The first prospective, randomized phase III trial of a noncovalent Bruton’s tyrosine kinase (BTK) inhibitor exclusively in treatment-naive patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL)—BRUIN CLL-313—demonstrated a statistically significant and clinically meaningful improvement in progression-free survival with pirtobrutinib vs bendamustine plus rituximab, representing one of the largest treatment effects ever observed for a single-agent BTK inhibitor against this comparator. Presented at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition and published in the Journal of Clinical Oncology, the final progression-free survival and interim overall survival analyses support this highly selective monotherapy as a standard of care for untreated patients, especially for older adults who may receive only one line of therapy.^1,2

Pirtobrutinib was initially granted accelerated approval by the U.S. Food and Drug Administration (FDA) for patients with CLL/SLL who were previously treated with both covalent BTK and BCL2 inhibitors. On December 3, 2025, it received traditional approval, expanding its indication to include all patients with relapsed or refractory disease who have received prior covalent BTK inhibitor therapy. Although covalent BTK inhibitors have been shown to improve outcomes in the first-line setting, at the time of this study design, no phase III data had evaluated noncovalent BTK inhibition—including pirtobrutinib—in a specifically treatment-naive population.

A recent head-to-head phase III trial, BRUIN CLL-314, also presented at this meeting, showed that pirtobrutinib achieved a favorable overall response rate and progression-free survival outcome compared with the covalent BTK inhibitor ibrutinib in a treatment-naive subgroup.³

“If we took this data together with BRUIN CLL-314…, we can be optimistic about the approval of the compound [in the first-line setting] possibly in early 2026,” commented presenting author Wojciech Jurczak, MD, PhD, of Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland, during a press briefing. 

Study Details

Patients with a confirmed diagnosis of CLL/SLL who were naive to systemic therapy for their disease and required treatment were eligible for enrollment. Additional eligibility criteria included an Eastern Cooperative Oncology Group performance status score of 0 to 2 and absence of a 17p deletion. They were also required to have a platelet count of at least 75 x 10⁹/L (or ≥ 50 x 10⁹/L in those with evidence of bone marrow infiltrate), a hemoglobin level of at least 8 g/dL, and an absolute neutrophil count of at least 0.75 x 10⁹/L.

A total of 282 patients were randomly assigned in a 1:1 ratio to receive oral pirtobrutinib monotherapy (200 mg once daily) or six cycles of intravenous bendamustine plus rituximab. Randomization was stratified by IGHV mutation status (mutated vs unmutated) and Rai stage (0–II [low/intermediate] vs III–IV [high]). Baseline characteristics appeared to be generally balanced between the arms.

Pirtobrutinib may be considered a potential new standard-of-care treatment for patients with untreated CLL/SLL, especially older patients who may receive only one line of therapy.

— WOJCIECH JURCZAK, MD, PhD

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At data cutoff, 87.9% of patients were still receiving pirtobrutinib, whereas all those who were administered bendamustine plus rituximab had completed or discontinued treatment. The primary reasons for treatment discontinuation were adverse events in both groups (pirtobrutinib: n = 6; bendamustine plus rituximab: n = 18), followed by patient withdrawal in the pirtobrutinib group (n = 4) and physician decision in the bendamustine plus rituximab group (n = 5). Crossover was allowed upon independent review committee–confirmed disease progression; the effective crossover rate was 52.9%.

The primary endpoint was progression-free survival by blinded independent review committee. Overall survival was identified as the key secondary endpoint. Other secondary endpoints included the overall response rate and safety measures.

Efficacy Findings 

Dr. Jurczak reported that the study “met its primary objective,” showing a statistically significant and clinically meaningful improvement in progression-free survival with pirtobrutinib vs bendamustine plus rituximab.

The 24-month progression-free survival rate was 93.4% (95% confidence interval [CI] = 87.6%–96.5%; median follow-up = 28.1 months) with pirtobrutinib and 70.7% (95% CI = 61.5%–78.1%; median follow-up = 28.3 months) with bendamustine plus rituximab. He highlighted “one of the best hazard ratios [HRs],” reflecting an 80% reduction in the risk of disease progression or death (HR = 0.20, 95% CI = 0.11–0.37; P < .0001).

“It was a knockout…,” Dr. Jurczak added during a press briefing. “If we compare the similar comparisons of bendamustine plus rituximab vs other BTK inhibitors like ibrutinib or zanubrutinib, the hazard ratio is about 0.35….”

Subgroup analyses revealed a consistent progression-free survival benefit with pirtobrutinib across all prespecified subgroups, including age and IGHV status. “We couldn’t find a weak point,” he emphasized during a press briefing.

“Overall survival data were immature but trended in favor of pirtobrutinib [HR = 0.26, 95% CI = 0.07–0.93; P = .0261],” Dr. Jurczak noted, “despite a high effective crossover rate.” The 24-month overall survival rate was 97.8% (95% CI = 93.3%–99.3%; median follow-up = 32.7 months) with pirtobrutinib and 93.0% (95% CI = 87.0%–96.3%; median follow-up = 31.7 months) with bendamustine plus rituximab.

The overall response rates with pirtobrutinib exceeded 90%, reaching 94.3% by both independent review committee and investigator assessment, and were consistently higher than with bendamustine plus rituximab (independent review committee: 80.9%; investigator assessment: 82.3%). “As expected,” Dr. Jurczak stated, most patients achieved a partial response with pirtobrutinib monotherapy.

Safety Findings 

“You have to read the [safety] data with a comment because bendamustine plus rituximab was a fixed-time regimen [median duration = 5.6 months]…[and] pirtobrutinib was until progression [median duration = 32.3 months],” Dr. Jurczak remarked during a press briefing, thus presenting both crude and time-adjusted analyses. But he stated, “Whichever the way you analyze, pirtobrutinib is better.”

Overall, according to Dr. Jurczak, the rate of grade 3 or higher treatment-emergent adverse events was lower with pirtobrutinib (40.0%) than with bendamustine plus rituximab (67.4%). “Despite higher frequencies of some treatment-emergent adverse events with pirtobrutinib, the exposure-adjusted incidence rates were lower,” he continued. No cases of Richter transformation were identified with pirtobrutinib; one was noted with bendamustine plus rituximab.

Dose reduction because of treatment-emergent adverse events was “much less frequent” with pirtobrutinib vs bendamustine plus rituximab (3.6% vs 31.1%), per Dr. Jurczak. Treatment-emergent adverse events leading to discontinuation, including death, were observed in 4.3% and 15.4% of the arms, respectively.

The adverse events of interest, Dr. Jurczak stated, were “mostly low grade and consistent with those seen in pirtobrutinib studies described before.” He highlighted that atrial fibrillation/flutter—often associated with first-generation BTK inhibitors—was “literally nonexistent” in this population (pirtobrutinib: 1.4%; bendamustine plus rituximab: 1.5%), with no increased risk with pirtobrutinib despite longer exposure; incidence remained low in patients aged at least 75 years (5.0% vs 4.3%).

The only adverse event of special interest that occurred more frequently with pirtobrutinib vs bendamustine plus rituximab was what Dr. Jurczak described as a “minor” bleeding tendency (25.7% vs 1.5%), emphasizing that just one case of grade 3 hemorrhage was observed (0.7%).

Dr. Jurczak concluded, “Pirtobrutinib had superior progression-free survival vs bendamustine plus rituximab for patients with treatment-naive CLL/SLL, with one of the largest treatment effects ever observed for a single-agent BTK inhibitor against this comparator. While overall survival data remain immature, a notable trend favoring pirtobrutinib was observed, despite 52.9% of bendamustine plus rituximab patients with progressive disease crossing over to receive pirtobrutinib. Pirtobrutinib was well tolerated, consistent with its known safety profile, with low rates of discontinuation and atrial fibrillation/flutter. Taken together, these data suggest that pirtobrutinib may be considered a potential new standard-of-care treatment for patients with untreated CLL/SLL, especially older patients who may receive only one line of therapy.”

DISCLOSURE: Dr. Jurczak has received research funding from Merck, AstraZeneca, Janssen, Gilead, AbbVie, Nurix Therapeutics, Roche, Takeda, BeOne Medicines (formerly BeiGene), and Eli Lilly; and has served as a consultant (including giving expert testimony) for AstraZeneca, Janssen, AbbVie, Nurix Therapeutics, Roche, Takeda, BeOne Medicines (formerly BeiGene), and Eli Lilly.

REFERENCES

1. Jurczak W, Kwiatek M, Czyz J, et al: Pirtobrutinib vs bendamustine plus rituximab in patients with CLL/SLL: First results from a randomized phase III study examining a non-covalent BTK inhibitor in untreated patients. 2025 ASH Annual Meeting & Exposition. Abstract LBA-3. Presented December 9, 2025.
2. Jurczak W, Kwiatek M, Czyz J, 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. December 9, 2025 (early release online).
3. Woyach J, Qiu L, Grosicki S, et al: Pirtobrutinib vs ibrutinib in treatment-naïve and relapsed/refractory CLL/SLL: Results from the first randomized phase III study comparing a non-covalent and covalent BTK inhibitor. 2025 ASH Annual Meeting & Exposition. Abstract 683. Presented December 7, 2025.

EXPERT POINT OF VIEW

Although describing the positive findings from the phase III BRUIN CLL-313 trial of the noncovalent Bruton’s tyrosine kinase (BTK) inhibitor pirtobrutinib vs bendamustine plus rituximab as not “surprising or shocking,” in an interview with The ASCO Post, John N. Allan, MD, of Weill Cornell Medicine, New York, noted that “it is nice to see that [the agent] meets and/or exceeds the landmarks [set by] our covalent BTK inhibitors” and that the results “put [it] on the map as a very legitimate potential frontline treatment” for patients with treatment-naive chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL).

Despite this enthusiasm, Dr. Allan emphasized that “there’s still going to be some hesitancy for broad use for all patients…,” citing the relative immaturity of the data. While ibrutinib now has a decade of follow-up, pirtobrutinib has only about 2 years, so “we understand toxicity, resistance profiles, and sequencing a little bit better for the covalent BTK inhibitors.”

“Based on the safety profile and clear efficacy of the drug, there are going to be some cases [in which it will be adopted initially]—probably for our older patients,” he noted, as these individuals often have a shorter remaining life expectancy and are unlikely to require multiple drug classes. “With time, though, I expect comfort levels will increase and we’ll start to see broader use of this drug….”

However, with limited data on resistance profiles and sequencing, Dr. Allan stated, “One group that I think people are very hesitant to use this agent in is the patients with the highest [molecular] risk because they are the most at risk of developing resistance….”

Dr. Allan said that, with respect to sequencing, “most of the data would suggest that the resistance mechanisms that occur on pirtobrutinib would actually render many of the covalent BTK inhibitors potentially ineffective” in the second line. Understanding why resistance develops—through mutation panels—he stated, will be important.

For now, he recommended sequencing pirtobrutinib as one would after resistance to a covalent BTK inhibitor: “In general…, [we] switch the class of drug to a BCL2 inhibitor. Currently, we only have venetoclax, but in the future, there will be others.” He highlighted that two BCL2 inhibitors are in development and may offer advantages over venetoclax in this clinical context.

Alongside these agents, according to Dr. Allan, other emerging therapeutic strategies for rescuing patients and regaining response after resistance to front-line pirtobrutinib “look very exciting” and “are likely to become very relevant in the next 5 years.” He pointed to BTK degraders, calling them “maybe ideal to utilize because [of] the resistance patterns [seen with] pirtobrutinib…. The only way to overcome [BTK mutations] would be to degrade the protein, in a sense.”

Whether pirtobrutinib could unseat covalent BTK inhibitors remains an open question. “I don't think it [will]…in the next 1 to 3 years,” Dr. Allan said. As data mature, he expects confidence to grow for its use in certain subgroups, but for now, “covalent BTK inhibitors [will] still maintain the majority of the initial starts.”

DISCLOSURE: Dr. Allan has received research funding from Adaptive Biotechnologies, BeOne Medicines (formerly BeiGene), BMS, and Genentech; and has served as a consultant for AbbVie, Adaptive Biotechnologies, ADC Therapeutics, AstraZeneca, BeOne Medicines (formerly BeiGene), Genentech, Johnson and Johnson, Lilly, Merck, NeoGenomics, and Pharmacyclics.