Integrated safety analysis of umbralisib, a dual PI3Kδ/CK1ε inhibitor, in relapsed/refractory lymphoid malignancies

• Published in: Blood advances Vol. 5; no. 23; pp. 5332 - 5343
• Main Authors: 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., Knopińska-Posłuszny, 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, Chavez, Julio C., Pagel, John M., Sharman, Jeff P., Hsu, Yanzhi, Miskin, Hari P., Sportelli, Peter, Weiss, Michael S., Flinn, Ian W.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14-12-2021; American Society of Hematology
• Subjects: Adult; Aged; Clinical Trials and Observations; Heterocyclic Compounds, 4 or More Rings - adverse effects; Humans; Leukemia, Lymphocytic, Chronic, B-Cell - drug therapy; Lymphoma, B-Cell, Marginal Zone - drug therapy; Phosphoinositide-3 Kinase Inhibitors - adverse effects; Recurrence
• ISSN: 2473-9529; 2473-9537; 2473-9537
• DOI: 10.1182/bloodadvances.2021005132

Phosphoinositide 3-kinase-δ (PI3Kδ) inhibitors are active in lymphoid malignancies, although 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 tumor types [n = 25]) who were treated with the 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 months), and 107 patients (28.8%) received umbralisib for ≥12 months. Any-grade treatment-emergent adverse events (AEs) occurred in 366 (98.7%) of 371 patients, with the most frequent being diarrhea (52.3%), nausea (41.5%), and fatigue (31.8%). Grade 3 or higher treatment-emergent AEs occurred in 189 (50.9%) of 371 patients and included neutropenia (11.3%), diarrhea (7.3%), and increased aminotransferase levels (5.7%). Treatment-emergent serious AEs occurred in 95 (25.6%) of 371 patients. AEs of special interest were limited and included pneumonia (29 of 371 [7.8%]), noninfectious colitis (9 of 371 [2.4%]), and pneumonitis (4 of 371 [1.1%]). AEs led to discontinuation of umbralisib in 51 patients (13.7%). Four patients (1.1%) died of AEs, none of which was 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.
•Umbralisib is a unique PI3Kδ/casein kinase-1ε inhibitor with a tolerable safety profile in relapsed/refractory lymphoid malignancies.•Low rates of immune-mediated toxicities were observed with umbralisib.
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