Page 101 - Haematologica Vol. 110 - January 2025

ARTICLE - Pirtobrutinib in patients with prior intolerance to BTKi N.N. Shah et al.
reasons for pirtobrutinib discontinuation were progressive disease (26.8%), AE (10.2%) or death (5.5%). The most frequent treatment-emergent AE were fatigue (39.4%) and neutropenia (37.0%). Among patients who discontinued a prior BTKi for a cardiac issue, 75% had no recurrence of their cardiac AE. No patient discontinued pirtobrutinib for the same AE that led to discontinuation of the prior BTKi. In 78 chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 21 mantle cell lymphoma (MCL) patients intolerant to prior BTKi, overall response rate to pirtobrutinib was 76.9% and 81.0%, respectively. Median progression-free survival for CLL/SLL was 28.4 months but was not estimable for MCL. These results suggest that pirtobrutinib was safe, well-tolerated, and an efficacious option in patients with prior BTKi-intolerance.
Introduction
Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) such as ibrutinib, acalabrutinib and zanubrutinib have changed the treatment landscape for patients with B-cell malignancies. These cBTKi are commonly administered as monotherapy using continuous dosing. However, a significant number of patients develop cBTKi intolerance due to therapy-limiting adverse events (AE) such as atrial fibrillation, bleeding, diar- rhea, rash, arthralgias, and infections.1,2 Real-world analyses have suggested that intolerance accounts for about half of discontinuations for patients treated with ibrutinib.3,4 AE that lead to BTKi discontinuation may limit efficacy, as continued inhibition of the B-cell receptor signaling path- way is key to its mechanism of action. Similarly, treatment interruptions and dose reductions due to AE may further reduce efficacy and impact long-term outcomes.5 The tox- icity profile of cBTKi agents has largely been attributed to the variable selectivity for BTK and binding to off-target ki- nases that leads to adverse off-target events.1,2,6 The binding of cBTKi agents, for example, to epidermal growth factor receptor (EGFR) may lead to diarrhea and rash, whereas off-target tec protein tyrosine kinase (TEC) inhibition may lead to platelet dysfunction and bleeding.2 Although later generation cBTKi appear to be more selective than ibruti- nib, leading to a more favorable toxicity profile, intolerance still remains a concern. Phase II studies have examined acalabrutinib and zanubrutinib, which have been shown to have improved selectivity compared to ibrutinib, in patients that have demonstrated intolerance to a previous cBTKi. Despite improved toxicity profiles with reduced rates of recurrence of AE after intolerance to another cBTKi, ther- apy with these agents also resulted in some toxicity. For patients who received acalabrutinib after prior ibrutinib in- tolerance, 27 ibrutinib intolerance events occurred in 24/60 (40%) acalabrutinib-treated patients, with 18 events at a lower grade, 8 events at the same grade, and one event at a higher grade with acalabrutinib than had been observed with ibrutinib.7 In addition, 7/34 ibrutinib intolerance events and 2/3 acalabrutinib events still recurred with a thera- peutic switch to zanubrutinib.8 Discontinuations after prior cBTKi intolerance due to AE occurred in 16.7% of patients that received acalabrutinib and in up to 20% of those who transitioned to zanubrutinib.7,8
Pirtobrutinib is a highly selective non-covalent (reversible)
BTKi with favorable oral pharmacology that enables con- tinuous BTK inhibition throughout the once daily dosing interval, regardless of intrinsic rate of BTK turnover. It has greater than 300-fold selectivity for BTK compared to 363 (98%) of 370 other kinases tested, thereby potentially lowering the risk of off-target toxicities.9 Data also suggest that pirtobrutinib binding enhances the stability of BTK in its closed, inactive conformation whereas cBTKi binding favors the open active conformation.10 The inactive BTK conformation by pirtobrutinib binding may interact with fewer cellular proteins than cBTKi-bound BTK, thereby inhibiting kinase-independent BTK cellular signaling, and potentially limiting toxicity.10 Pirtobrutinib selectivity for BTK has translated into a tolerable safety profile across multi- ple B-cell malignancies, with low overall treatment-related AE and few discontinuations due to drug-related AE: 2.8% in patients with chronic lymphocytic / small lymphocytic lymphoma (CLL/SLL) and 3% in patients with relapsed / refractory mantle cell lymphoma (MCL).11,12 In January 2023, pirtobrutinib received accelerated approval in the USA to treat relapsed or refractory MCL after at least 2 lines of systemic therapy including prior BTKi treatment.13 On De- cember 1, 2023, the US Food and Drug Administration (FDA) granted accelerated approval to pirtobrutinib for adults with CLL/SLL who have received at least 2 prior lines of therapy, including a BTK inhibitor and a BCL2 inhibitor.14 Here we explored the safety and efficacy of pirtobrutinib in patients from the phase I/II BRUIN study who had previ- ously demonstrated intolerance to BTKi therapy and were without progressive disease.
Methods
Patients
Patients previously treated for CLL/SLL, MCL, and other B-cell non-Hodgkin lymphoma (NHL) were enrolled in the open-label, multi-center phase I/II BRUIN study.9,11 Patients received pirtobrutinib at doses ranging from 25 to 300 mg once daily in 28-day cycles in the phase I portion, and the recommended dose of 200 mg once daily in the phase II portion. The BRUIN study permitted enrollment of patients with ongoing anti-coagulation / anti-platelet treatment (ex- cluding warfarin) and patients with controlled atrial fibril- lation at the time of enrollment. Patients with a history of
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