The addition of idelalisib to bendamustine and rituximab (BR) reduced the risk of progression or death by 67% compared with BR alone for patients with relapsed/refractory chronic lymphocytic leukemia.
Andrew D. Zelenetz, MD, PhD
Adding idelalisib to bendamustine and rituximab (BR) reduced the risk of progression or death by 67% compared with BR alone for patients with relapsed/refractory chronic lymphocytic leukemia (CLL), according to data from a phase III trial presented at the 2015 ASH Annual Meeting.
After 12 months of follow-up, the median progression-free survival (PFS) with idelalisib was 23.1 months compared with 11.1 months for BR alone (HR, 0.33; 95% CI, 0.24-0.45; P <.0001). Additionally, there was a 45% reduction in the risk of death with the addition of idelalisib to BR, although the median OS had not yet been reached in either arm (HR, 0.55; 95% CI, 0.36-0.86; P = .008).
“The combination of idelalisib plus BR was superior to BR alone. If your plan is to use a chemotherapy regimen, then chemotherapy with idelalisib clearly has important benefits for the patients, in terms of progression-free and overall survival,” said Andrew D. Zelenetz, MD, PhD, Department of Medicine, Lymphoma Service, Memorial Sloan Kettering Cancer Center. "Idelalisib plus BR represents an important new option over a standard of care.”
Based on these benefits, the trial was unblinded early to allow patients in the control arm to receive idelalisib, following a recommendation from an independent data monitoring committee. Findings from the study are being submitted to the FDA and European Medicines Agency early next year, according to the developer of idelalisib, Gilead Sciences.
“There was a prespecified interim analysis once 67% of events had occurred in mid-October,” said Zelenetz. “It was recommended that the study should be stopped and that the results should be made public, because of an overwhelming benefit for the addition of idelalisib to the conventional arm.”
In the phase III study, 416 patients with CLL received 6 cycles of BR with idelalisib (n = 207) or placebo (n = 209). Bendamustine was administered at 70 mg/m2 on day 1 and 2 of each 28-day cycle along with rituximab at 375 mg/m2 during cycle 1 and 500 mg/m2 in subsequent cycles. Continuous idelalisib was administered at 150 mg twice daily until progression or unacceptable toxicity.
Patients in the study were primarily male (76%) and 42% were ≥65 years old. The median time since completion of prior therapy was 16 months and the median number of previous therapies was 2 (range, 1-13). A number of patients had high-risk features, including del17p (32.9%), unmutated IgHV (83.2%), and refractory disease (29.8%). The primary endpoint of the study was PFS, with OS and overall response rate (ORR) as a secondary outcome measures.
The PFS benefit seen with idelalisib was consistent across subgroups. In those with del17p or TP53, the HR for PFS was 0.50. For del17p alone, the HR was 0.63. Those with neither del17p nor TP53 experienced a 78% reduction in the risk of progression or death with the addition of idelalisib (HR, 0.22; 0.14-0.35).
“If we look at the various risk groups, this benefit was seen across risk groups for progression-free survival,” said Zelenetz. “This was not without toxicity, virtually all patients in both arms experienced treatment-related toxicity.”
Grade ≥3 adverse events (AEs) were experienced by 93% of patients in the idelalisib arm versus 76% of those in the BR alone group. Serious AEs were seen in 66% of patients treated with idelalisib versus 44% of those in the control arm. AEs led to a dose reduction or treatment discontinuation in the idelalisib arm for 11% and 26% of patients, respectively. This was nearly double what was seen in the control arm, at 6% and 13%, respectively.
The most common all-grade AEs with idelalisib plus BR were neutropenia (63.3%), ALT abnormalities (59.9%), AST abnormalities (52.2%), and pyrexia (41.5%). The most common grade ≥3 AEs were neutropenia (59.9%), ALT abnormality (21.3%), febrile neutropenia (20.3%), and AST abnormality (15.5%).
For BR alone, the most frequent all-grade AEs were neutropenia (53.6%), nausea (34.4%), ALT abnormalities (30.6%), and AST abnormalities (27.8%). The most common grade ≥3 AEs were neutropenia (45.9%) and anemia (12%). Grade ≥3 ALT and AST abnormalities were seen in 2.9% and 3.3% of patients in the placebo arm, respectively.
Grade ≥3 diarrhea occurred in 7.2% of patients treated with idelalisib versus 1.9% of those who received placebo. Additionally, serious pneumonitis occurred in 1.4% of patients treated with idelalisib compared with 0% for the placebo arm.
“Serious adverse events were more common when idelalisib was added to the conventional BR arm, and there was more discontinuation of study drug in the idelalisib plus BR arm,” said Zelenetz. “This safety profile is consistent with what we know for idelalisib, bendamustine, and rituximab.”
The FDA initially approved Idelalisib in July 2014 in combination with rituximab for patients with high-risk relapsed or refractory CLL and as a single-agent for two types of indolent non-Hodgkin lymphoma. The agent carries a Boxed Warning and a Risk Evaluation and Mitigation Strategy regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation.
In addition to these indications, data are currently with the FDA from the phase III Study 119, which showed an improvement in ORR and PFS with the combination of idelalisib and ofatumumab compared with the CD20 inhibitor alone in patients with previously treated CLL.
Zelenetz AD, Robak T, Coiffier B, et al. Idelalisib Plus Bendamustine and Rituximab (BR) Is Superior to BR Alone in Patients with Relapsed/Refractory Chronic Lymphocytic Leukemia: Results of a Phase 3 Randomized Double-Blind Placebo-Controlled Study. Presented at: 57th American Society of Hematology Annual Meeting; Orlando, Florida; December 5-8, 2015. Abstract LBA-5.