Pirtobrutinib Matches Ibrutinib in ORR, Shows Potential PFS Edge in BTK Inhibitor–Naive CLL/SLL

In the phase 3 BRUIN CLL-314 trial (NCT05254743), pirtobrutinib (Jaypirca) achieved noninferior overall response rates (ORR) compared with ibrutinib (Imbruvica) in patients with previously untreated or relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) who had not previously received a Bruton tyrosine kinase (BTK) inhibitor. Notably, early results also suggested a progression-free survival (PFS) advantage with pirtobrutinib, according to data presented by Jennifer Woyach, MD, at the 2025 American Society of Hematology Annual Meeting and Exposition.

In the intent-to-treat (ITT) population of patients with either R/R or treatment-naive CLL/SLL, the ORR was 87% in patients randomly assigned to pirtobrutinib (n = 331) vs 78.5% in those randomly assigned 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 randomly assigned to ibrutinib (n = 113; P = .0886). The ORR ratio was 1.0797 (95% CI, 0.989-1.179). The best overall responses with pirtobrutinib vs ibrutinib, respectively, were 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 R/R population, the ORR was 84.0% in patients randomly assigned to pirtobrutinib (n = 219) vs 74.8% in those randomly assigned 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 responses with pirtobrutinib vs ibrutinib, respectively, were 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 R/R populations,” said Woyach, director of the Division of Hematology at The Ohio State University Comprehensive Cancer Center–Arthur G. James Cancer Hospital and Richard J. Solove Research Institute in Columbus.

PFS data, although 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 R/R 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 R/R and treatment-naive populations,” Woyach said. “The most pronounced effect [was] in the treatment-naive population, which had the longest follow-up at this data cutoff.”