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
Author(s): ,
Anthony R. Mato
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, New York,United States
,
Nirav N. Shah
Affiliations:
Medical College of Wisconsin,Brookfield, Wisconsin,United States
,
Nicole Lamanna
Affiliations:
Herbert Irving Comprehensive Cancer Center, Columbia University,New York, New York,United States
,
Toby A. Eyre
Affiliations:
Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center,Oxford,United Kingdom
,
Wojciech Jurczak
Affiliations:
Maria Sklodowska-Curie National Research Institute of Oncology,Krakow,Poland
,
Jennifer A. Woyach
Affiliations:
The Ohio State University Comprehensive Cancer Center,Columbus, Ohio,United States
,
Ewa Lech-Maranda
Affiliations:
Institute of Hematology and Transfusion Medicine,Warsaw,Poland
,
William G. Wierda
Affiliations:
MD Anderson Cancer Center,Houston, Texas,United States
,
David Lewis
Affiliations:
Plymouth Hospitals NHS Trust – Derriford Hospital,Plymouth,United Kingdom
,
Meghan C. Thompson
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, New York,United States
,
Denise Wang
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
,
Ming Yin
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
,
Minna Balbas
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
,
Binoj C. Nair
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
,
Edward Y. Zhu
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
,
Donald E. Tsai
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
,
Nora C. Ku
Affiliations:
Loxo Oncology at Lilly,Stamford, Connecticut,United States
Catherine C. Coombs
Affiliations:
University of North Carolina at Chapel Hill,Chapel Hill, North Carolina,United States
EHA Library. R. Mato A. 06/09/21; 325284; EP524
Anthony R. Mato
Anthony R. Mato
Contributions
Abstract
Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP524

Type: E-Poster Presentation

Session title: Aggressive Non-Hodgkin lymphoma - Clinical

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 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.

Aims
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 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 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 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 initial response assessment. No new safety signals were identified in RT pts. Since data cut, 8 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.

Keyword(s): B cell lymphoma, Chronic lymphocytic leukemia, Phase I/II, Targeted therapy

Presentation during EHA2021: All e-poster presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: EP524

Type: E-Poster Presentation

Session title: Aggressive Non-Hodgkin lymphoma - Clinical

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 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.

Aims
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 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 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 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 initial response assessment. No new safety signals were identified in RT pts. Since data cut, 8 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.

Keyword(s): B cell lymphoma, Chronic lymphocytic leukemia, Phase I/II, Targeted therapy

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