Abstract CT167: Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study
Authors: Rhodes Joanna , Lewis David , Ghia Paolo , Shah Nirav N. , Coombs Catherine C. , Cheah Chan Y. , Woyach Jennifer , Lamanna Nicole , Hoffmann Marc S. , Ma Shuo , Eyre Toby A. , Munir Talha , Patel Manish R. , Alencar Alvaro J. , Tam Constantine S. , Seymour John F. , Jurczak Wojciech , Lech-Maranda Ewa , Roeker Lindsey E. , Thompson Philip A. , Abada Paolo B. , Wang Chunxiao , Nair Binoj , Liu Hui , Tsai Donald E. , Mato Anthony R. , Wierda William G. 
Published: April 2023

Abstract
Background: Richter transformation (RT) is an aggressive diffuse large B-cell lymphoma that can occur in 10% of patients with chronic lymphocytic leukemia (CLL). RT has no approved therapies, poor prognosis, and an estimated median overall survival (OS) of 3-11 months. Pirtobrutinib is a well-tolerated highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi) with favorable oral pharmacology and promising efficacy in patients with poor-prognosis B-cell malignancies following prior covalent BTKi therapy. We now report on RT patients from BRUIN.
Methods: Patients previously treated for B-cell malignancies were eligible for pirtobrutinib monotherapy in dose escalation/expansion within the phase 1/2 BRUIN study. Key endpoints: investigator-assessed overall response rate (ORR) and duration of response (DoR) per Lugano 2014 criteria, and safety. The response-evaluable cohort consisted of patients with RT who completed either first response assessment or discontinued therapy. The safety cohort consisted of patients who received ≥1 dose of pirtobrutinib monotherapy (n=725). Data cut was 31 January 2022.
Results: Of 57 RT patients (median age: 67 years), 91% (n=52) received at least 1 prior RT-directed therapy. Median lines of prior RT therapy were 2: (anti-CD20 antibody [86%, n=49], chemotherapy [79%, n=45], BCL-2 inhibitor [35%, n=20], BTKi [28%, n=16], PI3K inhibitor [12%, n=7], CAR-T [9%, n=5], immunomodulator [5%, n=3], stem cell transplant [4%, n=2], other systemic therapy [33%, n=19]) and median lines of prior CLL were 2: (BTKi [60%, n=34], anti-CD20 antibody [60%, n=34], chemotherapy [47%, n=27], BCL-2 inhibitor [42%, n=24], immunomodulator [9%, n=5], PI3K inhibitor [7%, n=4], stem cell transplant [7%, n=4], CAR-T [2%, n=1], other systemic therapy [11%, n=6]). ORR for patients within phase 2 (n=56, 200mg once/day starting dose) was 54% (95% CI, 39-68): 5 complete responses, 22 partial responses. Median DoR was 8.6 months (95% CI, 1.9-NE, 63% censored) and median OS was 13.1 months (95% CI, 7.1-NE) at a median follow up time of 5.5 months and 9.7 months respectively. Six patients electively discontinued pirtobrutinib to pursue curative-intent therapy (allogeneic transplant, n=6, 3.8 months median time-on-therapy). The most frequent TEAEs were fatigue (26%, n=191), diarrhea (22%, n=160), and contusion (19%, n=138). Of Grade≥3 TEAEs, neutropenia (20%, n=143) was the most frequent and hypertension (3%, n=20), hemorrhage (2%, n=16), and atrial fibrillation/flutter (1%, n=7) were of low grade. Fifteen (2%) patients discontinued due to a treatment-related AE.
Conclusions: Pirtobrutinib demonstrated promising preliminary efficacy and was well tolerated for patients who received prior RT-directed chemoimmunotherapy and covalent BTKi. Presented:ASH2022.
Citation Format: Joanna Rhodes, David Lewis, Paolo Ghia, Nirav N. Shah, Catherine C. Coombs, Chan Y. Cheah, Jennifer Woyach, Nicole Lamanna, Marc S. Hoffmann, Shuo Ma, Toby A. Eyre, Talha Munir, Manish R. Patel, Alvaro J. Alencar, Constantine S. Tam, John F. Seymour, Wojciech Jurczak, Ewa Lech-Maranda, Lindsey E. Roeker, Philip A. Thompson, Paolo B. Abada, Chunxiao Wang, Binoj Nair, Hui Liu, Donald E. Tsai, Anthony R. Mato, William G. Wierda. Efficacy of pirtobrutinib, a highly selective, non-covalent (reversible) BTK inhibitor in Richter transformation: Results from the phase 1/2 BRUIN study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT167.