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Treatment with the noncovalent BTK inhibitor pirtobrutinib (Jaypirca) led to an objective response rate (ORR) of 81.6% (95% CI, 76.5%-85.9%) in patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) previously treated with a covalent BTK inhibitor, according to findings from the final analysis of the phase 1/2 BRUIN trial (NCT03740529) that were presented at the 2025 ASH Annual Meeting.¹

Best responses included complete response (CR; n = 11; 3.9%), CR with incomplete blood count recovery (n = 1; 0.4%), non–partial response (PR; n = 3; 1.1%), PR (n = 189; 67.0%), and PR with lymphocytosis (n = 26; 9.2%). In subgroup analysis, the highest ORRs were seen in patients with deletion 11q (n = 47; ORR, 91.5%; 95% CI, 79.6%-97.6%), complex karyotype (n = 33; ORR, 90.9%; 95% CI, 75.7%-98.1%), and 17p deletion and/or TP53 mutation (n = 104; ORR, 87.5%; 95% CI, 79.6%-93.2%). The populations that appeared to derive the least benefit were patients with mutated PLCg2 (n = 18; ORR, 55.6%; 95% CI, 30.8%-78.5%), unmutated BTK C481 (n = 97; ORR, 74.2%; 95% CI, 64.3%-82.6%), and mutated IGHV (n = 32; ORR, 75.0%; 95% CI, 56.6%-88.5%).

“Pirtobrutinib continues to show favorable efficacy and promising overall survival [OS],” William G. Wierda, MD, PhD, lead study author and Endowed Distinguished Professor Jane and John Justin Distinguished Chair in Leukemia Research in the Department of Leukemia, Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, and coauthors wrote in the poster.

What challenges drive the need for a non-covalent BTK inhibitor like pirtobrutinib?

Intolerance or treatment resistance remains an issue with covalent BTK inhibitors despite their valued integration into the CLL/SLL armamentarium. Pirtobrutinib is a selective, noncovalent BTK inhibitor that was designed to work against common mechanisms associated with resistance to covalent inhibitors.

Earlier findings from the BRUIN trial illustrated the agent’s efficacy and safety in patients with relapsed/refractory disease, including those with prior exposure to covalent inhibition. Data from the trial led to the agent’s accelerated approval from the FDA in December 2023, which was converted to full approval on December 3, 2025.^2,3 

The phase 1 dose-escalation and -expansion portion of the trial modeled a 3+3 design, which allowed for intra-patient dose escalation, cohort expansion at doses deemed safe, and treatment with 25 to 300 mg of once daily pirtobrutinib via 28-day cycles.¹ In phase 2, patients received 200 mg of once-daily pirtobrutinib.

A total of 778 patients were enrolled: 166 with mantle cell lymphoma, 317 with CLL/SLL, and 295 with other malignancies. Of the 317 patients with CLL/SLL, 35 were BTK naive, and 282 had been exposed to covalent BTK inhibition. Of the latter group, 154 patients were BCL2 naive, and 128 had received BCL2 inhibition.

Eligible patients were at least 18 years old and had previously treated, active disease in need of therapy, and an ECOG performance status between 0 and 2.

Key end points included safety/tolerability, determination of the maximum tolerated dose/recommended phase 2 dose, pharmacokinetics, ORR, progression-free survival (PFS), time to next treatment (TTNT), and OS.

Baseline characteristics across the board of patients with prior exposure to covalent BTK inhibition, BCL2 inhibition, and those naive to BCL2 inhibition revealed that most were male; had received prior BTK inhibition, anti-CD20 therapy, and chemotherapy; had discontinued treatment because of progressive disease; and had unmutated IGHV.

How effective is pirtobrutinib after prior covalent BTK inhibition?

The median duration of response (DOR) was 18.4 months (95% CI, 14.8-20.3), and the 36-month DOR rate was 28.0% (95% CI, 21.6%-34.7%). At median follow-up of 49.9 months the median TTNT was 23.2 months (95% CI, 20.3-29.4). The 12-, 24-, 36-, 48-, and 60-month TTNT rates were 74.7%, 49.9%, 34.1%, 23.3%, and 21.5%, respectively.

Median PFS was 18.7 months (95% CI, 16.6-21.8) at median follow-up of 44.2 months. The 12-, 24-, 36-, 48-, and 60-month PFS rates were 67.1%, 38.1%, 25.0%, 21.6%, and 17.6%, respectively. PFS was also subdivided between patients who were BCL2 naive and exposed. The median PFS was 15.9 months (95% CI, 13.6-17.5) in the exposed population and 22.3 months (95% CI, 19.3-27.6) in the naive population. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the exposed cohort were 60.8%, 25.0%, 14.0%, 14.0%, and 14.0%, respectively. The 12-, 24-, 36-, 48-, and 60-month PFS rates in the naive cohort were 72.1%, 47.9%, 32.9%, 27.7%, and 21.7%, respectively.

In all patients who received covalent BTK inhibition, the median OS was not estimable (95% CI, 47.8 months-NE) at a median follow-up of 46.5 months. The 12-, 24-, 36-, 48-, and 60-month OS rates were 85.5%, 72.2%, 62.0%, 56.0%, and 54.2%, respectively.

What does the safety profile reveal about pirtobrutinib’s tolerability?

The median time on treatment was 20.0 months (IQR, 9.6-37.7). TRAEs leading to dose reduction and discontinuation occurred in 11 (3.9%) and 9 (3.2%) patients, respectively.

All-cause adverse effects (AEs) that occurred in at least 20% of patients included fatigue (any grade, 38.7%; grade ≥3, 1.8%), neutropenia (35.8%; 29.8%), diarrhea (30.5%; 0.4%), cough (29.8%; 0%), contusion (27.7%; 0%), COVID-19 (28.4%; 6.0%), dyspnea (23.4%; 2.5%), nausea (23.4%; 0%), and abdominal pain (21.6%; 2.1%). AEs of interest included infections (76.2%; 36.5%), bruising (31.2%; 0%), rash (25.2%; 1.1%), arthralgia (23.0%; 1.4%), hemorrhage (25.2%; 3.2%), hypertension (16.0%; 5.3%), and atrial fibrillation/flutter (5.0%; 2.1%).

Treatment-related adverse effects (TRAEs) that occurred in at least 20% of patients included fatigue (any grade, 3.9%; grade ≥3, 0%), neutropenia (20.6%; 16.3%), diarrhea (8.9%; 0%), cough (2.1%; 0%), contusion (18.8%; 0%), COVID-19 (0.7%; 0%), dyspnea (0.7%; 0.4%), nausea (3.9%; 0%), and abdominal pain (2.1%; 0.4%). AEs of interest included infections (14.9%; 5.7%), bruising (20.2%; 0%), rash (5.7%; 0.4%), arthralgia (4.6%; 0%), hemorrhage (8.2%; 1.4%), hypertension (3.9%; 0.7%), and atrial fibrillation/flutter (1.4%; 0.7%).

“Pirtobrutinib remains well tolerated with low rates of dose reduction or discontinuation due to TRAEs and low rates of grade 3 or greater hypertension, hemorrhage/hematoma, and atrial fibrillation/atrial flutter, which are risks with covalent BTK inhibitor treatment,” the authors concluded.

Disclosures: No disclosures were listed.

References

1. Wierda W, Brown J, Ghia P, et al. Pirtobrutinib in post-BTKi CLL/SLL: final update from the phase 1/2 BRUIN study with more than 5-years follow-up. Blood. 2025;146(suppl 1):2115. doi:10.1182/blood-2025-2115
2. FDA grants accelerated approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. Updated December 7, 2023. Accessed December 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-accelerated-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic
3. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. FDA. December 3, 2025. Accessed December 7, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-grants-traditional-approval-pirtobrutinib-chronic-lymphocytic-leukemia-and-small-lymphocytic

More than half of patients with newly diagnosed large B-cell lymphoma (LBCL) may reduce or remove chemotherapy with a targeted therapy–first strategy, according to data from the primary analysis of the Smart Stop trial (NCT04978584) presented at the 2025 ASH Annual Meeting.¹ Further, the “smart” strategy of utilizing targeted therapy first appeared to be successful and preserve curative intent and did not impact patient response to chemotherapy.

“In this study, we showed very promising outcomes, both in terms of response rates and durability of response,” Jason Westin, MD, professor in the Department of Lymphoma and Myeloma, director of the Lymphoma Clinical Research Program, executive leader of the Lymphoma & Myeloma Service Line, and chief of Aggressive and Indolent Lymphoma at The University of Texas MD Anderson Cancer Center, in Houston, said during a presentation of the data.

How effective is the “smart” strategy in treating LBCL?

In the study, 61 patients were treated in 21-day cycles with 25 mg lenalidomide (Revlimid) daily on days 1 through 10; 12mg/kg intravenous (IV) tafasitamab (Monjuvi) weekly on day 1, 8, and 15; 375 mg/m2 IV rituximab (Rituxan) on day 1; and 100 mg oral acalabrutinib (Calquence) twice daily on days 1 to 21 (LTRA). Patients received LTRA only for the first 4 cycles. All patients continued the LTRA regimen for 6 additional cycles, which included 6 cycles of CHOP if patients did not achieve an initial CR (groups B and D). In cohort 1, those in CR received only 2 cycles of CHOP (group A); in cohort 2, those in CR continued without CHOP (group C).

After 4 cycles of the LTRA regimen, the overall response rate (ORR) was 90%, including complete response (CR) and partial response (PR) rates of 57% and 33%, respectively. In addition, the CR rate at the end of treatment was 96.7%.

In particular, cohort 1 experienced a 100% ORR, which included CR and PR rates of 63% and 37%, respectively. “Remember, these patients already had a complete response at the end of LTRA, so they maintain that throughout the duration of their treatment,” Westin said. Cohort 2 demonstrated CR and PR rates of 52% and 29%, respectively.

The 2-year progression-free survival (PFS) and overall survival (OS) rates were 86.5% and 98.4%, respectively, after a median follow-up of 25.3 months. “In patients who had the two cycles of CHOP, their progression-free survival has been outstanding,” Westin explained.

After a median follow-up of 19 months, 12 patients are ongoing with a CR. Westin noted that all 4 patients who had progression have achieved a complete response with subsequent frontline chemotherapy regimens.

Among those who had less than a CR after 4 cycles of LTRA and went on to receive CHOP plus LTRA therapy for 6 cycles, CR rate was 92%. “This is important. This shows that lack of response to the target therapy did not compromise the ability to deliver and have a promising result to the chemotherapy,” Westin said.

Why focus on administering targeted therapy first in newly diagnosed LBCL?

Westin noted that the CHOP regimen, although successful over the past 50 years, fails to cure 1 in 3 patients with newly diagnosed LBCL. “It’s poorly targeted,” he said, adding that the current classification system is also limiting in this disease setting. “We don’t have access to our current classification systems in real time to make treatment decisions, and I would also argue that they have limited utility in determining which treatment will benefit which patient.”

However, he acknowledged that the budding problem in the LBCL space may be a good one to have, in that there are a variety of emerging therapies. “We have an emerging problem in large B-cell lymphoma of an incredible wealth of new agents that are [are being evaluated] in phase 3 [trials]. But effectively, these studies are all 1970s chemotherapy vs 1970s chemotherapy with a novel agent added to it,” Westin said. “But I would argue we’ve got a coming challenge, which I like to call a coming chaos of choice. We have so many cool new drugs coming along that we are going to enter an era very soon [where] all of these great new agents showing promise in phase 3 trials [will be met] with uncertainty as to which patient will benefit from which therapy.”

With that, he added that the question of the role of chemotherapy in this era of emerging therapies remains. To this end, the investigators conducted the Smart Stop trial, which was designed to evaluate whether chemotherapy could be reduced or removed in patients with newly diagnosed LBCL who respond to initial targeted therapy.

How was the Smart Stop trial conducted?

The phase 2, open-label, single center trial enrolled patients with newly diagnosed LBCL who were at least 18 years of age, had an ECOG performance status of less than 3, and had adequate organ and bone marrow function. Patients were ineligible if they had central nervous system involvement with their lymphoma. The primary objectives of the study were to determine the ORR after 4 cycles of LTRA and CR at the end of therapy with LTRA, with or without CHOP.

The median patient age was 61 years (range, 23-91). More than half of patients reported with an ECOG performance status of 1 (56%), 70% had elevated lactate dehydrogenase, 75% of patients reported with stage III or IV disease, and, of note, 56% had an International Prognostic Index score of 3 to 5, with 72% of patients being high risk in the study. Further, Westin noted that there was an enrichment for the non–Germinal Center B-cell (GCB)–like subtype. “However, more than one-third of patients had the GCB subtype on this study, and notably via FISH testing, we had 16% of patients with MYC and BCL2 or BCL6 translocations, aka double hit.”

Preliminary results from cohort 1 (n = 30), previously reported at the 2023 ASH Annual Meeting,² showed that 63% of patients achieved a CR by PET/CT and 33% had undetectable circulating tumor DNA using the phasED-Seq assay after 4 cycles of targeted therapy. Further, at end of treatment, 100% of patients experienced a CR.

The majority of planned doses of lenalidomide (88%), tafasitamab (93%), and acalabrutinib (100%) were received. The median number of LTRA cycles delivered was 10 (range, 1-10).¹

What was the safety profile of the Smart Stop approach?

The most common any-grade adverse effects were anemia (90%), neutropenia (87%), platelet count decreased (77%), fatigue (67%), maculopapular rash (46%), transaminitis (43%), nausea (38%), headache (36%), increased creatinine (36%), infections and infestations (33%), infusion-related reaction (31%), constipation (31%), edema (28%), peripheral sensory neuropathy (23%), COVID infection (21%), cough (18%), dizziness (16%), diarrhea (15%), vomiting (15%), oral mucositis (12%), and febrile neutropenia (7%).

“The smart strategy of targeted therapy first is successful, and it preserves curative intent,” Westin said. “In this study, we showed very promising outcomes, both in terms of response rates and durability of response. The smart strategy of targeted therapy first showed that more than half of patients may reduce or remove chemotherapy for newly diagnosed diffuse large B-cell lymphoma…Smart strategy, targeted therapy first does not impact the response to chemotherapy. So, for those patients who did not achieve a complete response or had a complete response and ultimately had progression of their disease, they had very favorable outcomes when they received CHOP regimens.”

What are the next steps for this research?

Next, Westin noted that the investigators plan to expand the Smart Stop trial to a multisite trial, as well as evaluate glofitamab (Columvi), polatuzumab (Polivy), and golcadomide as a smart strategy.

“We’re also very optimistic about the potential for multiple randomized trials using the smart strategy of targeted therapy combinations, saving chemotherapy for those who don’t benefit, randomized against our chemotherapy,” Westin concluded.

Disclosures: Westin disclosed serving in a consultancy role for Allogene Therapeutics, AbbVie/Genmab, Regeneron, Genentech/Roche, AstraZeneca, Chugai Pharma, ADC Therapeutics, Bristol Myers Squibb, Nurix, Kite/Gilead, Morphosys/Incyte, Novartis, Pfizer, and Janssen. Research funding was provided by Allogene Therapeutics, Regeneron, Genentech/Roche, AstraZeneca, ADC Therapeutics, Bristol Myers Squibb, Nurix, Kite/Gilead, Morphosys/Incyte, Novartis, and Janssen.

References

1. Westin J, Fayad L, Steiner R, et al. Primary analysis of the smart stop trial: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy in newly diagnosed diffuse large B-cell lymphoma. Blood. 2025;146(suppl 1):abstract 477. doi:10.1182/blood-2025-477
2. Westin J, Steiner RE, Chihara D, et al. Smart Stop: Lenalidomide, tafasitamab, rituximab, and acalabrutinib alone and with combination chemotherapy for the treatment of newly diagnosed diffuse large B-cell lymphoma. Blood. 2023;142(suppl 1):856. doi:10.1182/blood-2023-180381