Receiving rituximab (Rituxan) with idelalisib, rather than rituximab with placebo, “significantly improved progression-free survival, response rate, and overall survival” among patients with relapsed chronic lymphocytic leukemia (CLL) who were less able to undergo chemotherapy because of clinically significant coexisting medical conditions, according to results of a phase III study. “On the basis of response rates and progression-free survival results, the combination of idelalisib and rituximab may be a treatment option for these patients,” researchers reported in The New England Journal of Medicine.
The multicenter double-blind, placebo-controlled trial randomly assigned 220 patients with decreased renal function, previous therapy-induced myelosuppression, or major coexisting illnesses to receive rituximab and either idelalisib (at a dose of 150 mg) or placebo twice daily. Idelalisib (formerly called GS-1101 and CAL-101) is an oral inhibitor of the delta isoform of phosphatidylinositol 3-kinase (PI3K-delta). The activation of PI3K, in part, mediates signaling through the B-cell receptor, which plays a key role in the pathogenesis of CLL, the investigators explained.
In phase I studies, idelalisib either alone or combined with other agents (including rituximab) “had clinically significant activity with an acceptable profile in patients with relapsed or refractory CLL,” they wrote. This led to the current phase III study, which at the first prespecified interim analysis, “was stopped early on the recommendation of the data and safety monitoring board owing to overwhelming efficacy,” the researchers stated. Because of this, the duration of treatment was short—a median of 3.8 months.
The median age of patients was 71. Nearly two-thirds had advanced-stage disease. “Patients in the two study groups had received a median of three previous agents, including regimens containing rituximab, cyclophosphamide, fludarabine, and bendamustine” (Treanda), the researchers noted.
Median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group = 0.15, P < .001), the researchers reported. “Improvement in progression-free survival was observed not only in the overall study population but also in all subgroups examined, including patients with poor prognostic features, such as 17p deletion or TP53 mutations and unmutated immunoglobulin heavy-chain variable region.”
Patients receiving idelalisib also had superior overall survival rates: 92% at 12 months vs 80% for those receiving placebo (hazard ratio for death = 0.28, P = .02). “Sixteen patients died while participating in the study: 4 patients (4%) in the idelalisib group and 12 patients (11%) in the placebo group,” according to the study report. The overall response rate, evaluated for 88 patients in each group who had at least one postbaseline assessment or discontinued the study before the first assessment at the time of the analysis was 81% in the idelalisib vs 13% for those receiving placebo (P < .001).
More than 90% of patients had at least one adverse event. The most common adverse events in the idelalisib group were pyrexia, fatigue, nausea, chills, and diarrhea. The most common adverse events in the placebo group were infusion-related reactions, fatigue, cough, nausea, and dyspnea. Serious adverse events occurred in 40% of patients receiving idelalisib and 35% of those receiving placebo, with the most frequent in both groups being pneumonia, pyrexia, and febrile neutropenia. “A surprising finding was a reduction in rates of infusion-related toxicity from rituximab in the idelalisib group,” the authors commented.
Contributing equally to the study were Richard R. Furman, MD, of Weill Cornell Medical College in New York, Jeff P. Sharman, MD, of U.S. Oncology Research in Springfield, Oregon, and Steven E. Coutre, MD, of Stanford University School of Medicine in California. The study was funded by Gilead Sciences of Foster City, California. Its ClinicalTrials.gov identifier is NCT01539512. ■