The efficacy and safety of pirtobrutinib in patients with CLL/SLL: A phase 2 dose optimization trial in progress Free

Introduction: The treatment landscape for patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) has significantly evolved over the last decade, leading to improved long-term outcomes. However, those with high-risk features such as deletion 17p [del(17p)] continue to face poor prognoses and limited benefit from chemoimmunotherapy. Covalent Bruton tyrosine kinase inhibitors (cBTKi) have transformed the therapeutic landscape for CLL/SLL, including in high-risk populations. Despite these advances, their long-term use is often limited by intolerance or the emergence of resistance, which often leads to disease progression and diminished treatment options. Pirtobrutinib, a highly selective, non-covalent BTKi, has demonstrated promising efficacy and a favorable safety profile in patients with CLL/SLL after cBTKi therapy, including patients harboring del(17p) (Sharman JP, et al JCO 2025;0:25-00166, Mato AR, et al NEJM 2023; 389:33-44). Pirtobrutinib is approved in the EU, Brazil, and Saudi Arabia for the treatment of relapsed/refractory (R/R) CLL after prior treatment with a BTK inhibitor and under accelerated approval by the FDA for adults with CLL/SLL after at least two prior lines of therapy, including a BTK inhibitor and a BCL-2 inhibitor. However, most data to date reflect use in later-line settings, and relatively few patients received doses below the approved dose of 200 mg. This has prompted further evaluation of lower doses to determine if there is an improved safety profile without compromising efficacy. Additionally, enrollment of patients with treatment-naive CLL with del(17p) will further our clinical understanding of pirtobrutinib activity in this patient population and fill an important clinical gap. This ongoing phase 2, open-label, randomized study (NCT06588478) evaluates the efficacy and safety of 3 dose levels of pirtobrutinib in the R/R CLL/SLL population, and includes a separate cohort to evaluate pirtobrutinib in treatment naïve CLL/SLL patients with del(17p).

Methods: This multicenter, global study has two parts. In Part 1, approximately 249 previously treated patients with CLL/SLL will be randomly allocated across three different dose groups and stratified by del(17p) status (present vs absent) and number of lines of prior treatment (1 vs 2-3). Part 2 will enroll up to 100 patients with treatment-naive del(17p) CLL/SLL to receive pirtobrutinib at its approved dose (200 mg, once daily). Eligible patients must have a confirmed CLL/SLL diagnosis and a requirement for treatment per iwCLL 2018 criteria. Patients in Part 1 must have received 1-3 prior lines of therapy, including a cBTKi, and have known del(17p) status. Patients in Part 2 must be treatment-naive and must have del(17p). For both parts, exclusion criteria include central nervous system involvement by CLL/SLL, prior Richter transformation, prior treatment with a BTK degrader or non-covalent BTKi, or a hematopoietic stem cell transplant or chimeric antigen receptor T-cell therapy within 90 days of C1D1. Patients will receive pirtobrutinib continuously in this study until discontinuation criteria are met, including disease progression, withdrawal of consent, requirement for alternative anticancer therapy, or safety reasons per investigator judgement.

For Part 1, the primary endpoint is investigator-assessed overall response rate (ORR) per iwCLL 2018 criteria for each of the three dose levels. Secondary endpoints include investigator-assessed duration of response, and safety and tolerability. For Part 2, the primary endpoint is ORR assessed by an Independent Review Committee (IRC) per iwCLL 2018 criteria. Secondary endpoints include investigator-assessed ORR, investigator-assessed and IRC-assessed duration of response, and safety and tolerability. ORR is defined as the proportion of participants who achieve the best overall response of complete remission, complete remission with incomplete hematologic recovery, nodular partial remission, or partial remission at or before the initiation of subsequent anticancer therapy.

Results: This study is a Trial in Progress.