Steven E. Coutre, MD
The novel agents idelalisib and ABT-199 in combination with rituximab have demonstrated impressive activity with manageable toxicity for patients with relapsed or refractory chronic lymphocytic leukemia (CLL), according to two separate studies presented in a poster highlight session at the 2014 ASCO Annual Meeting.
At the second interim analysis of the phase III Study 116 trial, the combination of the PI3K-delta inhibitor idelalisib and rituximab demonstrated an improvement in progression-free survival (PFS) of 82% and a 72% elevation in overall survival (OS). Additionally, in an early phase Ib trial, the novel Bcl-2 inhibitor ABT-199 demonstrated an overall response rate (ORR) of 84% when it was combined with rituximab.
"[Study 116] clearly demonstrates that adding idelalisib to rituximab is superior. Patients have a longer duration of response and they live longer—a dramatic benefit from that standpoint," study author Steven E. Coutre, MD, a professor of medicine (hematology) at the Stanford University Medical Center, said in an interview with OncLive
. "If you're a practicing oncologist and you think about the patients that you've treated with rituximab in this setting then adding idelalisib to that would make sense, based on these results."
Idelalisib Efficacy Established in Phase III
In the phase III study,1
220 patients with a median age of 71 years were randomized in a 1:1 ratio to receive rituximab plus idelalisib (n = 110) or rituximab and placebo (n = 110). Patients in the study had received 3 prior therapies, including prior treatment with rituximab.
Based on findings from the first analysis, the trial was halted and crossover was allowed following a positive risk–benefit review. At the second analysis of the study, the median PFS for idelalisib plus rituximab had not been reached, compared with 5.5 months with placebo plus rituximab (HR = 0.18; 95% CI, 0.10-0.32; P
< .0001). At 24 weeks, 90% of patients treated with idelalisib remained progression-free compared with 50% with placebo.
The ORR with idelalisib was 77% versus 15% with placebo (P
< .0001). Of evaluable patients, 92% treated with idelalisib experienced a greater than 50% reduction in lymph node size compared with 6% with placebo (P
< .0001). Additionally, treatment with idelalisib plus rituximab was superior across all organomegaly and hematologic response criteria.
Altogether, 44% of patients harbored a del(17p)/TP53
mutation. In this high-risk population, the combination of idelalisib and rituximab demonstrated comparable efficacy to the entire population, with an ORR of 77% and an HR for PFS of 0.13.
In the initial portion of the trial, patients received idelalisib at 150 mg twice daily. An expansion study explored single-agent idelalisib at 150 mg twice daily for patients progressing on the combination or at 300 mg for patients in the control arm.
At the time of the analysis, the median OS, including the extension portion, was not yet reached in each arm (HR = 0.28; 95% CI, 0.11-0.69; P
= .003). At 24 weeks, the OS rate for patients treated with idelalisib was 96% compared with 86% for those in the placebo arm.
Adverse events of any grade occurred in 95% of patients in both arms of the trial. The incidence of grade 3/4 adverse events was 64% with idelalisib versus 52% with placebo. The discontinuation rate associated with adverse events was 5% in the idelalisib arm and 6% in the placebo group.
The FDA is currently reviewing an application for idelalisib in CLL, which was granted a breakthrough therapy designation in 2013. Additionally, the FDA is considering the treatment for indolent non-Hodgkin's lymphoma (iNHL).
ABT-199 Shows Early Promise
ABT-199 demonstrated promising efficacy in patients who received the drug in combination with rituximab in a phase Ib study.2
Patients in the study had a median age of 69 years and had received a median of two prior therapies, including rituximab (91%) and fludarabine (47%). Altogether, 24% of patients entering the trial were refractory to rituximab.
In 25 evaluable patients, the ORR was 84%, with 36% achieving a complete response (CR) and 48% with a partial response. Lymph node size was reduced by 50% in 94% of patients treated with ABT-199, with a median time to reduction of 12 weeks. Seven patients with a CR were analyzed for minimal residual disease (MRD), of which 5 (71%) were deemed MRD-negative.
The initial dose of ABT-199 in the trial began at 50 mg but was modified to 20 mg as a result of a fatal episode of tumor lysis syndrome (TLS) that occurred during the lead-in period. Following this modification and increased monitoring, further TLS events did not occur. These events were not considered to be dose limiting. The final dose selected for phase II studies with induction was 400 mg.