Pirtobrutinib, a highly selective, noncovalent Bruton’s tyrosine kinase inhibitor (BTKi), shows substantial improvements in progression-free survival over the chemotherapy regimen of bendamustine plus rituximab (BendaR) in treatment-naive chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).

The study showed that “pirtobrutinib had a superior progression-free survival vs bendamustine/rituximab patients with treatment-naive CLL/SLL, [representing] one of the largest treatment effects ever observed for a single BTK inhibitor against this competitor,” said first author Wojciech Jurczack, MD, PhD, of theNational Research Institute of Oncology, Krakow, Poland, in presenting the findings at the American Society of Hematology (ASH) 2025 Annual Meeting. 

“Taken together, these data [overall] suggest that pirtobrutinib may be considered a potential new standard of care for patients with untreated CLL/SLL, especially for the elderly and fragile patients who may receive only one line of therapy,” he said.

The results are from the open-label, phase 3 BRUIN CLL-313 trial, involving 282 patients with previously untreated CLL/SLL, without the higher-risk del(17p) mutation.

For the study, patients were randomly assigned in a 1:1 ratio to receive treatment with pirtobrutinib monotherapy (200 mg/d ) or six cycles of BendaR. 

At a median follow-up of 28.1 months, those treated with pirtobrutinib (n = 141) were significantly more likely to have achieved the primary endpoint of 24-month progression-free survival than those treated with BendaR (93.4% vs 70.7%; hazard ratio [HR], 0.19; P < .0001).

“It was a knockout,” Jurczack said in an ASH press briefing. “In similar comparisons of BendaR with other BTK inhibitors like ibrutinib or zanubrutinib, the HR is about 0.35.”

“This means there is a reduction in the risk of progression to disease or death by 80%.”

The improvement was observed across clinically relevant patient subgroups, including patients older than 65 years (who made up 52% of the study population; HR, 0.24), and higher-risk patients with mutated IGHV (HR, 0.293) and unmutated IGHV (HR, 0.172).

The investigator-assessed overall response rates (ORR) were 94.3% with pirtobrutinib and 82.3% with BendaR.

While the overall survival rate was not considered mature in the analysis, “a notable trend” favoring pirtobrutinib was observed (HR, 0.257; P = .0261), Jurczack noted.

The study excluded patients with known CLL/SLL central nervous system involvement, Richter transformation, or significant cardiovascular disease. 

The safety and tolerability profile among patients receiving pirtobrutinib was consistent with that of previous studies, including a notably low rate of atrial fibrillation of 1.4% compared with 0.7% with BendaR, which is not associated with an increased risk for atrial fibrillation. Rates of atrial fibrillation remained low in patients aged 75 or older, at 5.0% with pirtobrutinib vs 4.3% with BendaR.

Grade 3 or higher treatment-emergent adverse events occurred in 40% of patients on pirtobrutinib vs 67.4% of those on BendaR. In adverse events of interest, the pirtobrutinib group had significantly lower grade 3 or higher infections (13.6% vs 8.3%) and grade 3 or higher neutropenia (9.3% vs 45.5%).

“To our knowledge, BRUIN CLL-313 is the first prospective, randomized phase 3 study examining the efficacy and safety of a noncovalent BTKi exclusively in patients with untreated CLL/SLL,” the authors noted in the study, which was published simultaneously in the Journal of Clinical Oncology (JCO).

With separate new findings from the BRUIN-CLL 314 trial, also presented at the meeting, showing noninferiority of pirtobrutinib vs ibrutinib in ORR among relapsed/refractory or treatment-naive CLL/SLL, the combined evidence “raises important questions on the optimal choice of BTK inhibitor therapy in frontline CLL,” the authors noted in the study.

“Factors such as patient age, comorbidities, and genetic risk factors are important to consider while making first-line treatment choices,” they added.

While pirtobrutinib received accelerated approval from the FDA in 2023 for adults with CLL/SLL who have received at least two prior lines of therapy, including a BTKi and a B-cell lymphoma 2 inhibitor, the agency this month granted traditional approval to adults with CLL/SLL previously treated with a covalent BTKi.

BendaR Outdated, but Findings Still Important

Commenting on the study to Medscape Medical News, Jonathan W. Friedberg, MD, who is the editor in chief of JCO and director of the Wilmot Cancer Institute at the University of Rochester Medical Center in Rochester, New York, noted that “these findings confirm safety and efficacy of pirtobrutinib in the upfront setting of CLL.”

“This noncovalent BTK inhibitor has already demonstrated activity in the relapsed/refractory setting, [and] this manuscript definitively shows a potential place of this treatment in the previously untreated setting,” he said.

A notable caveat is that the comparator of BendaR is not something that is commonly used anymore, with an ever-expanding array of more effective therapies becoming available as alternatives.

“BendaR is outdated, and I do not believe there is a place for BendaR to be used as part of upfront treatment of CLL,” he said. In fact, “this comparator is responsible for the very low HR and may be responsible for the overall survival signal,” Friedberg noted.

“However, it does not detract from the findings of long progression-free survival and the tolerability demonstrated in the pirtobrutinib arm of the trial.”

Other limitations include that patients with the del(17p) mutation, among whom covalent BTKi are considered a standard, were not included.

“I would expect a high level of activity in those patients with pirtobrutinib, but the current study is not informative in that regard,” he said.

In an editorial published concurrently with the two new pirtobrutinib trials, Matthew S. Davids, MD, of the Department of Medical Oncology at Dana-Farber Cancer Institute in Boston, says the findings beg the question of how pirtobrutinib will compare with newer agents.

Best Choice for Older Patients?

Frontline pirtobrutinib should be considered for “older patients with CLL (particularly those with significant comorbidities) who choose to start on continuous BTKi,” said Davids.

“In such patients, the excellent tolerability of pirtobrutinib makes it an appealing option, and concerns about the durability of response to subsequent lines of therapy may be less salient since many of these patients will only require one or two lines of CLL therapy and are likely to die of other causes before additional therapies beyond that are required.”

“It should be noted, however, that more selective cBTKis are also highly effective and well tolerated in this older population, as demonstrated in studies such as the recently reported CLL-FRAIL trial of acalabrutinib in a population of frontline patients with CLL who were exclusively 80 years or older,” Davids wrote.

The study authors noted that an analysis with longer-term follow-up is planned to further evaluate the performance of pirtobrutinib in first-line CLL/SLL.

Jurczak’s disclosures included consulting for and/or having other relationships with BeOne, Lilly, AbbVie/Genentech, Takeda, Roche, AstraZeneca, and Janssen-Cilag. Friedberg reported having no disclosures. Davids’ disclosures included consulting for or having other relationships with Curio Science, Aptitude Health, Bio Ascend, PlatformQ Health, Plexus, Genentech, Janssen, AbbVie, AstraZeneca, Adaptive Biotechnologies, Ascentage Pharma, BeOne, Lilly, Bristol Myers Squibb, Genmab, Merck, MEI Pharma, Nuvalent Galapagos NV, and Schroedinger.