Idelalisib plus Bendamustine/Rituximab versus Bendamustine/Rituximab in Relapsed/Refractory CLL: Results of a Phase 3 Study
Idelalisib is a first-in-class PI3K delta inhibitor that is approved in combination with rituximab for the treatment of patients with relapsed chronic lymphocytic leukemia (CLL) and as first-line therapy in patients with 17p deletion or TP53 mutation who are unsuitable for chemoimmunotherapy.1 Zelenetz and colleagues presented the results of a phase 3, randomized, double-blind, placebo-controlled study that evaluated the efficacy of idelalisib plus standard bendamustine/rituximab (BR) versus BR in 416 patients with relapsed/refractory CLL.2 In this trial, patients were randomized to receive idelalisib 150 mg BID or placebo (administered continuously) plus BR for 6 cycles Q 28 days.
A prespecified interim analysis was performed when 75% of the total number of 260 planned events of CLL progression or death from any cause had occurred. The interim analysis demonstrated that the primary end point of progression-free survival (PFS) and overall survival (OS) were superior with idelalisib-BR versus control therapy, based on which the Independent Data Monitoring Committee recommended unblinding the study. In the intent-to-treat analysis, idelalisib/BR therapy resulted in a significant improvement in PFS compared with BR therapy (hazard ratio [HR], 0.33; P <.0001), corresponding to a 67% reduction in the risk of progression and a doubling of median PFS (23.1 months vs 11.1 months). The PFS benefit extended to all patient subgroups, including those with high-risk features (refractory: HR, 0.41; unmutated IgHV: HR, 0.38; del 17p/TP53: HR, 0.50). Patients treated with idelalisib also achieved a higher overall response rate (68% vs 45%), the majority of which were partial responses. Idelalisib treatment was associated with a significant improvement in OS compared to BR treatment alone (HR, 0.55; P = .006); the median OS was not reached in either arm. The OS benefit was achieved by most patient subgroups except for patients with refractory disease. All patients experienced adverse events (AEs) of any grade, and grade 3/4 AEs were higher in the idelalisib arm (93% vs 76%). The most common adverse events (all grades) associated with idelalisib/BR therapy were neutropenia (63%) and pyrexia (42%); grade 3/4 neutropenia occurred in 60% of patients, pyrexia in 7%, and febrile neutropenia in 20%. Also, idelalisib/BR therapy was associated with higher incidence of grade ?3 diarrhea (7% vs 2%) and pneumonitis (11% vs 6 %). Based on these results, the authors concluded that idelalisib in combination with BR is superior to BR alone in terms of PFS and OS, with a safety profile consistent with those described previously.
- Advani RH, et al. J Clin Oncol. 2013;31-88-94.
- Fowler N. ASH 2012. Abstract 156.
- Zelenetz A, et al. ASH 2015. Abstract LBA5.