Pirtobrutinib Carves Out Its Place in Relapsed/Refractory CLL/SLL

Although pirtobrutinib (Jaypirca) is now fully approved by the FDA for the treatment of patients with relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL), additional data are needed to fully integrate the agent into the community setting alongside established drugs such as zanubrutinib (Brukinsa), according to Ralph Boccia, MD, FACP.

“[Pirtobrutinib] is going to take time to resonate,” Boccia, the founder of The Center for Cancer and Blood Disorders in Maryland, said. “Since the field may be moving toward time-limited therapy, there's still a huge role for the older, frailer patients for whom it's very easy just to take a pill a day.”

During an OncLive® Scientific Interchange and Workshop held on December 8, 2025, Boccia was joined by other experts in the field of CLL/SLL to discuss how data presented during the 2025 ASH Annual Meeting & Exposition could shift the role of BTK inhibitors in relapsed/refractory CLL/SLL.¹ The faculty members also discussed the progress of multiple BTK degraders that are in early-phase development.

What are the key updates with BTK inhibitors in the second line and beyond?

In December 2025, the FDA granted traditional approval to pirtobrutinib for the treatment of adult patients with relapsed/refractory CLL/SLL who have previously received a covalent BTK inhibitor.² The regulatory decision was supported by data from the phase 3 BRUIN CLL-321 trial (NCT04666038).

The faculty members focused their discussion on the role of pirtobrutinib for the second-line treatment of patients with relapsed/refractory CLL/SLL. Findings from a pooled analysis of BRUIN CLL-321 and the phase 1/2 BRUIN LOXO-BTK-18001 study (NCT03740529) revealed that patients who received pirtobrutinib in the second-line setting (n = 37) experienced a median investigator-assessed progression-free survival (PFS) of 19.5 months (95% CI, 11.7-44.7) at a median follow-up of 30.3 months.³ The investigator-assessed overall response rate (ORR) was 67.6% (95% CI, 50.2%-82.0%), including a complete remission (CR)/CR with incomplete count recovery (CRi) rate of 13.5%.

At a median follow-up of 30.5 months, the median time to next treatment was 32.5 months (95% CI, 16.6-47.4). Notably, the median overall survival (OS) was not reached (NR; 95% CI, not evaluable [NE]-NE) at a median follow-up of 29.2 months.

“I still would've expected a higher PFS; this is truly second-line [patients]. We say that pirtobrutinib works for patients who are BTK refractory, but this is truly that population,” Nitin Jain, MD, a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, commented. “Maybe we got unlucky with these patients [and they] just happened to have high-risk genomics. We need a larger dataset.”

“That seems to be a general trend that pirtobrutinib is [better] the earlier you give it. That tends to be true of most drugs, but maybe it's truer in this case, potentially compared [with] other [agents]. That was a narrative at ASH,” Andrew H. Lipsky, MD, an assistant professor of medicine at Columbia University Medical Center in New York, New York, added.

Beyond pirtobrutinib, another FDA-approved option for patients with relapsed/refractory CLL/SLL is zanubrutinib, which earned approval in January 2023.⁴ At a median follow-up of 54.2 months (range, 0.1-73.5), findings from a long-term extension of the phase 3 ALPINE trial (NCT03734016) showed that patients who received zanubrutinib (n = 327) experienced a median PFS of 52.5 months (95% CI, 49.7-65.8).⁵ The median PFS after adjusting for COVID-19 was 60.3 months (95% CI, 49.9-NR). The 60-month PFS rates in the overall cohort and following COVID-19 adjustment were 47.3% and 50.4%, respectively.

How could BTK degraders affect the relapsed/refractory CLL treatment landscape?

The faculty concluded their discussion by highlighting 2 BTK degraders that are moving through the development pipeline: bexobrutideg (NX-5948) and BGB-16673. Bexobrutideg was examined in a first-in-human phase 1a/b study (NCT05131022) for the treatment of patients with relapsed/refractory B-cell malignancies, including CLL/SLL.

At a median follow-up of 8.7 months (range, 0.3-28.6), findings from the first-in-human trial presented during ASH demonstrated that response-evaluable patients with CLL/SLL (n = 84) who received bexobrutideg achieved an ORR of 78.6%, including 1 CR.⁶ The median duration of response was NR (95% CI, 12.2 months-NR). In the safety population (n = 97), the most common any-grade treatment-emergent adverse effects (TEAEs) included purpura/contusion (38.1%), neutropenia (29.9%), fatigue (25.8%), and diarrhea (23.7%). No dose-limiting toxicities were reported and treatment discontinuation due to TEAEs occurred at a rate of 5.2%.

BGB-16673 was evaluated in the phase 1 CaDAnCe-101 study (NCT05006716) for the treatment of patients with relapsed/refractory B-cell malignancies, including CLL/SLL.⁷ Patients who received the BTK degrader (n = 68) achieved an ORR of 85.3% and a CR/CRi rate of 2.9%. Patients who received the agent at 200 mg (n = 18) experienced an ORR of 94.4% with 1 CR/CRi. At a median follow-up of 19.8 months (range, 0.3-34.0+), the 12-month PFS rate in the overall population was 73.5% (95% CI, 59.3%-83.3%).

In terms of safety, any-grade TEAEs occurred in 95.6%. Serious TEAEs (48.5%) as well as TEAEs leading to death (7.4%) and treatment discontinuation (17.6%) also occurred. The most common any-grade TEAEs were fatigue (36.8%) and contusion (30.9%).

References

1. Next-generation decisions in CLL: redefining BTK inhibitors across the frontline and relapsed settings.An OncLive Scientific Interchange and Workshop. OncLive. December 8, 2025. Accessed January 6, 2026.
2. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed January 6, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic?utm_medium=email&utm_source=govdelivery
3. Eyre T, Davids MS, Sharman J, et al. Pirtobrutinib outcomes in second-line (2L) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) after first-line (1L) cBTKi therapy: a pooled analysis from the BRUIN LOXO-BTK-18001 and BRUIN CLL-321 studies. Blood. 2025;146(suppl 1):5670. doi:10.1182/blood-2025-5670
4. FDA approves zanubrutinib for chronic lymphocytic leukemia or small lymphocytic lymphoma. FDA. January 19, 2023. Accessed January 6, 2026. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-zanubrutinib-chronic-lymphocytic-leukemia-or-small-lymphocytic-lymphoma
5. Tam C, Mital A, Weinkove R, et al. Long-term results of patients receiving zanubrutinib in the phase 3 ALPINE study confirm sustained benefit of zanubrutinib in patients with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (R/R CLL/SLL): up to 6 years of follow-up with the long-term extension (LTE1). Blood. 2025;146(suppl 1):2123. doi:10.1182/blood-2025-2123
6. Omer Z, Danilov A, Forconi F, et al. Bexobrutideg (NX-5948), a novel Bruton's tyrosine kinase (BTK) degrader, demonstrates rapid and durable clinical responses in relapsed/refractory chronic lymphocytic leukemia (CLL): new and updated findings from an ongoing phase 1a/b trial. Blood. 2025;146(suppl 1):86. doi:10.1182/blood-2025-86
7. Ahn I, Parrondo R, Thompson M, et al. Updated efficacy and safety results of the Bruton tyrosine kinase (BTK) degrader BGB-16673 in patients with relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) from the ongoing phase 1 CaDAnCe-101 study. Blood. 2025;146(suppl 1):85. doi:10.1182/blood-2025-85