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. 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.
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.
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.
Authors: Hagop M Kantarjian; Nitin Jain; Guillermo Garcia-Manero; Mary Alma Welch; Farhad Ravandi; William G Wierda; Elias J Jabbour Journal: Cancer Date: 2021-10-06 Impact factor: 6.860
Authors: Deborah M Stephens; Ying Huang; Amy S Ruppert; Janek S Walker; Daniel Canfield; Casey B Cempre; Qiang Fu; Sharyn Baker; Boyu Hu; Harsh Shah; Renee Vadeboncoeur; Kerry A Rogers; Seema Bhat; Samantha M Jaglowski; Hank Lockman; Rosa Lapalombella; John C Byrd; Jennifer A Woyach Journal: Clin Cancer Res Date: 2022-08-02 Impact factor: 13.801