PI3Kδ–CK1ϵ Inhibitor Umbralisib Shows Promise in R/R Indolent NHL

Despite the fact that PI3K inhibitors have shown promise in relapsed or refractory (R/R) B-cell malignancies, their long-term use is limited by toxicities, which may be mediated in part by lack of specificity of these inhibitors for the isoform of PI3K (PI3Kδ) selectively expressed by B cells. The highly selective oral PI3Kδ inhibitor umbralisib—which also inhibits casein kinase 1ϵ (CK1ϵ), a protein involved in regulation of the WNT–β-catenin pathway and translation of some oncoproteins—has demonstrated signs of activity in R/R B-cell cancers. Fowler and colleagues conducted an open-label phase IIb trial of umbralisib in 208 patients with indolent non-Hodgkin lymphoma (NHL) that was resistant to or relapsed following rituximab and at least one line of anti-CD20 therapy. Sixty-nine patients (33%) had marginal zone lymphoma (MZL), 117 patients (56%) had follicular lymphoma, and 22 patients (11%) had small lymphocytic lymphoma (SLL). In an intention-to-treat analysis, the overall response rate was 49% for patients with MZL, 45% for patients with follicular lymphoma, and 50% for patients with SLL, with the complete response rates being 16%, 5%, and 5%, respectively. Additionally, 33% of patients with MZL, 34% of patients with follicular lymphoma, and 36% of patients with SLL experienced stable disease. After a median follow-up period of 21.4 months, among patients whose disease responded to umbralisib, the median duration of response was not reached for MZL, 11.1 months for follicular lymphoma, and 18.3 months for SLL. Safety data were consistent with those from the prior phase I dose-escalation study, with the most common treatment-emergent adverse events (TEAE) being diarrhea, nausea, fatigue, and vomiting; also of note, ALT or AST increased in 20% and 19% of patients, respectively. Ultimately, 15% of patients discontinued umbralisib treatment due to TEAEs. Although cross-trial comparisons should be made with great caution, these results suggest that umbralisib may have greater tolerability than other PI3K inhibitors for R/R B-cell malignancies, and this trial supports umbralisib's efficacy in indolent NHL.

Fowler NH, Samaniego F, Jurczak W, Ghosh N, Derenzini E, Reeves JA, et al. Umbralisib, a dual PI3Kδ/CK1ϵ inhibitor in patients with relapsed or refractory indolent lymphoma. J Clin Oncol 2021 Mar 8 [Epub ahead of print].

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