Background: Covalent Bruton's tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Two covalent BTKi, ibrutinib and acalabrutinib, are currently approved for CLL/SLL and a third, zanubrutinib, is pending review. Covalent BTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life), which collectively may lead to suboptimal BTK target coverage (Wang et al. Blood 2021;138:381), ultimately manifesting as acquired resistance in some patients (Mato et al. Lancet 2021;397:892-901). Additionally, tolerability issues limit long-term dose intensity and may compromise efficacy. Novel agents that address both intolerance and resistance while also improving efficacy are needed. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with CLL/SLL regardless of prior therapy (including covalent BTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior covalent BTKi discontinuation (Mato et al. Lancet 2021;397:892-901). Based on the efficacy of pirtobrutinib in patients previously treated with covalent BTKi, we hypothesized that pirtobrutinib could be a more effective BTKi when used as initial BTK therapy. In this global, phase 3, open-label, randomized study, we aim to compare the efficacy and tolerability of pirtobrutinib vs ibrutinib in patients with CLL/SLL.

Study Design and Methods: BRUIN CLL-314 is a global, phase 3, open-label, randomized study comparing pirtobrutinib with ibrutinib. Approximately 650 BTKi-naïve patients, either treatment-naïve or previously treated with other agents, will be randomized 1:1 to receive daily 200 mg pirtobrutinib (recommended phase 2 dose from the BRUIN study) or 420 mg ibrutinib as continuous monotherapy. Randomization will be stratified by del(17p) status (present vs not present) and number of prior lines of therapy (0 vs 1 vs ≥2). Eligible patients are adults ≥18 years with a CLL/SLL diagnosis and requirement for therapy per International Workshop on Chronic Lymphocytic Leukemia (iwCLL) 2018 criteria. Key exclusion criteria include prior exposure to BTKi, use of certain concomitant therapeutics including anticoagulants such as warfarin and other vitamin K antagonists, significant cardiovascular disease, active infections, and other clinically significant conditions. The primary objective is to establish non-inferiority of pirtobrutinib vs ibrutinib by comparing the ORR in accordance with iwCLL guidelines assessed by an independent review committee. Superiority of pirtobrutinib vs ibrutinib in event-free survival and progression-free survival are key secondary objectives. Other endpoints include duration of response, overall survival, time-to-next treatment, safety and tolerability, and patient-reported outcomes. Trial efficacy and safety will be monitored by an independent data monitoring committee. This global study is currently enrolling patients (NCT05254743).

Woyach:MorphoSys: Consultancy, Research Funding; Karyopharm Therapeutics: Research Funding; ArQule: Consultancy; Schrodinger: Research Funding; Janssen: Consultancy; Genentech: Consultancy; AstraZeneca: Consultancy; Loxo@Lilly: Research Funding; BeiGene: Consultancy; AbbVie: Consultancy, Research Funding; Pharmacyclics: Consultancy; Newave: Consultancy. Wierda:Xencor: Research Funding; Sunesis: Research Funding; Pharmacyclics LLC: Research Funding; Janssen: Research Funding; AbbVie: Research Funding; AstraZeneca/Acerta Pharma. Inc.: Research Funding; Cyclacel: Research Funding; Genentech: Research Funding; Juno: Research Funding; Sanofi: Consultancy; Karyopharm: Research Funding; Genzyme: Consultancy; Gilead Sciences: Research Funding; Miragen: Research Funding; Bristol Meyers Squibb (Juno and Celgene): Research Funding; Kite, a Gilead Company: Research Funding; Loxo Oncology, Inc./Lilly: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; GSK/Novartis: Research Funding. Coombs:TG Therapeutics: Honoraria; Loxo/Lilly: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Speakers Bureau; AstraZeneca: Consultancy, Honoraria; MEI Pharma: Honoraria; Genentech: Consultancy, Honoraria; Novartis: Honoraria; CTI Biopharma: Current equity holder in publicly-traded company; Beigene: Consultancy, Honoraria. Lewis:Janssen: Honoraria, Patents & Royalties; Loxo-Lilly: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Novartis: Patents & Royalties; Roche: Consultancy, Honoraria; IQVIA: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy, Honoraria. Gribben:Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Gilead Sciences: Consultancy, Honoraria; Morphosys AG: Consultancy; AstraZeneca: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; European Hematological Association: Membership on an entity's Board of Directors or advisory committees. Escalon:Loxo Oncology: Current Employment, Current equity holder in publicly-traded company. Ceccarelli:Loxo Oncology: Current Employment, Current equity holder in publicly-traded company. Wu:Loxo Oncology: Current Employment, Current equity holder in publicly-traded company. Mato:Adaptive Biotechnologies: Honoraria; Johnson & Johnson: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; DTRM Biopharma: Honoraria, Research Funding; Nurix: Research Funding; LOXO: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Pharmacyclics, LLC: Honoraria, Research Funding; TG Therapeutics, Inc: Honoraria, Research Funding; BeiGene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Octopharma: Honoraria, Research Funding; Pfizer: Research Funding; Curio: Honoraria; Dava: Honoraria; BMS: Honoraria; Medscape: Honoraria; Acerta: Research Funding; PER: Honoraria; PerView: Honoraria.

We will be presenting data from the BRUIN trial. Pirtobrutinib is not approved yet.

Author notes

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Asterisk with author names denotes non-ASH members.

© 2022 by The American Society of Hematology
2022
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