PIRTOBRUTINIB (LOXO-305), A NEXT GENERATION, HIGHLY SELECTIVE, NON-COVALENT BTK INHIBITOR IN PREVIOUSLY TREATED CLL/SLL: RESULTS FROM THE PHASE 1/2 BRUIN STUDY
Author(s): ,
Lindsey Roeker
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, New York,United States
,
John M. Pagel
Affiliations:
Swedish Cancer Institute,Seattle, Washington,United States
,
Catherine C. Coombs
Affiliations:
University of North Carolina at Chapel Hill,Chapel Hill,United States
,
Nirav N. Shah
Affiliations:
Medical College of Wisconsin,Brookfield, Wisconsin,United States
,
Nicole Lamanna
Affiliations:
Herbert Irving Comprehensive Cancer Center, Columbia University,Columbia, New York,United States
,
Ewa Lech-Maranda
Affiliations:
Institute of Hematology and Transfusion Medicine,Warsaw,Poland
,
Toby A Eyre
Affiliations:
Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center,Oxford,United Kingdom
,
Jennifer A Woyach
Affiliations:
The Ohio State University Comprehensive Cancer Center,Columbus, Ohio,United States
,
William G Wierda
Affiliations:
MD Anderson Cancer Center,Houston, Texas,United States
,
Chan Y. Cheah
Affiliations:
Linear Clinical Research and Sir Charles Gairdner Hospital,Perth,Australia
,
Manish R. Patel
Affiliations:
Florida Cancer Specialists/Sarah Cannon Research Institute,Sarasota, Florida,United States
,
Bita Fakhri
Affiliations:
University of California San Francisco,San Francisco, California,United States
,
Minal A. Barve
Affiliations:
Mary Crowley Cancer Research,Dallas, Texas,United States
,
Constantine S. Tam
Affiliations:
Peter MacCallum Cancer Center, Royal Melbourne Hospital, and University of Melbourne,Melbourne,Australia
,
David Lewis
Affiliations:
Plymouth Hospitals NHS Trust – Derriford Hospital,Plymouth,United Kingdom
,
James N. Gerson
Affiliations:
Lymphoma Program, Abramson Cancer Center, University of Pennsylvania,Philadelphia, Pennsylvania,United States
,
Alvaro Alencar
Affiliations:
University of Miami Miller School of Medicine,Miami, Florida,United States
,
Justin Taylor
Affiliations:
University of Miami Miller School of Medicine,Miami, Florida,United States
,
Omar Abdel-Wahab
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, New York,United States
,
Paolo Ghia
Affiliations:
Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele,Milan,Italy
,
Stephen J. Schuster
Affiliations:
Lymphoma Program, Abramson Cancer Center, University of Pennsylvania,Philadelphia, Pennsylvania,United States
,
Jessica Chen
Affiliations:
Eli Lilly and Company,Indianapolis, Indiana,United States
,
Binoj Nair
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
,
Matthew S. Davids
Affiliations:
Dana-Farber Cancer Institute and Harvard Medical School,Boston, Massachusetts,United States
,
Jennifer R. Brown
Affiliations:
Dana-Farber Cancer Institute and Harvard Medical School,Boston,United States
,
Wojciech Jurczak
Affiliations:
Maria Sklodowska-Curie National Research Institute of Oncology,Krakow,Poland
Anthony R. Mato
Affiliations:
Memorial Sloan Kettering Cancer Center,New York, New York,United States
EHA Library. Roeker L. 06/09/21; 325393; EP633
Lindsey Roeker
Lindsey Roeker
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: EP633

Type: E-Poster Presentation

Session title: Chronic lymphocytic leukemia and related disorders - Clinical

Background
Despite the marked efficacy of covalent BTK inhibitors (BTKi) in CLL/SLL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Moreover, pharmacological liabilities of these agents such as low oral bioavailability or short half-life can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). To address these limitations, pirtobrutinib (LOXO-305), a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal low nM potency was developed.

Aims
To evaluate safety and efficacy of pirtobrutinib in previously treated CLL/SLL.

Methods
BRUIN is a multicenter phase 1/2 trial (NCT03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Oral pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary endpoint was MTD/RP2D identification. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Safety was assessed in all pts (n=323). Response was assessed according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L).

Results
As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25-300mg QD). Among the 170 CLL/SLL pts, the median age was 69 (range 36-84) years. Median number of prior lines of therapies was 3 (range 1-11), 86% of CLL/SLL pts had received a prior BTKi, and 67% an anti-CD20 antibody, chemotherapy, and BTKi; 21% had received a PI3K inhibitor and 34% venetoclax. At enrollment, high risk features such as 17p deletion were present in 25% (20/81), TP53 mutation in 30% (27/91), and unmutated IGHV in 88% (71/81). Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. Consistent with pirtobrutinib’s selectivity, the only treatment-emergent adverse events regardless of attribution or grade seen in >10% of pts (n=323) were fatigue (20%), diarrhea (17%) and contusion (13%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 150 CLL/SLL pts remained on therapy and 139 were efficacy evaluable (121 BTKi-treated). Median follow-up was 6 months (range 0.6-17.8+) for efficacy evaluable pts. The ORR was 63% with 69 PRs, 19 PR-Ls, 45 SDs, 1 PD, and 5 discontinued prior to first response assessment (Figure). An additional 37 pts were ongoing and awaiting initial radiologic assessment. Responses deepened over time; among pts with at least 10 months of follow-up (n=29), the ORR was 86%. ORR was not influenced by the reason for prior BTKi discontinuation (i.e. progression vs intolerance), or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor). Of the 88 responding pts, all except 5 remain on therapy (4 progressed, and 1 achieved a PR and electively discontinued). The longest followed responding pt continues on treatment for 17.8+ months.

Conclusion
Pirtobrutinib demonstrated promising efficacy in CLL/SLL pts following multiple prior lines of therapy including a covalent BTKi and a BCL2 inhibitor. Importantly, the activity of pirtobrutinib was not restricted to pts with BTK C481 mutations. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index.

Keyword(s): Chronic lymphocytic leukemia, Clinical trial, 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: EP633

Type: E-Poster Presentation

Session title: Chronic lymphocytic leukemia and related disorders - Clinical

Background
Despite the marked efficacy of covalent BTK inhibitors (BTKi) in CLL/SLL, the development of resistance and discontinuation for adverse events can lead to treatment failure. Moreover, pharmacological liabilities of these agents such as low oral bioavailability or short half-life can lead to suboptimal BTK target coverage and ultimately result in acquired resistance in some patients (pts). To address these limitations, pirtobrutinib (LOXO-305), a highly selective, non-covalent BTKi that inhibits both WT and C481-mutated BTK with equal low nM potency was developed.

Aims
To evaluate safety and efficacy of pirtobrutinib in previously treated CLL/SLL.

Methods
BRUIN is a multicenter phase 1/2 trial (NCT03740529) enrolling pts with advanced B-cell malignancies who have received >2 prior therapies. Oral pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary endpoint was MTD/RP2D identification. Efficacy evaluable pts included all dosed pts who underwent their first response evaluation or discontinued therapy. Safety was assessed in all pts (n=323). Response was assessed according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L).

Results
As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, and 66 other B-cell lymphomas) were treated on 7 dose levels (25-300mg QD). Among the 170 CLL/SLL pts, the median age was 69 (range 36-84) years. Median number of prior lines of therapies was 3 (range 1-11), 86% of CLL/SLL pts had received a prior BTKi, and 67% an anti-CD20 antibody, chemotherapy, and BTKi; 21% had received a PI3K inhibitor and 34% venetoclax. At enrollment, high risk features such as 17p deletion were present in 25% (20/81), TP53 mutation in 30% (27/91), and unmutated IGHV in 88% (71/81). Pirtobrutinib demonstrated high oral exposures, with doses ≥100mg QD exceeding the BTK IC90 for the entirety of the dosing interval. No DLTs occurred. Consistent with pirtobrutinib’s selectivity, the only treatment-emergent adverse events regardless of attribution or grade seen in >10% of pts (n=323) were fatigue (20%), diarrhea (17%) and contusion (13%). Responses were observed at the first dose level of 25mg QD. A RP2D of 200mg QD was selected for future studies. At the efficacy cutoff date, 150 CLL/SLL pts remained on therapy and 139 were efficacy evaluable (121 BTKi-treated). Median follow-up was 6 months (range 0.6-17.8+) for efficacy evaluable pts. The ORR was 63% with 69 PRs, 19 PR-Ls, 45 SDs, 1 PD, and 5 discontinued prior to first response assessment (Figure). An additional 37 pts were ongoing and awaiting initial radiologic assessment. Responses deepened over time; among pts with at least 10 months of follow-up (n=29), the ORR was 86%. ORR was not influenced by the reason for prior BTKi discontinuation (i.e. progression vs intolerance), or other classes of prior therapy received (including a covalent BTK and a BCL2 inhibitor). Of the 88 responding pts, all except 5 remain on therapy (4 progressed, and 1 achieved a PR and electively discontinued). The longest followed responding pt continues on treatment for 17.8+ months.

Conclusion
Pirtobrutinib demonstrated promising efficacy in CLL/SLL pts following multiple prior lines of therapy including a covalent BTKi and a BCL2 inhibitor. Importantly, the activity of pirtobrutinib was not restricted to pts with BTK C481 mutations. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index.

Keyword(s): Chronic lymphocytic leukemia, Clinical trial, Phase I/II, Targeted therapy

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