An Integrated Safety Analysis of the Next Generation PI3Kδ Inhibitor Umbralisib (TGR-1202) in Patients with Relapsed/Refractory Lymphoid Malignancies

Introduction: First generation PI3Kδ inhibitors such as idelalisib and duvelisib are active in patients (pts) with lymphoid malignancies but are often associated with significant immune-mediated adverse events, including transaminitis, diarrhea/colitis, and pneumonitis, as well as an increased risk of serious infections. These toxicities can be severe, and frequently lead to treatment discontinuation. Umbralisib (TGR-1202) is a next generation, once-daily, oral PI3Kδ inhibitor, that is active in pts with relapsed/refractory (R/R) lymphoid malignancies, with a 94% ORR in previously treated CLL (Burris et al, 2015). Umbralisib has a markedly different chemical structure and pharmacologic profile compared to idelalisib and duvelisib, and kinome-profiling further differentiates umbralisib from these agents. All three compounds are selective for the PI3Kδ isoform, however the PI3Kγ isoform, which promotes pro-inflammatory cytokines and increased recruitment and cytotoxicity of T cells, is not inhibited by umbralisib (Kaneda et al, Nature 2016). Umbralisib also has an additional effect on casein kinase-1 epsilon (CK-1ε), a protein which may have an inhibitory effect on regulatory T-cell function (Deng et al, 2016). Collectively, these pharmacologic features provide a potential rationale for the differentiated toxicity profile of umbralisib compared to other PI3Kδ inhibitors. Here, we present an integrated safety analysis for pts dosed with umbralisib either as monotherapy or in combination with other agents.