In the phase III BRUIN CLL-314 trial, response rates were found to be as good with the noncovalent Bruton's tyrosine kinase (BTK) inhibitor pirtobrutinib as with ibrutinib in both patients with treatment-naive and relapsed or refractory chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who were not previously exposed to a BTK inhibitor, meeting the study’s primary endpoint. Notably, the early results heralded a progression-free survival advantage with pirtobrutinib, Jennifer Woyach, MD, Professor, Division of Hematology, The Ohio State University, Columbus, reported at the 2025 American Society of Hematology (ASH) Annual Meeting & Exposition.¹ These findings were simultaneously published in the Journal of Clinical Oncology.²

These data, along with the other frontline trial [BRUIN CLL-313], will allow pirtobrutinib to be used in earlier lines of therapy.

— JENNIFER WOYACH, MD

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“Pirtobrutinib demonstrated consistently higher objective response rates than ibrutinib across all patients, including treatment-naive and relapsed or refractory populations,” said Dr. Woyach. “Pirtobrutinib was clearly noninferior to ibrutinib, and the response rate actually favors pirtobrutinib in the total cohort. This shows that pirtobrutinib is a reasonable choice in both settings.”

Although the data for progression-free survival, a key secondary endpoint, remain immature, she further reported that the risk was reduced by 43% in the descriptive analysis.

Noncovalent BTK inhibitors such as pirtobrutinib were initially developed to overcome resistance to covalent BTK inhibitors, the first of which was ibrutinib. This study is the first phase III clinical trial to directly compare a noncovalent and covalent BTK inhibitor in patients with CLL or SLL.

The study enrolled 662 patients with CLL or SLL. Of this population, 225 were treatment-naive, and 437 had relapsed or were refractory to prior therapy but had not received a BTK inhibitor. In the intention-to-treat population, the objective response rate by blinded independent review was 87.0% in patients randomly assigned to receive pirtobrutinib vs 78.5% in those treated with ibrutinib (P = .0035). Response rates were 92.9% vs 85.8% (P = .0886) in the treatment-naive population and 84.0% vs 74.8% in the relapsed or refractory population (P = .0175), respectively, she reported. 

At a press briefing, Dr. Woyach was asked how these results might reposition pirtobrutinib in the clinic. She responded, “Hopefully, these data, along with the other front-line trial presented here of pirtobrutinib vs bendamustine–rituximab [BRUIN CLL-313], will allow pirtobrutinib to be used in earlier lines of therapy. Longer follow-up with a continued look at the safety profile will be needed to really decide which groups of patients are most appropriate for this in the frontline setting, but potentially those who are older or more frail might benefit, given the drug’s excellent (so far) safety profile.”³

More Details on Response

The analysis also assessed the objective response rate ratio, defined as the proportion of patients achieving a complete remission, complete remission with incomplete hematologic recovery, nodular partial response, or partial response at or before subsequent anticancer therapy. In the intention-to-treat population, this was 1.1080 (95% confidence interval [CI] = 1.034–1.187; P < .0001 for noninferiority); in the treatment-naive population, it was 1.0797 (95% CI = 0.989–1.179; Pnot determined); and in the relapsed or refractory population, it was 1.1233 (95% CI = 1.020–1.237; P < .0001 for noninferiority).

Best overall responses with pirtobrutinib vs ibrutinib, respectively, were complete remission or complete remission with incomplete hematologic recovery in 4.8% vs 2.4%, partial or nodular partial remission in 82.2% vs 76.1%, and partial remission with lymphocytosis in 2.4% vs 3.9%.

In the treatment-naive population, complete remission or complete remission with incomplete hematologic recovery was achieved by 7.1% of patients treated with pirtobrutinib vs 3.5% of those who received ibrutinib; in the relapsed/refractory population, this degree of response was achieved by 3.7% vs 1.8%, respectively. Partial and nodular partial remissions were achieved in 85.7% and 82.3% of patients in the treatment-naive group in the respective treatment arms, and in 80.4% and 72.9% of those in the relapsed or refractory group.

“Objective response rates favored pirtobrutinib in high-risk subgroups, including 17p deletion, unmutated IGHV status, and complex karyotype, which was consistent across the treatment-naive and relapsed or refractory populations,” Dr. Woyach said.

Progression-Free Survival

Acknowledging the prematurity of the data, Dr. Woyach noted, “Early trends in progression-free survival favored pirtobrutinib among all patients and in the relapsed or refractory and treatment-naive populations. The most pronounced effect was in the treatment-naive population, which had the longest follow-up at this data cutoff [> 22 months].”

In the intention-to-treat population, at a median follow-up of 22.0 months with pirtobrutinib and 19.7 months with ibrutinib, the 18-month progression-free survival rates per investigator assessment were 86.9% vs 82.3%, respectively (hazard ratio [HR] = 0.569, 95% CI = 0.388–0.834; P = .0034). The rates were also higher with pirtobrutinib in the treatment-naive (95.3% vs 87.6%; HR = 0.239; P = .0007) and relapsed or refractory (81.7% vs 79.2%; HR = 0.729; P = .1563) populations.

The rates of treatment-emergent adverse events and related discontinuations were found to be overall similar between the arms. However, patients treated with pirtobrutinib vs ibrutinib had fewer dose reductions and discontinuations, as well as a lower incidence of atrial fibrillation and atrial flutter, particularly among the subset aged 75 years and older. Richter transformation was seen in one patient treated with pirtobrutinib, compared with four who received ibrutinib.

DISCLOSURE: Dr. Woyach reported relationships with AbbVie, Newave, AstraZeneca, Merck, Schrödinger, BeOne Medicines (formerly BeiGene), and Loxo@Lilly.

REFERENCES

1. 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.
2. Woyach JA, Qiu L, Grosicki S, et al: Pirtobrutinib versus ibrutinib in treatment-naïve and relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma. J Clin Oncol. December 7, 2025 (early release online).
3. 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.

Expert Point of View

Matthew S. Davids, MD, MMSc, Associate Professor of Medicine at Harvard Medical School, and Attending Physician and Director of Clinical Research in the Division of Lymphoma at Dana-Farber Cancer Institute, Boston, shared his thoughts on the results of the BRUIN CLL-314 trial in an interview with The ASCO Post.

He noted that in a somewhat unusual design, BRUIN CLL-314 included both patients with previously untreated and relapsed or refractory disease (although stratified at randomization), so pirtobrutinib was evaluated as a front-line and second-line agent. “To me, the more interesting aspect was the front-line component,” he said, “because this was the first trial we’ve ever seen comparing any two BTK [Bruton’s tyrosine kinase] inhibitors in this setting.”

Matthew S. Davids, MD, MMSc

The primary endpoint, overall response rate, demonstrated noninferiority; however, progression-free survival—which remains immature—will be the more important endpoint, Dr. Davids said. “From what we can tell from the descriptive analysis, the outcomes may favor pirtobrutinib, as the hazard ratio [HR] was 0.57, but longer follow-up will be needed to see if there is a statistically significant difference.”

In addition, he stated that other observations are supportive of pirtobrutinib as a front-line BTK inhibitor. “One is its very high response rate in relapsed or refractory patients, which suggests that pirtobrutinib might overcome resistance. For example, we can see that it does overcome resistance to the common resistance mutations like BTK C481. Secondly, pirtobrutinib is a very well tolerated drug, which may be because of its selectivity as a noncovalent inhibitor.”

Dr. Davids considers the safety profile to be reassuring, though some hypertension and neutropenia were observed in a small percentage of pirtobrutinib-treated patients. Importantly, the incidence of atrial fibrillation was lower with this drug. “I think it’s pretty clear that pirtobrutinib is a safer drug than ibrutinib,” he commented. 

The front-line use of pirtobrutinib is also now supported by the phase III BRUIN CLL-313 study, which was presented as a late-breaker at this meeting.^1,2 Compared with bendamustine plus rituximab in treatment-naive patients, pirtobrutinib reduced the risk of disease progression or death by approximately 80% (HR = 0.199; P < .0001); the 24-month progression-free survival rates were 93.4% vs 70.7%, respectively. Although the control arm is now an outdated regimen, Dr. Davids predicted the robust findings will contribute to the regulatory approval of pirtobrutinib as a frontline agent.

The findings from the BRUIN CLL-314 and BRUIN CLL-313 trials will most certainly have implications for sequencing these BTK inhibitors in the clinic, he said, though possibly not until longer-term progression-free survival data can be submitted to regulators. He added that regardless of the drug’s approval status in the front-line setting, however, there are issues that clinicians should consider. 

“Right now, we know we can start with a covalent BTK inhibitor and that patients will respond well to pirtobrutinib when they progress on those. We don’t know what happens the other way around. If you start with pirtobrutinib front-line, how well will you respond to a covalent BTK inhibitor? We don’t have data, so in the absence of that, I don’t think [BRUIN] CLL-314 supports the broad use of pirtobrutinib for all patients with CLL as initial therapy,” Dr. Davids remarked. “That being said, however, because the tolerability is so good, I might start with this drug in an older patient, who may need only one line of treatment and for whom the sequencing question is not so important.” 

DISCLOSURE: Dr. Davids reported relationships with AbbVie, Ascentage Pharma, AstraZeneca, BeOne Medicines (formerly BeiGene), Bristol Myers Squibb, Eli Lilly, Genentech, Genmab, Janssen, Merck, Nuvalent, and Schrödinger.

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. Davids MS: BRUIN 313 and 314 trials open the door for noncovalent Bruton tyrosine kinase inhibition as initial therapy for chronic lymphocytic leukemia. J Clin Oncol. December 9, 2025 (early release online).

MORE INFORMATION

To hear more from Jennifer Woyach, MD, on the results of the BRUIN CLL-314 trial from the 2025 ASH Annual Meeting & Exposition, see a video on The ASCO Post Newsreels at ascopost.com/videos.