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

Introduction: 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 non-covalent 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. Here we report the safety and efficacy of pirtobrutinib in previously treated pts with RT. Methods: Pts with previously treated RT were enrolled to either the dose escalation or expansion portion of the phase 1/2 BRUIN study (NCT03740529). The primary endpoint for this analysis was ORR per Lugano criteria. A key secondary endpoint was 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 ≥1 prior RT directed therapy, and the median number of prior RT directed 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 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 initial response assessment. No new safety signals were identified in RT pts. Since data cut, 8 additional prior 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. EA – previously submitted to EHA 2021. The research was funded by: Loxo Oncology at Lilly Keywords: Aggressive B-cell non-Hodgkin lymphoma, Chronic Lymphocytic Leukemia (CLL), Molecular Targeted Therapies Conflicts of interests pertinent to the abstract W. Jurczak Research funding: Loxo Oncology, Janssen, AstraZeneca, Beigene N. N. Shah Other remuneration: Loxo Oncology N. Lamanna Research funding: Loxo Oncology T. A. Eyre Other remuneration: Loxo Oncology J. Woyach Other remuneration: Loxo Oncology D. Wang Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly M. Yin Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly M. Balbas Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly B. C. Nair Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly E. Y. Zhu Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly D. E. Tsai Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly N. C. Ku Employment or leadership position: Loxo Oncology at Lilly Stock ownership: Loxo Oncology at Lilly C. C. Coombs Honoraria: Loxo Oncology Research funding: Loxo Oncology Other remuneration: Loxo Oncology A. R. Mato Consultant or advisory role: TG Therapeutics, Verastem Research funding: Loxo Oncology, Genentech, Abbvie, AstraZeneca, Adaptive, Pharmacyclics, Curio Sciences, Sunesis, Regeneron, Pfizer, Aprea, Aptose, Verastem, and DTRM Other remuneration: Loxo Oncology, Genentech, Abbvie, AstraZeneca, Adaptive, Pharmacyclics, and Curio Sciences

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