Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results.
Adult; Agammaglobulinaemia Tyrosine Kinase; Aged; Aged, 80 and over; Antineoplastic Agents; Benzamides; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm Recurrence, Local; Protein Kinase Inhibitors; Pyrazines; Treatment Outcome
Therapeutic targeting of Bruton tyrosine kinase (BTK) has dramatically improved survival outcomes for patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). Acalabrutinib is an oral, highly selective BTK inhibitor that allows for twice-daily dosing due to its selectivity. In this phase 1b/2 study, 134 patients with relapsed/refractory CLL or SLL (median age, 66 years [range, 42-85 years]; median prior therapies, 2 [range, 1-13]) received acalabrutinib 100 mg twice daily for a median of 41 months (range, 0.2-58 months). Median trough BTK occupancy at steady state was 97%. Most adverse events (AEs) were mild or moderate, and were most commonly diarrhea (52%) and headache (51%). Grade ≥3 AEs (occurring in ≥5% of patients) were neutropenia (14%), pneumonia (11%), hypertension (7%), anemia (7%), and diarrhea (5%). Atrial fibrillation and major bleeding AEs (all grades) occurred in 7% and 5% of patients, respectively. Most patients (56%) remain on treatment; the primary reasons for discontinuation were progressive disease (21%) and AEs (11%). The overall response rate, including partial response with lymphocytosis, with acalabrutinib was 94%; responses were similar regardless of genomic features (presence of del(11)(q22.3), del(17)(p13.1), complex karyotype, or immunoglobulin variable region heavy chain mutation status). Median duration of response and progression-free survival (PFS) have not been reached; the estimated 45-month PFS was 62% (95% confidence interval, 51% to 71%). BTK mutation was detected in 6 of 9 patients (67%) at relapse. This updated and expanded study confirms the efficacy, durability of response, and long-term safety of acalabrutinib, justifying its further investigation in previously untreated and treated patients with CLL/SLL. This trial was registered at www.clinicaltrials.gov as #NCT02029443.
Byrd, John C; Wierda, William G; Schuh, Anna; Devereux, Stephen; Chaves, Jorge M; Brown, Jennifer R; Hillmen, Peter; Martin, Peter; Awan, Farrukh T; Stephens, Deborah M; Ghia, Paolo; Barrientos, Jacqueline; Pagel, John M; Woyach, Jennifer A; Burke, Kathleen; Covey, Todd; Gulrajani, Michael; Hamdy, Ahmed; Izumi, Raquel; Frigault, Melanie M; Patel, Priti; Rothbaum, Wayne; Wang, Min Hui; O'Brien, Susan; and Furman, Richard R, "Acalabrutinib monotherapy in patients with relapsed/refractory chronic lymphocytic leukemia: updated phase 2 results." (2020). Articles, Abstracts, and Reports. 4000.