TY - JOUR
T1 - Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.
AU - Mato, Anthony R.
AU - Woyach, Jennifer A.
AU - Brown, Jennifer R.
AU - Ghia, Paolo
AU - Patel, Krish
AU - Eyre, Toby A.
AU - Munir, Talha
AU - Lech-Maranda, Ewa
AU - Lamanna, Nicole
AU - Tam, Constantine S.
AU - Shah, Nirav N.
AU - Coombs, Catherine C.
AU - Ujjani, Chaitra S.
AU - Fakhri, Bita
AU - Cheah, Chan Y.
AU - Patel, Manish R.
AU - Alencar, Alvaro J.
AU - Cohen, Jonathon B.
AU - Gerson, James N.
AU - Flinn, Ian W.
AU - Ma, Shuo
AU - Jagadeesh, Deepa
AU - Rhodes, Joanna M.
AU - Hernandez-Ilizaliturri, Francisco
AU - Zinzani, Pier L.
AU - Seymour, John F.
AU - Balbas, Minna
AU - Nair, Binoj
AU - Abada, Paolo
AU - Wang, Chunxiao
AU - Ruppert, Amy S.
AU - Wang, Denise
AU - Tsai, Donald E.
AU - Wierda, William G.
AU - Jurczak, Wojciech
N1 - Publisher Copyright:
© 2023 Massachusetts Medical Society.
PY - 2023
Y1 - 2023
N2 - Abstract Background Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. Methods We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. Results A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. Conclusions In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.)
AB - Abstract Background Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. Methods We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. Results A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. Conclusions In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.)
KW - Hematology/Oncology
KW - Leukemia/Lymphoma
KW - Treatments in Oncology
UR - http://www.scopus.com/inward/record.url?scp=85165276486&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85165276486&partnerID=8YFLogxK
U2 - 10.1056/NEJMoa2300696
DO - 10.1056/NEJMoa2300696
M3 - Article
C2 - 37407001
AN - SCOPUS:85165276486
SN - 0028-4793
VL - 389
SP - 33
EP - 44
JO - New England Journal of Medicine
JF - New England Journal of Medicine
IS - 1
ER -