February 2014, Vol 3, No 1
Idelalisib Improves Outcomes in Heavily Pretreated CLL Patients
A planned interim analysis of a phase 3 study shows that idelalisib, a first-in-class selective oral kinase inhibitor, when combined with rituximab is superior to rituximab alone on the end point of progression-free survival (PFS) in patients with heavily pretreated chronic lymphocytic leukemia (CLL).
The 24-week data from the randomized, placebo-controlled trial were presented by Richard Furman, MD, assistant professor of hematology and oncology, Weill Cornell Medical College, New York City.
Idelalisib plus rituximab “provided effective, durable disease control and improved overall survival for patients with relapsed CLL who were not suitable for cytotoxic chemotherapy, including high-risk patients,” said Furman.
The study provides the first phase 3 randomized data available for idelalisib, which has been granted breakthrough status by the FDA.
Idelalisib targets the delta isoform of the phosphatidylinositol-3-kinase (PI3K-?) enzyme, which is critical for the activation and survival of CLL cells and other low-grade B-cell lymphomas. It inhibits homing and retention of malignant B cells in lymphoid tissues, reducing B-cell survival, and it restrains proliferation and induces apoptosis in CLL cells.
In the study, 220 adult patients with relapsed CLL who were deemed unfit for further cytotoxic chemotherapy because of comorbidities and who had measurable lymphadenopathy that had progressed following completion of previous therapy were randomized to receive a combination of either idelalisib twice daily and rituximab or placebo twice daily and rituximab continuously until disease progression or death. Patients were eligible for the trial if they had received at least 1 anti-CD20 antibody-containing therapy or at least 2 cytotoxic therapies. Patients had a median of 3 prior therapies before enrollment, with 90% having received prior rituximab. The median patient age was 71 years.
After 24 weeks, the PFS for the combination idela- lisib/rituximab group was 93%, compared with 46% for those treated with rituximab alone (P<.0001). The median PFS has not yet been reached in the idelalisib/rituximab arm; it was 5.5 months in the rituximab/placebo arm. Patients in the idelalisib/rituximab arm had a significantly better overall response rate relative to the patients treated with rituximab alone (81% vs 13%, respectively; P<.0001) in addition to a higher lymph node response rate (93% vs 4%, respectively).
Patients randomized to idelalisib/rituximab also experienced a 72% improvement in overall survival compared with the control group (P=.018).
The combination of idelalisib plus rituximab had an acceptable adverse event profile, said Furman. Grade ?3 adverse events were reported in 56.4% of patients in the idelalisib/rituximab arm compared with 47.7% in the rituximab/placebo arm. The most common adverse events included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea, and infusion-related reactions.
Most study discontinuations were due to disease progression, though 9 patients in the combination arm and 11 in the control arm discontinued due to adverse events.
With several new agents on the horizon for the treatment of CLL, the optimal sequence of therapies will be ripe for exploration. Said Jennifer Brown, MD, PhD, director of the Chronic Lymphocytic Leukemia Center at Dana-Farber Cancer Institute, “That’s going to depend to some extent on emerging patterns of resistance and whether some agents may work better than others based on those emerging patterns of resistance. Certainly, combinations of these agents will be of great interest, and I think that’s what we’ll be evaluating over the next 5 years or so.”
Furman said that he sees idelalisib being used beyond the heavily pretreated CLL patient population. “Given the efficacy and low risk for long-term toxicities demonstrated, we believe this treatment could be applicable to all CLL patients because it eliminates the need for chemotherapy,” he said.
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