Idelalisib: targeting PI3Kδ in B-cell malignancies.

Idelalisib—a fi rst-in-class selective inhibitor of phosphoinositide-3kinase delta, which is expressed only in haemopoietic cells—has been shown to be eff ective for treatment of B-cell malignancies in two clinical trials. First, in a single-group phase 2 study, researchers enrolled 125 patients with refractory, indolent non-Hodgkin lymphoma. Idelalisib (150 mg orally, twice daily) induced an objective response in 71 patients (57%), of whom seven (6%) achieved a complete response. Median progression-free survival was 11 months. Res ponses were reported for patients with all sub types of indolent non-Hodgkin lym phoma studied, including marginal-zone lym phoma and lymphoplasma cytic lym phoma with or without Waldenström macroglobulinaemia. “Patients had disease that was refractory to both rituximab and alkylating agents”, said author Ajay Gopal (Fred Hutchinson Cancer Research Center and University of Washington, Seattle, WA, USA). “The most remarkable part of this study was effi cacy without major toxicity. Side-eff ects were very manageable.” Gopal added that, for disease that is managed rather than cured with chemotherapy, the aim should be to “maintain quality of life and eff ectively manage the disease for long periods of time”. He further commented: “One could envision—if future studies support this—using idelalisib up front instead of using toxic chemotherapy”. In a phase 3 study, idelalisib plus rituximab was compared with placebo plus rituximab for treatment of 220 patients with relapsed chronic lymphocytic leukaemia (CLL) who could not tolerate standard chemotherapeutic agents. Compared with patients receiving rituximab alone, more patients receiving idelalisib plus rituximab achieved overall response (81% vs 13%) and overall survival at 12 months (92% vs 80%). Median progression-free survival was also increased (not reached vs 5·5 months). Author Richard Furman (Weill Cornell Medical College, New York, NY, USA) said: “This placebo-controlled trial met its effi cacy endpoints at the fi rst interim data analysis, resulting in the data safety monitoring board halting the trial and moving everyone from placebo to active agent”. He added that “idelalisib is a paradigmchanging drug for patients with CLL”, with responses far better than he imagined. On Dec 6, 2013, an application was fi led with the Food and Drug Administration, and idelalisib for relapsed CLL was given Breakthrough Therapy designation.