Introduction: Patients with CLL/SLL commonly receive a covalent Bruton tyrosine kinase inhibitor (cBTKi) as 1L therapy. However, most patients treated with a cBTKi eventually experience disease progression or treatment intolerance, ultimately requiring 2L therapy. Pirtobrutinib is a highly selective, noncovalent BTKi that inhibits BTK with low nanomolar potency throughout the once-daily dosing interval. Pirtobrutinib showed promising safety and efficacy in the phase 1/2 BRUIN LOXO-BTK-18001 study (NCT03740529), which was confirmed in the phase 3 BRUIN CLL-321 study (NCT04666038). Both studies were conducted in a broad population of patients with relapsed/refractory (R/R) CLL/SLL, including those who previously received a cBTKi. Pirtobrutinib is approved in the European Union for the treatment of adults with R/R CLL after prior treatment with a BTKi and for adults in the United States with CLL/SLL who have received ≥2 lines of prior therapy, including a BTKi and a BCL-2 inhibitor (BCL2i). Here, we report the safety and efficacy of pirtobrutinib for patients with 2L CLL/SLL previously treated with 1L cBTKi therapy and no prior exposure to a BCL2i, using pooled data from the LOXO-BTK-18001 and CLL-321 studies.

Methods: This pooled analysis from the LOXO-BTK-18001 and CLL-321 studies included BCL2i-naïve patients with CLL/SLL who received 2L pirtobrutinib monotherapy after 1L therapy with a cBTKi, with or without an anti-CD20 antibody. Progression-free survival (PFS) based on investigator assessment using iwCLL 2018 criteria, overall survival (OS), time to next treatment (TTNT), and safety data were analyzed.

Results: All 37 eligible patients (LOXO-BTK-18001, N=17; CLL-321, N=20) received pirtobrutinib 200 mg once daily and received prior cBTKi treatment with ibrutinib (76%), acalabrutinib (14%), zanubrutinib (8%), or other cBTKi treatment (3%). Four patients (11%) also receivedan anti-CD20 antibody. The median age of patients was 69 years (range, 42–87). Among patients with evaluable samples, 22 of 26 (85%) had unmutated IGHV gene, 11 of 17 (65%) had complex karyotype (≥3 abnormalities), 13 of 30 (43%) had mutated TP53, and 15 of 31 (48%) had del(17p). Patients discontinued their prior cBTKi therapy due to disease progression (57%), toxicity (35%), or other reasons (8%). With a median follow-up of 30.3 months, median PFS was 19.5 months (95% confidence interval [CI], 11.7–44.7). For patients who discontinued their previous cBTKi due to disease progression (n=21), median PFS was 13.9 months (95% CI, 7.4–19.5) and for those who discontinued due to toxicity (n=13), median PFS was 44.7 months (95% CI, 10.6–not estimable). For all patients, median TTNT was 32.5 months (95% CI, 16.6–47.4). Median OS was not reached; the 24-month OS rate was 81.1% (95% CI, 61.9–91.3).

Median time on treatment was 17.6 months (range, 0.9–57.2), and 13 patients (35%) remained on pirtobrutinib at data cutoff. Thirty-sixpatients (97%) experienced ≥1 treatment-emergent adverse event (TEAE) of any grade. The most frequent TEAEs were anemia (27%), neutropenia/neutrophil count decreased (24%), hemorrhage/hematoma (22%), and pneumonia (22%). Grade ≥3 TEAEs occurred in 68% of patients. Four patients experienced grade 5 events of COVID-19 pneumonia (n=1), pneumonia legionella (n=1), and pneumonia (n=2), none of which were treatment-related. Any-grade TEAEs of atrial fibrillation/flutter occurred in 1 patient (grade 3–4), hypertension in 5 patients (grade 3–4, n=4; grade 1–2, n=1), and hemorrhage in 8 patients (grade 1–2, n=6; grade 3, n=1; grade 4, n=1). Treatment-related AEs (TRAEs) led to pirtobrutinib dose reductions in 3 patients. TRAEs led to pirtobrutinib discontinuation in 2 patients: grade 3 erythema and stomatitis (n=1), and grade 3 lymphocyte count increased (n=1).

Conclusions: Pirtobrutinib demonstrated clinical benefit and tolerability in patients with 2L CLL/SLL previously treated with a cBTKi, including those with high-risk genetic features. These findings support the potential use of pirtobrutinib as a 2L therapy option after 1L cBTKi use and may help inform future treatment sequencing strategies.

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2025
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