Pirtobrutinib in Chinese patients with relapsed or refractory B-cell malignancies: A single-arm, open-label, phase 2, multicenter trial

Abstract

Pirtobrutinib, a highly selective, noncovalent (reversible) Bruton tyrosine kinase inhibitor (BTKi), demonstrated clinically meaningful antitumor responses in covalent BTKi pretreated mantle cell lymphoma (MCL) and chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in the global phase 1/2 BRUIN study. In this multi-center, open-label, phase 2 trial, we investigated the efficacy and safety of pirtobrutinib in Chinese patients with BTKi pretreated relapsed/refractory (R/R) MCL, CLL/SLL, or other B-cell malignancies. All patients received pirtobrutinib once daily in continuous 28-day cycles. The primary endpoint was the overall response rate (ORR). Efficacy was assessed in patients with MCL and CLL/SLL with prior BTKi treatment and safety in all enrolled patients who received at least one dose of pirtobrutinib. Among 35 patients with covalent BTKis (cBTKi) pretreated MCL, the ORR was 62.9% (95% CI: 44.9, 78.5), the median duration of response (DOR) was not reached, and the 12-month DOR rate was 59.7% (95% CI: 35.3, 77.5). Among 11 patients with cBTKi pretreated CLL/SLL, the ORR was 63.6% (95% CI: 30.8, 89.1), and the 12-month DOR rate was 83.3% (95% CI: 27.3, 97.5). The most common adverse events in the safety population (n = 87) were anemia (32.2%) and neutrophil count decreased (31.0%). Grade ≥3 hemorrhage occurred in 2.3% of patients and there were no cases of atrial fibrillation/flutter. Pirtobrutinib demonstrated clinically meaningful efficacy in Chinese patients with cBTKi pretreated R/R MCL, preliminary antitumor activity in Chinese patients with cBTKi pretreated R/R CLL/SLL and was generally well-tolerated with no new safety signals observed.

Keywords: chronic lymphocytic leukemia/small lymphocytic lymphoma; mantle cell lymphoma; noncovalent BTK inhibitor; pirtobrutinib.

FIGURE 1

Analysis sets. ^aIncludes four BTKi naïve MCL patients. ^bIncludes two patients with blastoid MCL and five patients who were excluded due to central pathology indicated as blastoid MCL (n = 2), no adequate tumor sample was provided to the central lab (n = 2), or no measurable disease at baseline (n = 1). A total of 28 patients were centrally confirmed to have non‐blastoid MCL and had measurable disease as assessed by the investigator. ^cIncludes six BTKi naïve CLL/SLL patients. BTKi, Bruton tyrosine kinase inhibitor; CLL, chronic lymphocytic leukemia; MCL, mantle cell lymphoma; n, number; SLL, small lymphocytic lymphoma.

FIGURE 2

Waterfall plot showing the best change in tumor burden (covalent Bruton's tyrosine kinase inhibitor pretreated mantle cell lymphoma). CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, stable disease.

FIGURE 3

Duration of response (A), progression‐free survival (B), and overall survival rates in patients with cBTKi pretreated MCL. Vertical check marks represent censoring. cBTKi, covalent Bruton's tyrosine kinase inhibitor; CI, confidence interval; DOR, duration of response; MCL, mantle cell lymphoma; NE, not evaluable; NR, not reached; OS, overall survival; PFS, progression‐free survival.