Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study

doi:10.1016/S0140-6736(21)00224-5

Clinical Trial

. 2021 Mar 6;397(10277):892-901.

doi: 10.1016/S0140-6736(21)00224-5.

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study

Anthony R Mato¹, Nirav N Shah², Wojciech Jurczak³, Chan Y Cheah⁴, John M Pagel⁵, Jennifer A Woyach⁶, Bita Fakhri⁷, Toby A Eyre⁸, Nicole Lamanna⁹, Manish R Patel¹⁰, Alvaro Alencar¹¹, Ewa Lech-Maranda¹², William G Wierda¹³, Catherine C Coombs¹⁴, James N Gerson¹⁵, Paolo Ghia¹⁶, Steven Le Gouill¹⁷, David John Lewis¹⁸, Suchitra Sundaram¹⁹, Jonathon B Cohen²⁰, Ian W Flinn²¹, Constantine S Tam²², Minal A Barve²³, Bryone Kuss²⁴, Justin Taylor¹¹, Omar Abdel-Wahab²⁵, Stephen J Schuster¹⁵, M Lia Palomba²⁵, Katharine L Lewis⁴, Lindsey E Roeker²⁵, Matthew S Davids²⁶, Xuan Ni Tan⁴, Timothy S Fenske²⁷, Johan Wallin²⁸, Donald E Tsai²⁸, Nora C Ku²⁸, Edward Zhu²⁸, Jessica Chen²⁸, Ming Yin²⁸, Binoj Nair²⁸, Kevin Ebata²⁸, Narasimha Marella²⁸, Jennifer R Brown²⁶, Michael Wang²⁹

Affiliations

¹ Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: matoa@mskcc.org.
² Medical College of Wisconsin, Brookfield, WI, USA.
³ Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland.
⁴ Linear Clinical Research and Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia.
⁵ Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA.
⁶ The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
⁷ Division of Hematology and Oncology, University of California, San Francisco, CA, USA.
⁸ Churchill Cancer Center, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁹ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
¹⁰ Florida Cancer Specialists and Sarah Cannon Research Institute, Sarasota, FL, USA.
¹¹ Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
¹² Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
¹³ MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy.
¹⁷ Service d'hématologie clinique du CHU de Nantes, INSERM CRCINA Nantes-Angers, NeXT Université de Nantes, Nantes, France.
¹⁸ University Hospitals Plymouth NHS Trust, Plymouth, UK.
¹⁹ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
²⁰ Winship Cancer Institute, Emory University, Atlanta, GA, USA.
²¹ Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA.
²² Peter MacCallum Cancer Center, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia.
²³ Mary Crowley Cancer Research Center, Dallas, TX, USA.
²⁴ Flinders University Medical Centre, Bedford Park, SA, Australia.
²⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁶ Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
²⁷ Medical College of Wisconsin, Milwaukee, WI, USA.
²⁸ Loxo Oncology at Lilly, Stamford, CT, USA.
²⁹ MD Anderson Cancer Center, Houston, TX, USA. Electronic address: miwang@mdanderson.org.

PMID: 33676628
PMCID: PMC11758240
DOI: 10.1016/S0140-6736(21)00224-5

Clinical Trial

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study

Anthony R Mato et al. Lancet. 2021.

. 2021 Mar 6;397(10277):892-901.

doi: 10.1016/S0140-6736(21)00224-5.

Authors

Affiliations

¹ Memorial Sloan Kettering Cancer Center, New York, NY, USA. Electronic address: matoa@mskcc.org.
² Medical College of Wisconsin, Brookfield, WI, USA.
³ Maria Sklodowska-Curie National Research Institute of Oncology, Krakow, Poland.
⁴ Linear Clinical Research and Sir Charles Gairdner Hospital and University of Western Australia, Perth, WA, Australia.
⁵ Center for Blood Disorders and Stem Cell Transplantation, Swedish Cancer Institute, Seattle, WA, USA.
⁶ The Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
⁷ Division of Hematology and Oncology, University of California, San Francisco, CA, USA.
⁸ Churchill Cancer Center, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
⁹ Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY, USA.
¹⁰ Florida Cancer Specialists and Sarah Cannon Research Institute, Sarasota, FL, USA.
¹¹ Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, FL, USA.
¹² Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
¹³ MD Anderson Cancer Center, Houston, TX, USA.
¹⁴ Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
¹⁵ Lymphoma Program, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
¹⁶ Università Vita-Salute San Raffaele and IRCCS Ospedale San Raffaele, Milan, Italy.
¹⁷ Service d'hématologie clinique du CHU de Nantes, INSERM CRCINA Nantes-Angers, NeXT Université de Nantes, Nantes, France.
¹⁸ University Hospitals Plymouth NHS Trust, Plymouth, UK.
¹⁹ Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
²⁰ Winship Cancer Institute, Emory University, Atlanta, GA, USA.
²¹ Sarah Cannon Research Institute and Tennessee Oncology, Nashville, TN, USA.
²² Peter MacCallum Cancer Center, Royal Melbourne Hospital and University of Melbourne, Melbourne, VIC, Australia.
²³ Mary Crowley Cancer Research Center, Dallas, TX, USA.
²⁴ Flinders University Medical Centre, Bedford Park, SA, Australia.
²⁵ Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁶ Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
²⁷ Medical College of Wisconsin, Milwaukee, WI, USA.
²⁸ Loxo Oncology at Lilly, Stamford, CT, USA.
²⁹ MD Anderson Cancer Center, Houston, TX, USA. Electronic address: miwang@mdanderson.org.

PMID: 33676628
PMCID: PMC11758240
DOI: 10.1016/S0140-6736(21)00224-5

Abstract

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients.

Methods: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529.

Findings: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date.

Interpretation: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients.

Funding: Loxo Oncology.

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Conflict of interest statement

ARM reports grants, personal fees and other from TG Therapeutics, grants and personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, grants and personal fees from Genentech, grants and personal fees from Abbvie, grants and personal fees from AstraZeneca, grants from Sunesis, grants from Regeneron, grants and personal fees from Adaptive, grants and personal fees from Pharmacyclics, non-financial support from NCCN, non-financial support from CLL society, non-financial support from Lymphoma research foundation, grants and personal fees from Curio Sciences, grants from Pfizer, grants and other from Verastem, grants from Aprea, grants from Aptose, grants from DTRM, during the conduct of the study.

NNS reports personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company OXO, a wholly owned subsidiary of Eli Lilly and company, during the conduct of the study; personal fees and other from Miltenyi Biotec, personal fees from Incyte, personal fees from Celgene, personal fees from Kite, personal fees from Verastem, outside the submitted work.

WJ reports grants from Janssen, grants from AstraZeneca, grants from Beigene, grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study.

CYC reports personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; grants and personal fees from Roche, grants and personal fees from BMS, personal fees from Takeda, personal fees from AstraZeneca, personal fees from Ascentage Pharma, from TG Therapeutics, grants from Abbvie, personal fees from Janssen, personal fees from Gilead, outside the submitted work.

JMP reports other from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, other from AstraZeneca, other from Gilead, other from BeiGene, during the conduct of the study.

JAW reports personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; personal fees from Janssen, Pharmacyclics, AZ, Abbvie, Arqule, grants from Pharmacyclics, Janssen, Morphosys, Karyopharm, Verastem, Abbvie, personal fees from Pharmacyclics, LCC, an Abbvie Company, Abbvie, Janssen, AstraZeneca, ArQule, outside the submitted work.

BF has nothing to disclose.

TAE reports personal fees from Roche, personal fees and other from Gilead, personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, personal fees from Abbvie, personal fees from Janssen, personal fees from Beigene, personal fees from AstraZeneca, personal fees from KITE, outside the submitted work.

NL reports grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; grants, personal fees and other from Abbvie, AstraZeneca, BeiGene, Genentech, personal fees and other from Celgene, Gilead, Janssen, Pharmacyclics, grants from Juno, Octernal, Verastem, TG Therapeutics, MingSight, grants from Octapharma, outside the submitted work.

MRP reports other from Janssen, other from EMD serono, other from Pfizer, other from Pharmacyclics, other from Bayer, other from Genentech, other from Loxo a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study. AA reports grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; personal fees from Karyopharm, personal fees from Kite, other from Kite, personal fees from Amgen, personal fees from Celgene, personal fees from Spectrum Pharmaceuticals, outside the submitted work. ELM reports personal fees from Roche, Novartis, Takeda, Janssen-Cilag, Amgen, Gilead, Abbvie, Sanofi, personal fees from Roche, Amgen, Gilead, outside the submitted work.

WGW has nothing to disclose.

CCC reports personal fees and other from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; personal fees from Novartis, personal fees from AbbVie, personal fees from Genentech, personal fees from MEI Pharma, personal fees from Octapharma, other from Gilead, other from H3 Biomedicine, other from Incyte, outside the submitted work.

JNG reports grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; personal fees from Abbvie, Pharmacyclics, Genentech, outside the submitted work.

PG reports grants and personal fees from AbbVie, personal fees from Adaptive, personal fees from Celgene/Juno, personal fees from AstraZeneca, grants from Gilead, grants and personal fees from Janssen, personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, grants from Novartis, outside the submitted work.

SLG reports personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; personal fees from Roche, Genentech, Janssen-Cilag, Abbvie, Celgene, Jazz, Gilead-KITE, Daiichi-Sankyo, Servier, outside the submitted work.

DJL has nothing to disclose.

SS has nothing to disclose.

JBC reports grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; grants from Genentech, grants from Astra Zeneca, grants from Novartis, grants from Celgene, grants from M2Gen, grants from BioInvent, grants from Hutchison, personal fees from Adicet, personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, personal fees from Cellectar, personal fees from Kite/Gilead, personal fees from Beigene, personal fees from Aptitude health, personal fees from Pharmacyclics, outside the submitted work. IWF reports grants and other from AbbVie, grants and other from AstraZeneca, grants and other from BeiGene, grants and other from Gilead Sciences, other from Great Point Partners, other from Iksuda Therapeutics, grants and other from Janssen, grants and other from Juno Therapeutics, grants and other from Kite Pharma, grants and other from MorphoSys, other from Nurix Therapeutics, grants and other from Pharmacyclics, grants and other from Roche, grants and other from Seattle Genetics, grants and other from Takeda, grants and other from TG Therapeutics, grants and other from Unum Therapeutics, grants and other from Verastem, other from Yingli Pharmaceuticals, grants from Acerta Pharmaceuticals, grants from Agios, grants from ArQule grants from Calithera Biosciences, grants from Celgene, grants from Constellation Pharmaceuticals, grants from Curis, grants from Forma Therapeutics, grants from Forty Seven, grants from Genentech, grants from IGM Biosciences, grants from Incyte, grants from Infinity Pharmaceuticals, grants from Karyopharm Therapeutics, grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, grants from Merck, grants from Novartis, grants from Pfizer, grants from Portola Pharmaceuticals, grants from Rhizen Pharmaceuticals, grants from Teva, grants from Trillium Therapeutics, grants from Triphase Research & Development Corp., outside the submitted work.

CST reports grants and personal fees from Janssen, BeiGene, Abbvie, personal fees from Pharmacyclics, outside the submitted work.

MAB has nothing to disclose.

BK reports personal fees from Janssen, personal fees from AstraZeneca, personal fees from AbbVie, personal fees from Kyowa Kirin, personal fees from Mundipharma, outside the submitted work.

JT has nothing to disclose.

OAW reports grants and personal fees from H3 Biomedicine, grants from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, personal fees from Pfizer, personal fees from Prelude Therapeutics, personal fees from Foundation Medicine, personal fees from Incyte Pharmaceuticals, personal fees from Envisagenics Inc., personal fees from AI Chemy, during the conduct of the study; grants from LOXO Oncology, outside the submitted work.

SJS reports personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, during the conduct of the study; personal fees from AlloGene, AstraZeneca, BeiGene, Genentech, Inc./ F. Hoffmann-LaRoche, Juno/Celgene, Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, Nordic Nanovector, Novartis, Tessa Therapeutics, grants from Novartis, Genentech, F Hoffman-La Roche, outside the submitted work.

MLP reports personal fees from Novartis, personal fees and other from Merck & Co. Inc., personal fees and other from Pharmacyclics, personal fees and other from Kite, outside the submitted work; MLP has intellectual property interests (by virtue of immediate family member interests) related to CARs (Chimeric Antigen Receptors) and TCRs (T cell Receptors) that Memorial Sloan Kettering Cancer Center (MSK) has licensed to Juno Therapeutics.

KLL has nothing to disclose.

LER reports minority ownership interest in AbbVie and Abbott Laboratories, personal fees from Vaniam Group, personal fees from Janssen Biotech, grant funding from American Society of Hematology outside of the submitted work.

MSD reports grants and personal fees from AbbVie, personal fees from Adaptive Biotechnologies, grants and personal fees from Ascentage Pharma, grants and personal fees from AstraZeneca, personal fees from BeiGene, personal fees from Celgene, personal fees from Eli Lilly, grants and personal fees from Genentech, personal fees from Gilead Sciences, personal fees from Janssen, grants and personal fees from MEI Pharma, personal fees from Merck, grants and personal fees from Novartis, grants and personal fees from Pharmacyclics, personal fees from Research to Practice, grants from Surface Oncology, personal fees from Syros Pharmaceuticals, grants and personal fees from TG Therapeutics, grants and personal fees from Verastem, personal fees from Zentalis, outside the submitted work.

XNT reports grants from Department of Health, Western Australia, other from Novartis, outside the submitted work.

TSF has nothing to disclose.

DET reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

NCK reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

EZ reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

JC reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

MY reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

BN reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

KE reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

NM reports other from Loxo Oncology, a wholly owned subsidiary of Eli Lilly and Company during the conduct of the study.

JRB reports personal fees from Abbvie, personal fees from Acerta/AstraZeneca, personal fees from Astellas, personal fees from BeiGene, personal fees from Catapult Therapeutics, personal fees from Dynamo Therapeutics, personal fees from Genentech/Roche, grants and personal fees from Gilead, other from Invectys, personal fees from Janssen, personal fees from Juno/Celgene, personal fees from Kite, other from Morphosys, personal fees from Novartis, personal fees from Octapharma, personal fees from Pfizer, personal fees from Pharmacyclics, personal fees from Redx, grants from Sun, personal fees from Sunesis, personal fees from Teva, personal fees from TG Therapeutics, grants and personal fees from Verastem, personal fees from MEI Pharma, personal fees from Nextcea, personal fees from Rigel, grants and personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, outside the submitted work.

MW reports grants, personal fees and non-financial support from Pharmacyclics, grants, personal fees and non-financial support from Celgene, grants, personal fees and non-financial support from Janssen, grants and personal fees from AstraZeneca/Acerta Pharma, personal fees and non-financial support from OMI, personal fees from Pulse Biosciences, grants and personal fees from Juno, grants and personal fees from Loxo Oncology a wholly owned subsidiary of Eli Lilly and Company, grants and personal fees from VelosBio, grants from BioInvent, personal fees from Targeted Oncology, grants and personal fees from Kite Pharma, personal fees from Guidepoint Global, grants from Verastem, grants and personal fees from BeiGene, grants from Eli Lilly, grants and personal fees from InnoCare, grants from Molecular Templates, grants and personal fees from Oncternal, outside the submitted work.

Figures

**Figure 1.. Patient Flow Diagram (A) and CONSORT diagram (B)**
^aOther in the safety population includes DLBCL, FL, MZL, Richter’s transformation, B-PLL, Hairy Cell Leukemia, and other transformation. ^bEfficacy evaluable patients are those who had at least one post-baseline response assessment or had discontinued treatment prior to first post-baseline response assessment. Abbreviations: CLL, chronic lymphocytic leukemia; SLL, small lymphocytic lymphoma; MCL, mantle cell lymphoma; WM, Waldenstrom’s Macroglobulinemia; DLBCL, diffuse large B-cell lymphoma; FL, follicular lymphoma; MZL, marginal zone lymphoma, B-PLL, B-cell prolymphocytic leukemia; PD, progressive disease; AE, adverse event

**Figure 2.. Efficacy**
A) Change in tumour burden from baseline measured by changes in the sums of the products of the maximum perpendicular dimensions on axial CT images of index lesions (SPD) for efficacy evaluable patients with chronic lymphocytic leukaemia/small lymphocytic lymphoma, mantle cell lymphoma, and other B-cell lymphomas. For WM (†), the maximum change in IgM levels from baseline are shown. Color of bar indicates status of prior BTK inhibitor therapy and reason for discontinuation. Efficacy evaluable patients are those who had at least one post-baseline response assessment or had discontinued treatment prior to first post-baseline response assessment. Data for 41 patients (13 CLL/SLL, 11 MCL, and 17 other NHLs) are not shown due to 17 having no target lesions identified at baseline, ten with no/incomplete post-baseline lesion measurements, and 14 discontinued prior to first post-baseline disease assessment. ǂ indicates patients with >50% increase in SPD. B) Responses over time for CLL/SLL efficacy evaluable patients are shown. All includes the efficacy evaluable CLL/SLL patients at the time of data cutoff. Data at each timepoint includes the efficacy evaluable CLL/SLL patients who had the opportunity to be followed for at least the indicated amount of time. Abbreviations: CLL/SLL, chronic lymphocytic leukaemia/small lymphocytic lymphoma; MCL, mantle cell lymphoma, WM, Waldenström’s Macroglobulinemia; NHL, non-Hodgkin’s Lymphoma; PR, partial response; PR-L, partial response with lymphocytosis; SD, stable disease; NE, not evaluable; PD, progressive disease.

**Figure 3.. Kaplan-Meier Plots of Duration of Response in Patients with CLL/SLL and MCL**
Abbreviations: CLL/SLL, chronic lymphocytic leukaemia/small lymphocytic lymphoma; MCL, mantle cell lymphoma

See this image and copyright information in PMC

Comment in

Pirtobrutinib shows evidence to inaugurate a third generation of BTK inhibitors.
Michot JM, Ribrag V. Michot JM, et al. Lancet. 2021 Mar 6;397(10277):855-857. doi: 10.1016/S0140-6736(21)00235-X. Lancet. 2021. PMID: 33676615 No abstract available.
Initial pirtobrutinib data show promise.
Romero D. Romero D. Nat Rev Clin Oncol. 2021 May;18(5):258. doi: 10.1038/s41571-021-00505-0. Nat Rev Clin Oncol. 2021. PMID: 33758377 No abstract available.

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References

1. Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42. - PMC - PubMed
1. Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:2224–32. - PMC - PubMed
1. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med 2015;372:1430–40. - PubMed
1. Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507–16. - PMC - PubMed
1. Coutre SE, Byrd JC, Hillmen P, et al. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv 2019;3:1799–807. - PMC - PubMed

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[1] Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42. - PMC - PubMed

[2] Byrd JC, Furman RR, Coutre SE, et al. Targeting BTK with ibrutinib in relapsed chronic lymphocytic leukemia. N Engl J Med 2013;369:32–42. - PMC - PubMed

[3] Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:2224–32. - PMC - PubMed

[4] Noy A, de Vos S, Thieblemont C, et al. Targeting Bruton tyrosine kinase with ibrutinib in relapsed/refractory marginal zone lymphoma. Blood 2017;129:2224–32. - PMC - PubMed

[5] Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med 2015;372:1430–40. - PubMed

[6] Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom’s macroglobulinemia. N Engl J Med 2015;372:1430–40. - PubMed

[7] Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507–16. - PMC - PubMed

[8] Wang ML, Rule S, Martin P, et al. Targeting BTK with ibrutinib in relapsed or refractory mantle-cell lymphoma. N Engl J Med 2013;369:507–16. - PMC - PubMed

[9] Coutre SE, Byrd JC, Hillmen P, et al. Long-term safety of single-agent ibrutinib in patients with chronic lymphocytic leukemia in 3 pivotal studies. Blood Adv 2019;3:1799–807. - PMC - PubMed

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Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study

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Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study

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