Idelalisib: A Novel PI3Kδ Inhibitor for Chronic Lymphocytic Leukemia

To review and summarize data on idelalisib, which was approved by the Food and Drug Administration (FDA) in July 2014 for use in combination with rituximab for relapsed chronic lymphocytic leukemia (CLL).

A literature search using PubMed was conducted from January 2011 through May 2015 using the terms idelalisib, GS-101, CAL-101, PI3Kδ, and CLL. Data were also obtained through the FDA briefing documents, American Society of Clinical Oncology, and American Society of Hematology abstracts.

The literature search was limited to human studies published in English. Priority was placed on trials of idelalisib in CLL.

Idelalisib is a potent, first-in-class selective inhibitor of phosphatidylinositol-3-kinaseδ (PI3Kδ) approved by the FDA in July 2014 for the treatment of relapsed CLL, in combination with rituximab, in patients for whom rituximab monotherapy would be considered appropriate due to other comorbidities. PI3Kδ is hyperactivated in B-cell malignancies and plays a vital role in the B-cell receptor pathway, a key oncogenic driver in various B-cell malignancies, including CLL. Several phase I/II studies have demonstrated clinical activity of idelalisib in CLL, particularly in the setting of relapsed/refractory disease, with overall response rate ranging from 70% to 82%. The FDA approval was based on a phase III, randomized trial of rituximab monotherapy (n = 110) or idelalisib in combination with rituximab (n = 110) in heavily, pre-treated patients (median of 3 prior therapies) with relapsed CLL. Idelalisib was administered as 150 mg orally twice daily. Idelalisib plus rituximab was associated with an overall response rate of 81% and overall survival of 91% at 12 months. The median progression-free survival was not reached in the idelalisib arm at the time of the first interim analysis. The incidence of grade 3 or higher adverse events in the idelalisib plus rituximab arm was as follows: neutropenia (34%), thrombocytopenia (10%), anemia (5%), elevation in transaminases (5%), and diarrhea (4%).

Idelalisib in combination with rituximab is a safe and effective new treatment option for patients with relapsed CLL, including those with poor prognostic factors. As the results from various ongoing studies become available, the role of idelalisib will likely continue to expand.