ORLANDO, Fla. — Patients who took pirtobrutinib (Jaypirca) had a similar overall response rate to those who took ibrutinib. This was the case for those with both treatment-naive and relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL), in the first randomized phase 3 trial to compare noncovalent and covalent Bruton’s Tyrosine Kinase (BTK) inhibitors.

Pirtobrutinib was also linked to better safety and a trend toward better progression-free survival (PFS).

The overall response rates in 662 patients randomly assigned 1:1 to treatment or placebo were 87.0% for pirtobrutinib vs 78.5% with ibrutinib per an intention-to-treat analysis, reported Jennifer Woyach, MD, director of Hematology, Ohio State University, Columbus, Ohio, and colleagues, in their abstract from the American Society of Hematology (ASH) 2025 Annual Meeting. The findings were simultaneously published in the Journal of Clinical Oncology.

Among treatment-naive patients (n = 225), the response rates were 92.9% and 85.8%, respectively, and they were 84% and 74.8%, respectively, in the relapsed/refractory cohort (n = 437).

The presentation and publication of the BRUIN CLL-314 trial followed the FDA’s December 3 decision to expand approval for pirtobrutinib in CLL/SLL. The drug is now approved to treat relapsed/refractory CLL/SLL in patients who have previously been treated with a covalent BTK inhibitor. In 2023, it received accelerated approval in patients who have received at least two prior lines of therapy, including a BTK inhibitor and a B-cell lymphoma inhibitor.

“Although covalent BTK inhibitors have transformed the therapeutic landscape for patients with CLL and SLL, pharmacologic limitations may ultimately compromise their efficacy,” Woyach said during her presentation at the meeting.

The study findings and other new data “will potentially allow pirtobrutinib to be used in earlier lines of therapy,” she said.

Earlier this year, hematologists told Medscape Medical News that pirtobrutinib has become a standard treatment for certain patients with CLL since its approval in 2024. The drug is noncovalent, meaning it inhibits BTK in different ways than covalent drugs such as ibrutinib.

The global, multicenter, open-label BRUIN CLL-314 assigned patients to receive 200 mg pirtobrutinib orally once daily or 420 mg ibrutinib orally once daily (median age, 67 years; 64.7% men; 52.1% from Europe). Seven patients (one assigned to pirtobrutinib and six assigned to ibrutinib) did not receive treatment.

At data cutoff, 7.6% of those in the pirtobrutinib group and 7.3% of those in the ibrutinib group in the intention-to-treat population had died. The percentages were 10.0% (22/219) and 9.6% (21/218), respectively, in the relapsed/refractory population and 2.7% (3/112) and 2.7% (3/113), respectively, in the treatment-naive population.

After a median follow-up of approximately 20 months in the intention-to-treat population, “a trend in favor of pirtobrutinib was observed with a reduction in the risk of progression or death of 43% compared with ibrutinib,” Woyach said.

The 18-month PFS was 87% for pirtobrutinib vs 82% for ibrutinib in the intention-to-treat population. In the treatment-naive group, “a notable trend in favor of pirtobrutinib was observed with a risk reduction of progression or death of 76% compared with ibrutinib,” Woyach reported.

In a safety analysis of 655 patients treated for a median of 20.5 months (pirtobrutinib) and 19.3 months (ibrutinib), treatment-emergent adverse events of any grade were similar (97.0% vs 97.8%) as were events of grade 3 or higher (54.8% vs 53.5%).

One patient developed Richter’s transformation while on pirtobrutinib vs four patients on ibrutinib. The pirtobrutinib group had fewer dose reductions than the ibrutinib greoup (7.9% vs 18.2%) and similar rates of discontinuation due to adverse events (7.9% vs 7.3%).

“Overall discontinuation, especially discontinuation due to adverse events, is low compared to what’s historically seen with ibrutinib in more recent phase 3 studies,” Woyach said.

Lymphocytosis occurred in 3.6% of patients on pirtobrutinib and 5.8% of those on ibrutinib.

Highlighted adverse events were lower in the pirtobrutinib group than in the ibrutinib group: Atrial fibrillation/atrial flutter, 2.4% vs 13.5%; grade ≥ 3, 0.9% vs 4.0%; and hypertension, 10.6% vs 15.1%; grade ≥ 3, 3.3%, vs 4.9%).

In response to a question, Woyach said longer follow-up is needed to determine who should get frontline pirtobrutinib.

“Potentially, patients who are older and more frail could benefit from this drug given the excellent safety profile,” she said.

The published study lists two limitations: the limited median follow-up for PFS and the trial’s open-label design.

In an interview, Catherine S. Diefenbach, MD, associate professor of medicine with Perlmutter Cancer Center at NYU Langone Health, New York City, noted that the study is positive, showing a “significant response benefit” in relapsed/refractory patients. “However, that does not mean that it is superior to second-generation covalent BTKs such as acalabrutinib or zanubrutinib,” said Diefenbach, who was not involved in the study.

She added that significant benefit was not seen in treatment-naive patients, and no PFS benefit has been observed yet.

“PFS matters in CLL, so it would be important to show a PFS or overall survival benefit for this to have true clinical impact,” Diefenbach explained.

In addition, she said, there was no statistically significant benefit for different high-risk subgroups.

Eli Lilly funded this study. Woyach reported relationships with Merck, AbbVie, BeOne, Schrodinger, Janssen, Pharmacyclics, Newave, and AstraZeneca. Other authors reported various and multiple disclosures.

Diefenbach had no disclosures.