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

Phosphoinositide 3-kinase-delta (PI3K delta) inhibitors are active in lymphoid malignancies, although associated toxicities can limit their use. Umbralisib is a dual inhibitor of PI3K delta and casein kinase-1 epsilon (CK1 epsilon). 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%]), non-infectious 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.

Automated summary

Umbralisib, a dual inhibitor of PI3K delta and CK1 epsilon, showed favorable long-term tolerability in the treatment of lymphoid malignancies. Common adverse events include diarrhea, nausea, and fatigue, with low rates of serious adverse events of special interest.