CLL-cell survival and proliferation.3 Unlike covalent BTKis, pirtobrutinib binds independently of the C481 residue, retaining activity against both wild-type and C481-mutated BTK and offering a mechanistic advantage over covalent BTKis.3 In December 2025, pirtobrutinib was approved for adults with relapsed/refractory (R/R) CLL/SLL previously treated with a covalent BTKi.4

The FDA approval of pirtobrutinib for previously untreated CLL/SLL is supported by data from the Phase III BRUIN CLL-313 trial (NCT05023980), a randomized, open-label, global study, which evaluated the efficacy and safety of pirtobrutinib compared with BendaR in treatment-naïve patients with CLL/SLL without deletion of chromosome 17p.1 A total of 282 patients were randomized 1:1 to receive pirtobrutinib (n=141) until disease progression or BendaR (n=141) for six cycles. Pirtobrutinib demonstrated improved efficacy compared with BendaR, with significant improvement in progression-free survival (PFS) as the main efficacy outcome.1 At an estimated median follow-up for PFS of 28 months, the median PFS was not estimable (NE) (95% CI: NE, NE) in the pirtobrutinib arm and 33.5 months (95% CI: 32.7, NE) in the BendaR arm (Hazard ratio 0.20 [95% CI: 0.11, 0.37]; p-value <0.0001).1 Overall survival (OS) data were immature at the time of the primary PFS analysis, with median OS not reached in either arm. A total of 13 deaths were reported in the study: three deaths in the pirtobrutinib arm and ten deaths in the BendaR arm.1

Pirtobrutinib was well-tolerated, with a safety profile consistent with previously observed data. Non-laboratory adverse events (AEs) included upper respiratory tract infections, rash and COVID-19 occurring in 27%, 22%, and 21% of patients, respectively.1,2 Grade ≥3 treatment-related AEs occurred in 40% of patients receiving pirtobrutinib compared with 67.4% receiving BendaR, with decreased neutrophil count being the most common laboratory abnormality.1,2 Serious AEs occurred in 28% of patients in the pirtobrutinib arm.1

At ASH 2025, we heard from Wojciech Jurczak, MD, PhD, of Jagiellonian University, Krakow, Poland, who shared further insights from the BRUIN CLL-313 trial and highlighted the encouraging results supporting the use of pirtobrutinib in earlier lines of therapy:

To conclude, the approval of pirtobrutinib for previously untreated CLL/SLL reflects its favorable efficacy and safety profile compared with the traditional BendaR regimen. This approval expands the use of pirtobrutinib into the frontline setting, beyond its previous approval in R/R CLL.

References

  1. U.S. Food and Drug Administration. FDA approval pirtobrutinib for previously untreated chronic lymphocytic leukemia or small lymphocytic lymphoma. Available here. (Last Accessed 05/10/2026).
  2. Jurczak Wojciech, Kwiatek Michal, Czyz Jaroslaw, et al. BRUIN CLL-313: Randomized Phase III Trial of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients With Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma. J Clin Oncol. 2026; 44: 466-475.
  3. Eli Lilly and Company. Lilly’s Jaypirca (pirtobrutinib), the first-and-only approved non-covalent BTK inhibitor, receives expanded indication from U.S. FDA for certain patients with previously untreated CLL/SLL. Available here. (Last Accessed 05/10/2026).
  4. U.S. Food and Drug Administration. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. Available here. (Last Accessed 05/10/2026).

Written by Clare Harris

Reviewed by Hannah Elkhier