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PIRTOBRUTINIB, A HIGHLY SELECTIVE, NON-COVALENT (REVERSIBLE) BTK INHIBITOR IN PREVIOUSLY TREATED CLL/SLL: UPDATED RESULTS FROM THE PHASE 1/2 BRUIN STUDY
Author(s): ,
Anthony R. Mato
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,États-unis;Memorial Sloan Kettering Cancer Center,New York,Vereinigte Staaten;Memorial Sloan Kettering Cancer Center,New York,Stati Uniti;Memorial Sloan Kettering Cancer Center,New York,United States;Memorial Sloan Kettering Cancer Center,New York,Estados Unidos;Memorial Sloan Kettering Cancer Center,New York,Verenigde Staten;Memorial Sloan Kettering
,
John M. Pagel
Affiliations:
Loxo Oncology at Lilly,Stamford,États-unis;Loxo Oncology at Lilly,Stamford,Vereinigte Staaten;Loxo Oncology at Lilly,Stamford,Stati Uniti;Loxo Oncology at Lilly,Stamford,United States;Loxo Oncology at Lilly,Stamford,Estados Unidos;Loxo Oncology at Lilly,Stamford,Verenigde Staten;Loxo Oncology at Lilly,Stamford,Estados Unidos;Loxo Oncology at Lilly,Stamford,United States;Loxo Oncology at Lilly,Stam
,
Catherine C. Coombs
Affiliations:
University of North Carolina at Chapel Hill,Chapel Hill,États-unis;University of North Carolina at Chapel Hill,Chapel Hill,Vereinigte Staaten;University of North Carolina at Chapel Hill,Chapel Hill,Stati Uniti;University of North Carolina at Chapel Hill,Chapel Hill,United States;University of North Carolina at Chapel Hill,Chapel Hill,Estados Unidos;University of North Carolina at Chapel Hill,Chape
,
Nirav N. Shah
Affiliations:
Medical College of Wisconsin,Milwaukee,États-unis;Medical College of Wisconsin,Milwaukee,Vereinigte Staaten;Medical College of Wisconsin,Milwaukee,Stati Uniti;Medical College of Wisconsin,Milwaukee,United States;Medical College of Wisconsin,Milwaukee,Estados Unidos;Medical College of Wisconsin,Milwaukee,Verenigde Staten;Medical College of Wisconsin,Milwaukee,Estados Unidos;Medical College of Wisco
,
Nicole Lamanna
Affiliations:
Herbert Irving Comprehensive Cancer Center, Columbia University,New York,États-unis;Herbert Irving Comprehensive Cancer Center, Columbia University,New York,Vereinigte Staaten;Herbert Irving Comprehensive Cancer Center, Columbia University,New York,Stati Uniti;Herbert Irving Comprehensive Cancer Center, Columbia University,New York,United States;Herbert Irving Comprehensive Cancer Center, Columbia
,
Talha Munir
Affiliations:
Haematology,St. James's University Hospital,Leeds,Royaume-uni;Haematology,St. James's University Hospital,Leeds,Vereinigtes Königreich;Haematology,St. James's University Hospital,Leeds,Regno Unito;Haematology,St. James's University Hospital,Leeds,United Kingdom;Haematology,St. James's University Hospital,Leeds,Reino Unido;Haematology,St. James's University Hospital,Leeds,Verenigd Koninkrijk;Haemat
,
Ewa Lech-Maranda
Affiliations:
Institute of Hematology and Transfusion Medicine,Warsaw,Pologne;Institute of Hematology and Transfusion Medicine,Warsaw,Polen;Institute of Hematology and Transfusion Medicine,Warsaw,Polonia;Institute of Hematology and Transfusion Medicine,Warsaw,Poland;Institute of Hematology and Transfusion Medicine,Warsaw,Polonia;Institute of Hematology and Transfusion Medicine,Warsaw,Polen;Institute of Hematolo
,
Toby A. Eyre
Affiliations:
Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center,Oxford,Royaume-uni;Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center,Oxford,Vereinigtes Königreich;Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center,Oxford,Regno Unito;Oxford University Hospitals NHS Foundation Trust, Churchill Cancer Center,Oxford,United Kingdom;Oxford Univers
,
Jennifer A. Woyach
Affiliations:
The Ohio State University Comprehensive Cancer Center,Columbus,États-unis;The Ohio State University Comprehensive Cancer Center,Columbus,Vereinigte Staaten;The Ohio State University Comprehensive Cancer Center,Columbus,Stati Uniti;The Ohio State University Comprehensive Cancer Center,Columbus,United States;The Ohio State University Comprehensive Cancer Center,Columbus,Estados Unidos;The Ohio State
,
William G. Wierda
Affiliations:
MD Anderson Cancer Center,Houston,États-unis;MD Anderson Cancer Center,Houston,Vereinigte Staaten;MD Anderson Cancer Center,Houston,Stati Uniti;MD Anderson Cancer Center,Houston,United States;MD Anderson Cancer Center,Houston,Estados Unidos;MD Anderson Cancer Center,Houston,Verenigde Staten;MD Anderson Cancer Center,Houston,Estados Unidos;MD Anderson Cancer Center,Houston,United States;MD Anderson
,
Chan Y. Cheah
Affiliations:
Linear Clinical Research and Sir Charles Gairdner Hospital,Perth,Australie;Linear Clinical Research and Sir Charles Gairdner Hospital,Perth,Australien;Linear Clinical Research and Sir Charles Gairdner Hospital,Perth,Australia;Linear Clinical Research and Sir Charles Gairdner Hospital,Perth,Australia;Linear Clinical Research and Sir Charles Gairdner Hospital,Perth,Australia;Linear Clinical Research
,
Jonathon B. Cohen
Affiliations:
Winship Cancer Institute, Emory University,Atlanta,États-unis;Winship Cancer Institute, Emory University,Atlanta,Vereinigte Staaten;Winship Cancer Institute, Emory University,Atlanta,Stati Uniti;Winship Cancer Institute, Emory University,Atlanta,United States;Winship Cancer Institute, Emory University,Atlanta,Estados Unidos;Winship Cancer Institute, Emory University,Atlanta,Verenigde Staten;Winshi
,
Lindsey E. Roeker
Affiliations:
Memorial Sloan Kettering Cancer Center,New York,États-unis;Memorial Sloan Kettering Cancer Center,New York,Vereinigte Staaten;Memorial Sloan Kettering Cancer Center,New York,Stati Uniti;Memorial Sloan Kettering Cancer Center,New York,United States;Memorial Sloan Kettering Cancer Center,New York,Estados Unidos;Memorial Sloan Kettering Cancer Center,New York,Verenigde Staten;Memorial Sloan Kettering
,
Manish R. Patel
Affiliations:
Florida Cancer Specialists/Sarah Cannon Research Institute,Sarasota,États-unis;Florida Cancer Specialists/Sarah Cannon Research Institute,Sarasota,Vereinigte Staaten;Florida Cancer Specialists/Sarah Cannon Research Institute,Sarasota,Stati Uniti;Florida Cancer Specialists/Sarah Cannon Research Institute,Sarasota,United States;Florida Cancer Specialists/Sarah Cannon Research Institute,Sarasota,Esta
,
Bita Fakhri
Affiliations:
University of California San Francisco ,San Francisco,États-unis;University of California San Francisco ,San Francisco,Vereinigte Staaten;University of California San Francisco ,San Francisco,Stati Uniti;University of California San Francisco ,San Francisco,United States;University of California San Francisco ,San Francisco,Estados Unidos;University of California San Francisco ,San Francisco,Veren
,
Minal A. Barve
Affiliations:
Mary Crowley Cancer Research,Dallas,États-unis;Mary Crowley Cancer Research,Dallas,Vereinigte Staaten;Mary Crowley Cancer Research,Dallas,Stati Uniti;Mary Crowley Cancer Research,Dallas,United States;Mary Crowley Cancer Research,Dallas,Estados Unidos;Mary Crowley Cancer Research,Dallas,Verenigde Staten;Mary Crowley Cancer Research,Dallas,Estados Unidos;Mary Crowley Cancer Research,Dallas,United St
,
Constantine Tam
Affiliations:
Peter MacCallum Cancer Center, Royal Melbourne Hospital, and University of Melbourne ,Melbourne,Australie;Peter MacCallum Cancer Center, Royal Melbourne Hospital, and University of Melbourne ,Melbourne,Australien;Peter MacCallum Cancer Center, Royal Melbourne Hospital, and University of Melbourne ,Melbourne,Australia;Peter MacCallum Cancer Center, Royal Melbourne Hospital, and University of Melbou
,
David Lewis
Affiliations:
Plymouth Hospitals NHS Trust - Derriford Hospital ,Plymouth,Royaume-uni;Plymouth Hospitals NHS Trust - Derriford Hospital ,Plymouth,Vereinigtes Königreich;Plymouth Hospitals NHS Trust - Derriford Hospital ,Plymouth,Regno Unito;Plymouth Hospitals NHS Trust - Derriford Hospital ,Plymouth,United Kingdom;Plymouth Hospitals NHS Trust - Derriford Hospital ,Plymouth,Reino Unido;Plymouth Hospitals NHS Tru
,
James N. Gerson
Affiliations:
Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,États-unis;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,Vereinigte Staaten;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,Stati Uniti;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,United States;Lymphoma Pro
,
Alvaro J. Alencar
Affiliations:
University of Miami Miller School of Medicine ,Miami,États-unis;University of Miami Miller School of Medicine ,Miami,Vereinigte Staaten;University of Miami Miller School of Medicine ,Miami,Stati Uniti;University of Miami Miller School of Medicine ,Miami,United States;University of Miami Miller School of Medicine ,Miami,Estados Unidos;University of Miami Miller School of Medicine ,Miami,Verenigde S
,
Chaitra Ujjani
Affiliations:
Fred Hutchinson Cancer Research Center ,Seattle,États-unis;Fred Hutchinson Cancer Research Center ,Seattle,Vereinigte Staaten;Fred Hutchinson Cancer Research Center ,Seattle,Stati Uniti;Fred Hutchinson Cancer Research Center ,Seattle,United States;Fred Hutchinson Cancer Research Center ,Seattle,Estados Unidos;Fred Hutchinson Cancer Research Center ,Seattle,Verenigde Staten;Fred Hutchinson Cancer R
,
Ian Flinn
Affiliations:
Sarah Cannon Research Institute ,Nashville,États-unis;Sarah Cannon Research Institute ,Nashville,Vereinigte Staaten;Sarah Cannon Research Institute ,Nashville,Stati Uniti;Sarah Cannon Research Institute ,Nashville,United States;Sarah Cannon Research Institute ,Nashville,Estados Unidos;Sarah Cannon Research Institute ,Nashville,Verenigde Staten;Sarah Cannon Research Institute ,Nashville,Estados Uni
,
Suchitra Sundaram
Affiliations:
Hematology and Medical Oncology,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai ,New York,États-unis;Hematology and Medical Oncology,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai ,New York,Vereinigte Staaten;Hematology and Medical Oncology,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai ,New York,Stati Uniti;Hematology and Medical Oncology,Tisch Ca
,
Shuo Ma
Affiliations:
Robert H. Lurie Comprehensive Cancer Center of Northwestern University ,Chicago,États-unis;Robert H. Lurie Comprehensive Cancer Center of Northwestern University ,Chicago,Vereinigte Staaten;Robert H. Lurie Comprehensive Cancer Center of Northwestern University ,Chicago,Stati Uniti;Robert H. Lurie Comprehensive Cancer Center of Northwestern University ,Chicago,United States;Robert H. Lurie Comprehe
,
Deepa Jagadeesh
Affiliations:
Cleveland Clinic ,Cleveland,États-unis;Cleveland Clinic ,Cleveland,Vereinigte Staaten;Cleveland Clinic ,Cleveland,Stati Uniti;Cleveland Clinic ,Cleveland,United States;Cleveland Clinic ,Cleveland,Estados Unidos;Cleveland Clinic ,Cleveland,Verenigde Staten;Cleveland Clinic ,Cleveland,Estados Unidos;Cleveland Clinic ,Cleveland,United States;Cleveland Clinic ,Cleveland,USA
,
Joanna Rhodes
Affiliations:
Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health ,New Hyde Park,États-unis;Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health ,New Hyde Park,Vereinigte Staaten;Northwell Health Cancer Institute, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell Health ,New Hyde Park,S
,
Justin Taylor
Affiliations:
University of Miami Miller School of Medicine ,Miami,États-unis;University of Miami Miller School of Medicine ,Miami,Vereinigte Staaten;University of Miami Miller School of Medicine ,Miami,Stati Uniti;University of Miami Miller School of Medicine ,Miami,United States;University of Miami Miller School of Medicine ,Miami,Estados Unidos;University of Miami Miller School of Medicine ,Miami,Verenigde S
,
Omar Abdel-Wahab
Affiliations:
Memorial Sloan Kettering Cancer Center ,New York,États-unis;Memorial Sloan Kettering Cancer Center ,New York,Vereinigte Staaten;Memorial Sloan Kettering Cancer Center ,New York,Stati Uniti;Memorial Sloan Kettering Cancer Center ,New York,United States;Memorial Sloan Kettering Cancer Center ,New York,Estados Unidos;Memorial Sloan Kettering Cancer Center ,New York,Verenigde Staten;Memorial Sloan Ket
,
Paolo Ghia
Affiliations:
Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele ,Milan,Italie;Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele ,Milan,Italien;Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele ,Milan,Italia;Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele ,Milan,Italy;Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele ,Mil
,
Stephen J. Schuster
Affiliations:
Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,États-unis;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,Vereinigte Staaten;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,Stati Uniti;Lymphoma Program, Abramson Cancer Center, University of Pennsylvania ,Philadelphia,United States;Lymphoma Pro
,
Denise Wang
Affiliations:
Loxo Oncology at Lilly ,Stamford,États-unis;Loxo Oncology at Lilly ,Stamford,Vereinigte Staaten;Loxo Oncology at Lilly ,Stamford,Stati Uniti;Loxo Oncology at Lilly ,Stamford,United States;Loxo Oncology at Lilly ,Stamford,Estados Unidos;Loxo Oncology at Lilly ,Stamford,Verenigde Staten;Loxo Oncology at Lilly ,Stamford,Estados Unidos;Loxo Oncology at Lilly ,Stamford,United States;Loxo Oncology at Li
,
Binoj Nair
Affiliations:
Loxo Oncology at Lilly ,Stamford,États-unis;Loxo Oncology at Lilly ,Stamford,Vereinigte Staaten;Loxo Oncology at Lilly ,Stamford,Stati Uniti;Loxo Oncology at Lilly ,Stamford,United States;Loxo Oncology at Lilly ,Stamford,Estados Unidos;Loxo Oncology at Lilly ,Stamford,Verenigde Staten;Loxo Oncology at Lilly ,Stamford,Estados Unidos;Loxo Oncology at Lilly ,Stamford,United States;Loxo Oncology at Li
,
Edward Zhu
Affiliations:
Loxo Oncology at Lilly,Stamford,États-unis;Loxo Oncology at Lilly,Stamford,Vereinigte Staaten;Loxo Oncology at Lilly,Stamford,Stati Uniti;Loxo Oncology at Lilly,Stamford,United States;Loxo Oncology at Lilly,Stamford,Estados Unidos;Loxo Oncology at Lilly,Stamford,Verenigde Staten;Loxo Oncology at Lilly,Stamford,Estados Unidos;Loxo Oncology at Lilly,Stamford,United States;Loxo Oncology at Lilly,Stam
,
Donald E. Tsai
Affiliations:
Loxo Oncology at Lilly ,Stamford,États-unis;Loxo Oncology at Lilly ,Stamford,Vereinigte Staaten;Loxo Oncology at Lilly ,Stamford,Stati Uniti;Loxo Oncology at Lilly ,Stamford,United States;Loxo Oncology at Lilly ,Stamford,Estados Unidos;Loxo Oncology at Lilly ,Stamford,Verenigde Staten;Loxo Oncology at Lilly ,Stamford,Estados Unidos;Loxo Oncology at Lilly ,Stamford,United States;Loxo Oncology at Li
,
Matthew S. Davids
Affiliations:
Dana-Farber Cancer Institute and Harvard Medical School ,Boston,États-unis;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,Vereinigte Staaten;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,Stati Uniti;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,United States;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,Estados Unidos;Dana-Farb
,
Jennifer R. Brown
Affiliations:
Dana-Farber Cancer Institute and Harvard Medical School ,Boston,États-unis;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,Vereinigte Staaten;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,Stati Uniti;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,United States;Dana-Farber Cancer Institute and Harvard Medical School ,Boston,Estados Unidos;Dana-Farb
Wojciech Jurczak
Affiliations:
Maria Sklodowska-Curie National Research Institute of Oncology ,Krakow,Pologne;Maria Sklodowska-Curie National Research Institute of Oncology ,Krakow,Polen;Maria Sklodowska-Curie National Research Institute of Oncology ,Krakow,Polonia;Maria Sklodowska-Curie National Research Institute of Oncology ,Krakow,Poland;Maria Sklodowska-Curie National Research Institute of Oncology ,Krakow,Polonia;Maria Sk
(Abstract release date: 05/12/22) EHA Library. R. Mato A. 06/12/22; 357011; S147
Anthony R. Mato
Anthony R. Mato
Contributions
Abstract
Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S147

Type: Oral Presentation

Session title: CLL: Clinical

Background
Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but many patients (pts) will require additional treatmentPirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. 

Aims
BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. 

Methods
Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety and tolerability and pharmacokinetics. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L). Safety was assessed in all pts.

Results
As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other) were treated on 7 dose levels (25-300mg QD). Among the 170 pts with CLL/SLL, the median age was 69 (36-88) years. Median number of prior lines of therapies was 3 (1-11). Majority of the CLL/SLL pts had received a prior BTKi (86%), an anti-CD20 antibody (90%), or a chemotherapy (82%). High risk molecular features such as 17p deletion, TP53 mutation, and unmutated IGHV were present in 25% (20/81), 30% (27/91), and 88%  (71/81) of pts, respectively. No dose-limiting toxicities (DLTs) were reported and maximum tolerated dose (MTD) was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events (TEAEs) regardless of attribution or grade seen in >10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. 1% pts discontinued due to TEAEs. 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). The ORR was 63% (95% CI 55-71) among the 139 efficacy evaluable pts with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%), and 1 PD (1%), and 5  (4%) discontinued prior to first response assessment. Among the 121 BTKi pretreated pts, the ORR was 62% (95% CI 53-71). Responses deepened over time with an ORR of 86% among the pts with at least 10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other reasons (52%). Of the 88 responding pts, all except 5 remained on therapy (4 progressed and 1 achieved a PR and electively discontinued treatment to undergo transplant). The longest-followed responding patient had been on treatment for 17.8+ months.

Conclusion
Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts following multiple prior lines of therapy and in pts with BTK C481 mutations. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 100 new pts with CLL and an additional 10 months since the prior data cut will be presented.

Keyword(s): Chronic lymphocytic leukemia, Clinical trial

Presentation during EHA2022: All Oral presentations will be presented between Friday, June 10 and Sunday, June 12 and will be accessible for on-demand viewing from Monday, June 20 until Monday, August 15, 2022 on the Congress platform.

Abstract: S147

Type: Oral Presentation

Session title: CLL: Clinical

Background
Covalent BTK inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but many patients (pts) will require additional treatmentPirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. 

Aims
BRUIN is a phase 1/2 multicenter study (NCT03740529) of oral pirtobrutinib monotherapy in pts with advanced B-cell malignancies who have received >2 prior therapies. 

Methods
Pirtobrutinib was dose escalated in a standard 3+3 design in 28-day cycles. The primary objective for phase 1 was to determine the recommended phase 2 dose (RP2D) and the primary objective of phase 2 was overall response rate (ORR); secondary objectives included duration of response, progression-free survival, overall survival, safety and tolerability and pharmacokinetics. Response was assessed every 8 weeks from cycle 3, and every 12 weeks from cycle 13 and was measured according to the iwCLL 2018 criteria, including PR with lymphocytosis (PR-L). Safety was assessed in all pts.

Results
As of 27 September 2020, 323 pts with B-cell malignancies (170 CLL/SLL, 61 MCL, 26 WM, 26 DLBCL, 13 MZL, 12 FL, 9 RT, and 6 other) were treated on 7 dose levels (25-300mg QD). Among the 170 pts with CLL/SLL, the median age was 69 (36-88) years. Median number of prior lines of therapies was 3 (1-11). Majority of the CLL/SLL pts had received a prior BTKi (86%), an anti-CD20 antibody (90%), or a chemotherapy (82%). High risk molecular features such as 17p deletion, TP53 mutation, and unmutated IGHV were present in 25% (20/81), 30% (27/91), and 88%  (71/81) of pts, respectively. No dose-limiting toxicities (DLTs) were reported and maximum tolerated dose (MTD) was not reached (n=323). 200mg QD was selected as the RP2D. Fatigue (20%), diarrhea (17%) and contusion (13%) were the most frequent treatment-emergent adverse events (TEAEs) regardless of attribution or grade seen in >10% of pts (n=323). The most common adverse event of grade ≥3 was neutropenia (10%). Treatment-related hemorrhage and hypertension occurred in 5 (2%) and 4 (1%) pts, respectively. 1% pts discontinued due to TEAEs. 139 CLL/SLL pts were efficacy-evaluable with a median follow up time of 6 months (0.16-17.8+). The ORR was 63% (95% CI 55-71) among the 139 efficacy evaluable pts with 69 PRs (50%), 19 PR-Ls (14%), 45 SDs (32%), and 1 PD (1%), and 5  (4%) discontinued prior to first response assessment. Among the 121 BTKi pretreated pts, the ORR was 62% (95% CI 53-71). Responses deepened over time with an ORR of 86% among the pts with at least 10 months follow-up. ORR was similar in pts who discontinued prior BTKi due to progression (67%), or adverse events or other reasons (52%). Of the 88 responding pts, all except 5 remained on therapy (4 progressed and 1 achieved a PR and electively discontinued treatment to undergo transplant). The longest-followed responding patient had been on treatment for 17.8+ months.

Conclusion
Pirtobrutinib demonstrated promising efficacy in heavily pretreated CLL/SLL pts following multiple prior lines of therapy and in pts with BTK C481 mutations. Pirtobrutinib was well tolerated and exhibited a wide therapeutic index. Updated data, including approximately 100 new pts with CLL and an additional 10 months since the prior data cut will be presented.

Keyword(s): Chronic lymphocytic leukemia, Clinical trial

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