Idelalisib (Zydelig®) is an inhibitor of the B-cell receptor signaling pathway; it is indicated in combination with rituximab in adult patients with chronic lymphocytic leukaemia (CLL) who have received at least one prior therapy, or as first-line treatment for patients with deletion 17p and/or TP53 mutation who are unsuitable for chemoimmunotherapy. Idelalisib has been approved for this indication by both the EMA in September 2014 and the FDA in July 2014.
The marketing authorisation was based on the results of a phase III trial assessing idelalisib in combination with rituximab compared to placebo in combination with rituximab in 220 pretreated patients who were considered ineligible for further cytotoxic therapy.
Analyses showed a significant improvement of progression-free survival (PFS), overall survival (OS) and overall response rate (ORR). The median PFS was 5.5 months in the placebo group but was not yet reached in the idelalisib group. As a result of meeting its efficacy endpoints at the first interim data analysis, the trial was stopped early.
At least one adverse event occurred in 90% of patients in each group, but most of them were grade 2 or lower. 40% of patients in the idelalisib group and 35% of patients in the placebo group had at least one serious adverse event; most frequently were pneumonia, pyrexia and febrile neutropenia. Due to adverse events, 8% of idelalisib group patients and 10% of placebo group patients discontinued study treatment.
The combination therapy of idelalisib and rituximab is a feasible treatment option for patients with relapsed CLL who are ineligible for cytotoxic therapy; particularly for those with genetic factors including 17p deletion, TP53 mutation or unmutated IGVH. The median duration of exposure during the trial was about 5 months; therefore, no long-term data is available. Further trials are needed to evaluate efficacy and safety in long-term use of idelalisib. Moreover, the important issue of potential idelalisib resistance needs to be resolved.