PIRTOBRUTINIB (LOXO‐305), A NEXT GENERATION HIGHLY SELECTIVE NON‐COVALENT BTK INHIBITOR IN PREVIOUSLY TREATED RICHTER TRANSFORMATION: RESULTS FROM THE PHASE 1/2 BRUIN STUDY

Abstract

Background: Richter transformation (RT) is the development of an aggressive large cell lymphoma in the setting of underlying CLL and is a recurrent reason for treatment failure (5-15%) among patients (pts) receiving CLL-directed therapy. Outcomes for pts with relapsed RT are extremely poor, with no standard treatment and overall survival estimated at 5-8 months. Pirtobrutinib is a highly selective and potent noncovalent BTK inhibitor (BTKi) with high oral bioavailability and a long half-life, resulting in robust BTK target coverage even in high-grade malignancies with high BTK protein turnover. Aim: To evaluate pirtobrutinib safety and efficacy in previously treated pts with RT. Methods: Pts with previously treated RT were enrolled to either the dose escalation or expansion portion of the multicenter phase 1/2 BRUIN study (NCT03740529). The primary endpoint for this analysis was ORR according to Lugano criteria. A key secondary endpoint was the duration of response. Efficacy evaluable pts included all dosed RT pts who underwent their first response evaluation or discontinued therapy as of the data cut. Results: As of 27 September 2020, 323 pts with B-cell malignancies were treated including 9 pts with previously treated RT (8 of 9 RT pts received the RP2D of 200mg QD, 1 pt received 150mg QD). All 9 pts had received at least one prior RT-directed therapy, and the median number of prior RTdirected therapies was 2 (range 1-5). Pts had received a median of 4 prior lines of therapy for CLL (range 0-6). Prior RT directed therapies included chemoimmunotherapy (100%, n=9), covalent BTKi (44%, n=4), anti-PD-1 or PD-L1 antibody (33%, n=3), mTOR inhibitor (22%, n=2), PI3K inhibitor (22%, n=2), CAR-T cell therapy (n=1), autologous stem cell transplant (n=1), polatuzumab vedotin (n=1), and pomalidomide (n=1). The ORR for the 8 efficacy evaluable pts was 75% with 6 PR, 1 SD, and 1 NE. These 8 pts have been on treatment for 1.6, 2.3, 2.9+, 2.9+, 3.2+, 3.7, 6.4+, and 7.1+ months (+ indicates ongoing). The remaining pt continues on treatment and is awaiting an initial response assessment. No new safety signals were identified in RT pts. Since the data cut, eight additional previously treated pts with RT have been enrolled. Updated data with additional follow-up in all 17 RT pts will be presented. Conclusion: Pirtobrutinib showed promising initial efficacy in pts with pretreated RT with extremely poor prognosis, including in pts who had received prior chemoimmunotherapy and covalent BTK inhibitors.