February 2016, Vol. 5, No. 1
Idelalisib Combined with Bendamustine/Rituximab Boosts Survival in CLLASH 2015, ASH Highlights
Idelalisib combined with bendamustine/rituximab (BR) reduced the risk of disease progression and death versus BR alone in patients with relapsed/refractory (RR) chronic lymphocytic leukemia (CLL), according to results from a randomized, double-blind, placebo-controlled, phase 3 late-breaking trial presented at the meeting.
Lead investigator Andrew Zelenetz, MD, Memorial Sloan Kettering Cancer Center, New York City, hailed these results enthusiastically: “For the first time, we can begin to talk about cure for CLL with newer therapies. Idelalisib is an important option over the current standard of care.”
The study randomized 416 patients with RR CLL to idelalisib plus BR versus placebo plus BR. Patients were prestratified according to 17p deletion and TP53 mutation status, as well as IgHV mutation status.
A prespecified interim analysis found that the primary end point, progression-free survival (PFS), and a secondary end point, overall survival (OS), were superior in the idelalisib arm. An independent data monitoring committee recommended unblinding the study based on these findings.
Idelalisib achieved a highly statistically significant gain with a median PFS of 23.1 months versus 11.1 months for placebo (P <.0001). The difference represents a 67% reduction in risk of progression or death. The PFS benefit for idelalisib was consistent across all subgroups, regardless of the presence of high-risk genetic mutations (17p deletion, TP53 mutation).
Median OS has not been reached in either arm. The interim results suggested that idelalisib was 45% more likely to achieve a survival benefit than BR alone (P = .008). This benefit was also observed across all subgroups.
Toxicity was reported in both arms of the trial. However, serious adverse events as well as treatment discontinuations were more frequently reported in the idelalisib arm.
The most common all-grade adverse events in the idelalisib arm were neutropenia (63.3%) and pyrexia (41.5%); in the placebo plus BR arm, they were neutropenia (53.6%) and nausea (34.4%).
Grade 3 and higher adverse events in the idelalisib arm were neutropenia (59%) and febrile neutropenia (20.3%). The most common grade 3 and higher adverse events in the BR arm were neutropenia (45.9%) and anemia (12%). Grade 3 and higher diarrhea and pneumonitis and elevations in transaminase levels were all more frequent in the idelalisib arm.
Hepatotoxicity is the main side effect of concern with idelalisib. In this trial, ALT elevations of all grades were reported in 59.9% of idelalisib-treated patients versus 30.6% in the BR arm. Grade 3 or higher ALT elevations were 21.3% versus 2.9%, respectively. Elevated AST levels were more frequent in the idelalisib arm: 52.2% versus 27.8%, respectively, for all grades; grades 3 and higher elevated AST levels were reported in 15.5% versus 3.3%, respectively.
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