Efficacy of Pirtobrutinib in Covalent BTK-Inhibitor Pre-Treated Relapsed / Refractory CLL/SLL: Additional Patients and Extended Follow-up from the Phase 1/2 BRUIN Study

Abstract

Background: Covalent Bruton tyrosine kinase inhibitors (BTKi) have transformed the treatment landscape of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Despite the efficacy of covalent BTKi, treatment failure often occurs through development of resistance or intolerance. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. Pirtobrutinib is well tolerated and has demonstrated promising efficacy in patients (pts) with poor-prognosis B-cell malignancies following prior therapy, including prior covalent BTKi (Mato et al. Lancet, 2021). Here, we report updated CLL/SLL results from the BRUIN study (NCT03740529). Methods: Pts with previously treated B-cell malignancies, including CLL/SLL, were eligible for treatment with pirtobrutinib monotherapy in either the dose escalation or expansion portion of the multicenter BRUIN study. Key endpoints included overall response rate (ORR) per 2018 iwCLL response criteria, progression-free survival (PFS), and safety. The response evaluable cohort consisted of all CLL/SLL pts enrolled to either phase 1 or 2 who had received a prior covalent BTKi containing regimen and had undergone their first response assessment or discontinued therapy. The safety cohort consisted of all pts with B-cell malignancies who received at least one dose of pirtobrutinib monotherapy (n=725). A data cut of 31 January 2022 was utilized. Results: Among the 276 pts with CLL/SLL who had received a prior BTKi, median age was 69 (range 36-88) years and the median number of prior therapies was 3 (range 1-11). Additional prior therapies included anti-CD20 antibody (89%), chemotherapy (80%), BCL2 inhibitor (44%), PI3K inhibitor (24%), CAR-T cell therapy (6%), and stem cell transplantation (2%). High-risk features were frequent: del(17p) in 29% (58/197), mutated TP53 in 40% (91/230), and unmutated IGHV in 85% (188/220). The majority of pts (n=206, 75%) discontinued prior BTKi therapy due to disease progression. Overall, 84% (n=232) received the recommended phase 2 dose of 200 mg once daily as starting dose. In this group of heavily pretreated relapsed/refractory CLL/SLL patients, including all with prior BTKi use, the ORR by investigator assessment was 74% (95% CI, 68-79) (Table) including 3 complete responses (1%), 174 partial responses (PR; 64%), 23 PRs with lymphocytosis (PR-L; 8%), and 1 nodular PR (<1%). At a median follow up time of 13.9 months, the median PFS was 19.4 months (95% CI, 16.6-22.3) (Figure). The 12-month and 18-month estimated PFS rates were 68% (95% CI, 62-74) and 54% (95% CI, 46-61), respectively. The ORR and PFS across various patient subgroups are depicted in the Table. In the safety cohort of all pirtobrutinib treated pts with B-cell malignancies (n=725), the most common TEAEs, regardless of attribution, were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). The most frequent Grade ≥3 TEAE was neutropenia (20%, n=143). Low rates of Grade ≥3 TEAEs of hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were observed. Overall, 15 (2%) pts discontinued due to a treatment-related AE. Conclusion: In this updated analysis with additional pts and extended follow-up, pirtobrutinib continues to demonstrate promising and durable efficacy in heavily pre-treated R/R CLL/SLL pts who have been treated with a prior covalent BTKi, regardless of prior therapy, reason for prior BTKi discontinuation, age, high-risk TP53 mutations, C481 mutational status, and/or del(17p). Pirtobrutinib was well-tolerated with low-rates of discontinuation due to drug-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal