Idelalisib (Zydelig) reduced the risk for disease progression and death when added to bendamustine (Treanda) plus rituximab (Rituxan) versus bendamustine plus rituximab alone in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to the results of a randomized, double-blind, placebo-controlled, phase 3 late-breaking trial presented at ASH 2015.
Potential Cure for CLL
Lead investigator Andrew D. Zelenetz, MD, PhD, Medical Oncologist, Memorial Sloan Kettering Cancer Center, NY, hailed these results enthusiastically.
“For the first time, we can begin to talk about cure for CLL with newer therapies,” Dr Zelenetz said. “Idelalisib is an important option over the current standard of care.”
The study randomized 416 patients with relapsed or refractory CLL to idelalisib and bendamustine plus rituximab versus placebo plus bendamustine and rituximab. Patients were prestratified according to 17p deletion, TP53 mutation status, and IGHV mutation status.
A prespecified interim analysis showed that the primary end point of progression-free survival (PFS) and the secondary end point of overall survival (OS) were superior in the idelalisib arm. An independent, data-monitoring committee recommended unblinding the study based on these findings.
The addition of idelalisib achieved a very significant gain in PFS, with a median PFS of 23.1 months versus 11.1 months for placebo (P <.001). This difference represents a 67% risk reduction for progression or death.
The PFS benefit for idelalisib was consistent across all subgroups, regardless of the presence of high-risk genetic mutations (eg, 17p deletion or TP53 mutation).
The median OS has not yet been reached in either arm. The interim results suggested that the addition of idelalisib was 45% more likely to achieve a survival benefit than bendamustine plus rituximab alone (P = .008). This benefit was observed across all subgroups.
Toxicity
Toxicity was reported in both arms of the trial, but serious adverse events and treatment discontinuations were more common in the idelalisib arm.
The most common (63.3%) all-grade adverse events in the idelalisib arm were neutropenia and pyrexia compared with 41.5% in the bendamustine plus rituximab arm. The most common adverse events in the bendamustine plus rituximab arm were neutropenia and nausea (53.6% vs 34.4% in the idelalisib arm).
Grade ≥3 adverse events in the idelalisib arm included neutropenia (59%) and febrile neutropenia (20.3%). The most common grade ≥3 adverse events in the bendamustine plus rituximab arm were neutropenia (45.9%) and anemia (12%). Grade ≥3 diarrhea, pneumonitis, and elevations in transaminase levels were more frequent in the idelalisib arm.
Hepatotoxicity is the main side effect of concern with idelalisib. In this trial, alanine transaminase (ALT) elevations of all grades were reported in 59.9% of patients receiving idelalisib (vs 30.6% of the other arm).
Grade ≥3 ALT elevations were reported in 21.3% and 2.9% of these patients, respectively. Elevated aspartate transaminase (AST) levels were more frequent with idelalisib than with bendamustine plus placebo alone (52.2% vs 27.8%, respectively); grade ≥3 elevated AST levels were 15.5% and 3.3%, respectively.