Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers.

  • Major finding: Umbralisib is well tolerated and has activity against relapsed or refractory hematologic cancers.

  • Concept: Umbralisib has reduced autoimmune-like toxicity compared with structurally distinct PI3Kδ inhibitors.

  • Impact: Umbralisib's favorable safety profile supports further investigation in patients with hematologic cancer.

Class I phosphatidylinositol 3-kinases (PI3K) regulate cell proliferation, differentiation, and survival, and thus represent potential therapeutic targets in cancer. Expression of the PI3Kδ isoform is largely restricted to hematopoietic cells and it is often aberrantly activated in B-cell malignancies, supporting the development of isoform-selective PI3Kδ inhibitors. However, despite promising antitumor activity, the PI3Kδ-selective inhibitors idelalisib and duvelisib exhibited substantial toxicity, including autoimmune-like complications in clinical studies, thought to be due in part to off-target effects, suggesting the need for more specific inhibitors. Umbralisib, a structurally distinct next-generation PI3Kδ-selective inhibitor, which also inhibits casein kinase-1ϵ, exhibits potent antitumor activity in preclinical studies, and Burris and colleagues assessed its safety and efficacy in an open-label phase I dose-escalation study. Ninety patients with relapsed or refractory lymphoma were enrolled and treated with umbralisib. The primary endpoints were determination of safety, maximum tolerated dose, and pharmacokinetic profile of umbralisib. Secondary endpoints included objective response rate and the duration of response. The maximum tolerated dose was determined to be 1,200 mg. Umbralisib was well tolerated and exhibited fewer autoimmune-like toxicities (such as colitis) than previous PI3Kδ-selective inhibitors, although serious adverse events potentially related to treatment occurred in 8% of patients. Overall, 33 of 90 (37%) patients had an objective response, including 3 complete and 30 partial responses. Further, there was an 85% response rate in the 20 patients with relapsed or refractory chronic lymphocytic leukemia. The mean duration of response was 13.4 months in 16 patients with chronic lymphocytic leukemia, 6.4 months in 4 patients with diffuse large B-cell lymphoma, and 9.3 months in 9 patients with follicular lymphoma. In addition to suggesting umbralisib is safe and has antitumor activity in patients with relapsed or refractory hematologic malignancies, these findings demonstrate that umbralisib has a distinct safety profile from other PI3Kδ-selective inhibitors, supporting its further clinical investigation.

Burris HA III, Flinn IW, Patel MR, Fenske TS, Deng C, Brander DM, et al. Umbralisib, a novel PI3Kδ and casein kinase-1ϵ inhibitor, in relapsed or refractory chronic lymphocytic leukaemia and lymphoma: an open-label, phase 1, dose-escalation, first-in-human study. Lancet Oncol 2018 Feb 20 [Epub ahead of print].

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