Novel Rituximab Combinations Highly Effective in CLL

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.

Idelalisib Efficacy Established in Phase III

"[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."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.

ABT-199 Shows Early Promise

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 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.

Monotherapy Potential

In all 45 patients in the study, the most common all-grade adverse events were neutropenia (51%), nausea (38%), and diarrhea (33%). The most common serious adverse events were neutropenia (47%), anemia (16%), and thrombocytopenia (13%). Febrile neutropenia occurred in 7% of patients.Despite the promising results demonstrated in these trials, it remains unclear whether these agents are most effective in combination or as single-agents. "Our collective experience really does not tell us whether you need to add any other agent to any of these drugs, including an anti-CD20 antibody," Coutre said.

To answer this lingering question, further investigation of these treatments for patients with CLL is currently underway. Outside of CLL, ABT-199 and idelalisib have been explored as monotherapies in patients with NHL.

In a phase II study, monotherapy with idelalisib was explored in patients with refractory iNHL and demonstrated an ORR of 57%, a median duration of response of 12.5 months, and a median PFS of 11.0 months.³ Additionally, a phase I study explored single-agent ABT-199 in patients with relapsed NHL. In this study, the ORR was 48%, with a particularly strong response seen in diffuse large B-cell lymphoma and follicular lymphoma.⁴

In addition to these agents, the BTK inhibitor ibrutinib (Imbruvica) has also shown impressive findings for patients with CLL, leading to an FDA approval in February 2014. This agent has primarily been developed as a single-agent. In the phase III RESONATE trial, ibrutinib monotherapy tripled PFS, doubled OS, and substantially improved ORR when compared with ofatumumab for patients with relapsed CLL.⁵

"[Combinations] remain a very relevant question with ibrutinib because ibrutinib has been developed primarily as a single-agent, whereas idelalisib has been developed primarily in combination," Coutre observed. "It's not clear that you need to add anything to a single agent, and so we have trials that are starting to address that."

References

1. Coutre SE, Furman RR, Sharman JP, et al. Second interim analysis of a phase 3 study evaluating idelalisib and rituximab for relapsed CLL. J Clin Oncol. 2014;32:5s (suppl; abstr 7012).
2. Shou M, Seymour JF, Lanasa MC, et al. ABT-199 (GDC-0199) combined with rituximab (R) in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): Interim results of a phase 1b study. J Clin Oncol. 2014;32:5s (suppl; abstr 7013).
3. Wagner-Johnson, Gopal AK, Kahl BS, et al. Patient-reported outcomes data from a phase 2 study of idelalisib in patients with refractory indolent B-cell non-Hodgkin lymphoma (iNHL). J Clin Oncol. 2014; 32:5s (suppl; abstr e19554).
4. Davids MS, Seymour JF, Gerecitano JF, et al. Phase I study of ABT-199 (GDC-0199) in patients with relapsed/refractory (R/R) non-Hodgkin lymphoma (NHL): Responses observed in diffuse large B-cell (DLBCL) and follicular lymphoma (FL) at higher cohort doses. J Clin Oncol. 2014; 32:5s (suppl; abstr 8522).
5. Byrd JC, Brown JR, O'Brien SM, et al. Randomized comparison of ibrutinib versus ofatumumab in relapsed or refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma: Results from the phase III RESONATE trial. J Clin Oncol. 2014;32:5s (suppl; abstr LBA7008

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