New Orleans, LA—A planned interim analysis of the first phase 3 clinical trial shows that idelalisib, a first-in-class selective oral kinase inhibitor, when combined with rituximab (Rituxan), is superior to rituximab alone in 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 R. Furman, MD, Richard A. Stratton Assistant Professor in Hematology and Oncology, Weill Cornell Medical College, New York.
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 Dr Furman.
Idelalisib was granted Breakthrough Therapy status by the US Food and Drug Administration in 2013.
Idelalisib targets the delta isoform of the phosphoinositide-3-kinase 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 restrains proliferation and induces apoptosis in CLL cells.
Overall, 220 adult patients (median age, 71 years) with relapsed CLL who were deemed unfit for further cytotoxic chemotherapy and who had measurable lymphadenopathy that had progressed after the completion of previous therapy, were randomized to a combination of idelalisib twice daily plus rituximab or to 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 previous therapies before enrollment, with 90% previously treated with rituximab.
After 24 weeks, the PFS rate for patients receiving idelalisib plus rituximab was 93% compared with 46% for those receiving rituximab alone (P <.001). The median PFS has not yet been reached in the combination arm, but was 5.5 months in the rituximab plus placebo arm. The patients receiving idelalisib plus rituximab had a significantly better overall response rate (81%) versus patients receiving rituximab alone (13%; P <.001), in addition to a higher lymph-node response rate (93% vs 4%, respectively).
The patients who were randomized to idelalisib plus rituximab also had a 72% improvement in overall survival compared with the control group (P = .018).
The combination of idelalisib plus rituximab had an acceptable adverse event (AE) profile, said Dr Furman. Grade ≥3 AEs were reported in 56.4% of the patients in the combination arm compared with 47.7% of patients in the rituximab plus placebo arm. The most common AEs included transaminitis, pyrexia, fatigue, nausea, chills, diarrhea, and infusion-related reactions.
Most study discontinuations were a result of disease progression, although 9 patients in the combination arm and 11 in the control arm discontinued treatment because of AEs.
Promising Safety, Efficacy With several new agents on the horizon for the treatment of CLL, the optimal sequence of therapies will be ripe for exploration. Jennifer R. Brown, MD, PhD, Director, Chronic Lymphocytic Leukemia Center, Dana-Farber Cancer Institute, Boston, said, “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.”
Dr Furman said that he sees idelalisib being used beyond the heavily pretreated patient population with CLL. “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.