Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies.
washington; seattle; swedish; swedish cancer
Phosphoinositide 3-kinase-delta (PI3Kδ) inhibitors are active in lymphoid malignancies, though associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3Kδ and casein kinase-1ε (CK1ε). This study analyzed integrated comprehensive toxicity data from 4 open-label, phase 1 and 2 studies that included 371 adult patients (median age, 67 years) with relapsed/refractory non-Hodgkin lymphoma (follicular lymphoma [n = 147]; marginal zone lymphoma [n = 82]; diffuse large B-cell lymphoma/mantle cell lymphoma [n = 74]; chronic lymphocytic leukemia [n = 43]; and other [n = 25]) who were treated with recommended phase 2 dose of umbralisib 800 mg or higher once daily. At data cutoff, median duration of umbralisib treatment was 5.9 months (range, 0.1-75.1), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (TEAEs) occurred in 366/371 patients (98.7%), with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade ≥3 TEAEs occurred in 189/371 of patients (50.9%), including neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferases (5.7%). Treatment-emergent serious AEs occurred in 95/371 patients (25.6%). AEs of special interest were limited and included pneumonia (29/371 [7.8%]), noninfectious colitis (9/371 [2.4%]), and pneumonitis (4/371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died due to AEs, none of which were deemed related to umbralisib. No cumulative toxicities were reported. The favorable long-term tolerability profile and low rates of immune-mediated toxicities support the potential use of umbralisib for the benefit of a broad population of patients with lymphoid malignancies.
Davids, Matthew S; O'Connor, Owen A; Jurczak, Wojciech; Samaniego, Felipe; Fenske, Timothy S; Zinzani, Pier Luigi; Patel, Manish R; Ghosh, Nilanjan; Cheson, Bruce D; Derenzini, Enrico; Brander, Danielle M; Reeves, James A; Knopinska-Posluszny, Wanda; Allan, John N; Phillips, Tycel; Caimi, Paolo F; Lech-Maranda, Ewa; Burke, John M; Agajanian, Richy; Pettengell, Ruth; Leslie, Lori A; Cheah, Chan Y; Fonseca, Gustavo; Essell, James H; Chavez, Julio C; Pagel, John M; Sharman, Jeff P; Hsu, Yanzhi; Miskin, Hari P; Sportelli, Peter; Weiss, Michael S; and Flinn, Ian W, "Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies." (2021). Articles, Abstracts, and Reports. 5289.