Noninferior Responses Occur With Pirtobrutinib vs Ibrutinib in CLL

Data from the phase 3 BRUIN CLL-314 trial (NCT05254743) showed a noninferior overall response rate (ORR) with pirtobrutinib (Jaypirca) vs ibrutinib (Imbruvica) among patients with relapsed/refractory or treatment-naive chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to a presentation at the 2025 American Society of Hematology (ASH) Annual Meeting and Exposition.¹

The findings, presented by Jennifer Woyach, MD, also showed a trend towards improved progression-free survival (PFS) with pirtobrutinib.

In the ITT population of patients with either relapsed/refractory or treatment-naive CLL/SLL, the ORR was 87% in patients randomized to pirtobrutinib (n = 331) vs 78.5% in those randomized to ibrutinib (n = 331; P = .0035). The ORR ratio was 1.1080 (95% CI, 1.034–1.187; P value for noninferiority <.0001). The best overall response with pirtobrutinib vs ibrutinib, respectively, was complete remission (CR) or CR with incomplete hematologic recovery (CRi) of 4.8% vs 2.4%, partial remission (PR) or nodular partial remission (nPR) of 82.2% vs 76.1%, partial remission with lymphocytosis (PR-L) of 2.4% vs 3.9%, stable disease (SD) of 5.4% vs 10.9%, and progressive disease (PD) of 1.5% vs 1.2%.

In the treatment-naive population, the ORR was 92.9% in patients randomized to pirtobrutinib (n = 112) vs 85.8% in those randomized to ibrutinib (n = 113; P = .0886). The ORR ratio was 1.0797 (95% CI, 0.989–1.179). The best overall response with pirtobrutinib vs ibrutinib, respectively, was CR/CRi of 7.1% vs 3.5%, PR/nPR of 85.7% vs 82.3%, PR-L of 0.9% vs 2.7%, SD of 2.7% vs 4.4%, and no cases of PD.

In the relapsed/refractory population, the ORR was 84.0% in patients randomized to pirtobrutinib (n = 219) vs 74.8% in those randomized to ibrutinib (n = 218; P = .0886). The ORR ratio was 1.1233 (95% CI, 1.020–1.237; P value for noninferiority <.0001). The best overall response with pirtobrutinib vs ibrutinib, respectively, was CR/CRi of 3.7% vs 1.8%, PR/nPR of 80.4% vs 72.9%, PR-L of 3.2% vs 4.6%, SD of 6.8% vs 14.2%, and PD of 2.3% vs 1.8%

“Pirtobrutinib demonstrated consistently higher ORR than ibrutinib across all patients, including treatment-naive and relapsed/refractory populations,” said Woyach, director of the Division of Hematology, The Ohio State University Comprehensive Cancer Center.

PFS data, while immature, showed a trend in favor of pirtobrutinib. In the ITT population, at a median follow-up of 22.0 months with pirtobrutinib and 19.7 months with ibrutinib, the 18-month PFS rates per investigator assessment were 86.9% vs 82.3%, respectively (HR, 0.569; 95% CI 0.388–0.834; nominal P value = .0034). In the relapsed/refractory population, at a median follow-up of 18.4 months with pirtobrutinib and 15.8 months with ibrutinib, the investigator-assessed 18-month PFS rates were 81.7% vs 79.2%, respectively (HR, 0.729; 95% CI, 0.471–1.128; nominal P value = .1563). And in the treatment-naive population, at a median follow-up of 22.5 months with pirtobrutinib and 22.4 months with ibrutinib, the investigator-assessed 18-month PFS rates were 95.3% vs 87.6%, respectively (HR, 0.239; 95% CI, 0.098–0.586; nominal P value = .0007).

“Early trends in PFS favored pirtobrutinib among all patients and in the relapsed/refractory and treatment-naïve populations,” said Woyach, adding that, “The most pronounced effect [was] in the treatment-naive population, which had the longest follow-up at this data cutoff.”

Safety in BRUIN CLL-314

Regarding safety, the most common all grade treatment-emergent adverse events (TEAEs) with pirtobrutinib vs ibrutinib were neutropenia (22.7% vs 17.8%), upper respiratory tract infection (17.9% vs 19.4%), anemia (15.2% vs 14.2%), pneumonia (13.6% vs 15.1%), and diarrhea (13.3% vs 19.1%). The most common grade ≥3 TEAEs with pirtobrutinib vs ibrutinib were mostly similar: neutropenia (17.3% vs 13.2%), pneumonia (6.4% vs 8.6%), anemia (5.8% vs 3.7%).

Rates of all-grade (10.6% vs 15.1%) and grade ≥3 (3.3% vs 4.9%) hypertension were lower with pirtobrutinib vs ibrutinib. One patient developed Richter Transformation with pirtobrutinib vs 4 patients with ibrutinib.

“Pirtobrutinib was well tolerated with fewer dose reductions and discontinuations due to TEAEs than ibrutinib,” said Woyach.

She said that adverse events of special interest were mostly low-grade and consistent with prior studies of pirtobrutinib. Grade ≥3 neutropenia (25.2% vs 17.5%) and anemia (6.1% vs 3.7%) were higher with pirtobrutinib vs ibrutinib; however, grade ≥3 thrombocytopenia was lower with pirtobrutinib (3.6% vs 4.0%).

All-grade incidence of atrial fibrillation/flutter (2.4% vs 13.5%) was substantially lower with pirtobrutinib versus ibrutinib, particularly among patients aged ≥75 years (4.5% vs 21.4%).

BRUIN CLL-314 Design and Patient Characteristics

The phase 3 BRUIN CLL-314 study accrued patients with BTK inhibitor–naïve CLL/SLL, including both patients with treatment-naive and relapsed/refractory disease. Overall, there were 662 patients (ITT population) randomized in a 1:1 ratio to pirtobrutinib (n = 331) or ibrutinib (n = 331) between August 18, 2022, and June 17, 2024. The median age was 67 years in both the pirtobrutinib (range, 39–90) and ibrutinib (range, 34–86) arms, and the median number of prior therapies in both arms was 1. In the ITT population, 225 patients were treatment-naive and 437 patients were relapsed/refractory.

In patients with evaluable samples, 68% (n = 199/293) vs 66% (n = 183/277) of patients in the pirtobrutinib vs ibrutinib cohorts had unmutated IGHV. Further, 40% (n = 104/259) vs 34% (n = 78/227) and 15% (n = 50/331) vs 16% (n = 52/331) had complex karyotype ≥3 abnormalities and del(17p), respectively.

Pirtobrutinib was administered orally at 200 mg/daily and ibrutinib was administered orally at 420 mg/daily. The primary end point was non-inferiority of ORR in the ITT population or relapsed/refractory population. The key secondary end point was superiority of PFS in the ITT population or relapsed/refractory population.

Significance and Next Steps

CLL-314 is the first trial comparing pirtobrutinib and ibrutinib in treatment-naive patients and patients with BTK inhibitor–naive relapsed/refractory CLL/SLL.

Pirtobrutinib is currently approved by the FDA for patients with relapsed/refractory CLL/SLL who have previously received a BTK inhibitor.² When the PFS data from the BRUIN CLL-314 study fully mature, it is hoped that the trend favoring pirtobrutinib will be upheld and can lead to a regulatory filing for use of the agent in earlier CLL/SLL lines.

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. Blood. 2025;146(suppl 1):683. doi:10.1182/blood-2025-683
2. FDA grants traditional approval to pirtobrutinib for chronic lymphocytic leukemia and small lymphocytic lymphoma. Food and Drug Administration.Published 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