The triplet combination of idelalisib, bendamustine, and rituximab (BR) improved overall survival (OS) and progression-free survival (PFS) compared with BR alone in patients with relapsed and/or refractory chronic lymphocytic leukemia (CLL), according to results from a recent phase III, randomized, double-blind, placebo-controlled study presented as a late-breaking abstract at the 2015 ASH Annual Meeting.
“The combination of idelalisib plus BR was superior to BR alone,” said Andrew D. Zelenetz, MD, PhD, from the Department of Medicine, Lymphoma Service at Memorial Sloan Kettering Cancer Center in New York, during his discussion of the results. “Idelalisib plus BR represents an important new option over a standard of care. 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.” Idelalisib is a first-in-class phosphoinositide 3-kinase (PI3k) delta inhibitor that has been approved by the U.S. Food and Drug Administration for use in combination with rituximab for patients with relapsed CLL and as a first-line treatment in patients with del17p or TP53 mutation who are not eligible for chemoimmunotherapy.
The study enrolled 416 patients between June 2012 and August 2014. Patients were eligible for the study if they had received prior therapy containing a purine analog or bendamustine, prior treatment with an anti-CD20 antibody, CLL progression within 36 months of the completion of the last prior therapy, and were “fit” to receive cytotoxic therapy. The median time from prior therapy was 16 months, and the median number of prior therapies was two (range = 1-13).
Patients were randomized to receive:
- Idelalisib 150 mg plus bendamustine 70 mg/m2 and rituximab 375 mg/m2 during cycle 1 and 500 mg/m2 during cycles 2-6 (n=207)
- Bendamustine 70 mg/m2 and rituximab 375 mg/m2 during cycle 1 and 500 mg/m2 during cycles 2-6 plus placebo (n=209)
Treatment was continued until disease progression, death, intolerable toxicity, or withdrawal of consent. Computed tomography imaging was performed every 12 weeks to assess patients for disease progression.
After 12 months of follow-up, the median PFS in patients treated with idelalisib plus BR was more than double the median PFS in patients treated with BR alone: 23.1 months versus 11.1 months, respectively (hazard ratio [HR] = 0.33; 95% CI 0.24-0.45; p<0.0001).
Additionally, though the median OS had not been reached in either cohort at the time of reporting, there was a 45 percent reduction in the risk of death when idelalisib was added to treatment (HR=0.55; 95% CI; 0.36-0.86). As seen in the TABLE, the results were consistent across all patients, regardless of the presence of high-risk features (i.e., del17p, TP53, unmutated IGHV, and refractory disease).
At the pre-specified interim analysis (once 67% of events had occurred), an independent review committee recommended stopping the study early to allow patients in the control arm to receive idelalisib and unblinding the results. “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,” Dr. Zelenetz explained.
However, Dr. Zelenetz added, “this was not without toxicity, and virtually all patients in both arms experienced treatment-related toxicity.”
Ninety-three percent of patients in the idelalisib arm experienced a grade ≥3 adverse event (AE), while 76 percent of those in the BR-alone arm experienced a grade ≥3 AE. Serious AEs were seen in 66 percent of patients treated with idelalisib, compared with 44 percent of those in the control arm. Rates of dose reductions or treatment discontinuation due to AEs were 11 percent and 26 percent, respectively, in the idelalisib-treated arm. These rates were nearly double what was seen in the control arm, at 6 percent and 13 percent, respectively.
The most common treatment-related AEs for those receiving idelalisib plus BR were neutropenia (63.3%) and pyrexia (41.5%). Neutropenia was also the most common treatment-related adverse event for those receiving BR alone (53.6%), followed by nausea (34.4%).
“This safety profile is consistent with what we know for idelalisib, bendamustine, and rituximab,” he noted.
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. Abstract #LBA-5 from the 2015 ASH Annual Meeting, December 8, 2015; Orlando, Florida.