Efficacy of pirtobrutinib in CLL and SLL patients previously treated with covalent BTK inhibitors

July 2023 Clinical trials Andrea Enguita

Patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) experience poor outcomes after failure of covalent Bruton’s tyrosine kinase (BTK) inhibitor treatment. However, new findings of the BRUIN 1/2 trial, recently published in the New England Journal of Medicine, bring new hope to these patients. The results of this trial revealed promising efficacy and safety of the noncovalent BTK inhibitor pirtobrutinib in the treatment of CLL or SLL patients who had previously received a covalent BTK inhibitor.

Bruton’s tyrosine kinase (BTK) inhibitors have dramatically improved outcomes for patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL). Despite their effectiveness, these treatments are not curative, and patients often face poor outcomes when BTK inhibitor therapy fails. Pirtobrutinib, a selective and noncovalent (reversible) BTK inhibitor, effectively targets both wild-type and C481-mutant BTK, the most common mutation associated with resistance to covalent BTK inhibitors. Recently, pirtobrutinib obtained FDA approval for treating patients with relapsed or refractory (R/R) mantle-cell lymphoma with prior exposure to two lines of systemic therapy, including a BTK inhibitor. Based on these promising results, the phase 1/2 BRUIN trial evaluated the efficacy and safety of pirtobrutinib in R/R B-cell cancers, with this report focusing on the results among patients with R/R CLL or SLL receiving pirtobrutinib treatment.


The phase 1/2 BRUIN trial was a multicentre study conducted at 49 sites across 10 countries enrolling patients with different types of R/R B-cell cancers. In phase 1 of this study, patients received pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles. In the phase 2 portion, patients received the recommended dose of 200 mg once daily. Treatment continued until disease progression, unacceptable toxic effects, or patient withdrawal. Among patients with CLL or SLL, the primary endpoint was the overall response rate (ORR, partial response or better). Additional endpoints included the ORR including partial response with lymphocytosis and progression-free survival (PFS). This report presents the efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor, as well as safety results among all the patients with CLL or SLL.

Study findings

A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously been treated with a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3, and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. Pirtobrutinib demonstrated an ORR of 73.3%, which increased to 82.2% when patients with a partial response and lymphocytosis were included. The median PFS was 19.6 months. The most common adverse events among all 317 patients with CLL or SLL receiving pirtobrutinib were infections (71.0%), bleeding (42.6%), and neutropenia (32.5%). Notably, adverse events typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (14.2% of patients), atrial fibrillation or flutter (3.8%), and major haemorrhage (2.2%). Only 9 out of 317 patients (2.8%) discontinued pirtobrutinib due to a treatment-related adverse event.

In conclusion, the BTK inhibitor pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had had disease progression during previous treatment with a covalent BTK inhibitor. These findings highlight the potential therapeutic option of reestablishing BTK inhibition with pirtobrutinib, regardless of whether previous covalent BTK inhibitor therapy was discontinued due to disease progression, toxic effects, or other reasons


Mato AR, Woyach JA, Brown JR, et al. Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia. N Engl J Med. 2023; 389:33-44.