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FDA Approves Idelalisib for CLL, SLL, and Follicular Lymphoma

Silas Inman @silasinman
Published: Wednesday, Jul 23, 2014

Dr. Richard Pazdur

Richard Pazdur, MD

The FDA has approved idelalisib (Zydelig) in combination with rituximab (Rituxan) for patients with high-risk relapsed or refractory chronic lymphocytic leukemia (CLL) and as a single-agent for two types of indolent non-Hodgkin lymphoma (iNHL).

In the supporting CLL study, the addition of idelalisib to rituximab improved overall survival (OS) by 72% and progression-free survival (PFS) by 82% versus placebo and rituximab. Based on the magnitude of benefit, the trial was halted early and crossover was allowed following a positive risk–benefit review. In patients with relapsed iNHL, treatment with single-agent idelalisib demonstrated an overall response rate (ORR) of 54% for patients with follicular lymphoma (FL) and 61% for patients with small lymphocytic lymphoma (SLL).

The approval for idelalisib includes a Boxed Warning regarding fatal and serious liver toxicity, diarrhea, colitis, pneumonitis, and intestinal perforation associated with first-in-class PI3K-delta inhibitor. To address concerns with these side effects, idelalisib is also being approved along with a Risk Evaluation and Mitigation Strategy (REMS).

“In less than a year, we have seen considerable progress in the availability of treatments for chronic lymphocytic leukemia,” Richard Pazdur, MD, director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research, said in a release. “Zydelig’s approval to treat CLL reflects the promise of the breakthrough therapy designation program and represents the FDA’s commitment to working cooperatively with companies to expedite a drug’s development, review and approval.”

The phase III Study 116 trial randomized 220 previously treated patients with relapsed or refractory CLL in a 1:1 ratio to receive oral idelalisib plus rituximab (n = 110) or rituximab and placebo (n = 110). All patients had measurable lymphadenopathy and comorbidities that rendered them ineligible for cytotoxic therapy. Patients had received a median of 3 prior therapies, 44% had del17p or TP53 mutations, and 84% were IGHV-unmutated.

In the study, idelalisib was administered at a 150-mg dose twice daily. In both arms, rituximab was administered at an initial dose of 375 mg/m2 followed by 500 mg/m2 every 2 weeks for 4 cycles and then every 4 weeks for 3 cycles. The primary endpoint of the study was PFS. 

In an updated interim analysis presented at the 2014 ASCO Annual Meeting, 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. In an analysis provided by the FDA, the median PFS was noted as 10.7 months for patients treated with idelalisib and rituximab compared with 5.5 months with rituximab and 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).

Treatment with idelalisib plus rituximab was superior across all organomegaly and hematologic response criteria. In high-risk patients, 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.

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 rituximab plus placebo 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.

“Zydelig is a much needed new treatment option for appropriate patients with CLL and these indolent lymphomas who have experienced relapses and have limited, if any, treatment options,” Bruce Cheson, MD, professor of medicine, Head of Hematology and Director of Hematology Research at Lombardi Comprehensive Cancer Center at Georgetown University, said in a press release.

In the single-arm phase II study, 125 patients with relapsed iNHL were treated with idelalisib at 150 mg twice daily. The primary endpoint of the study was ORR, with secondary endpoints including duration of response and PFS.

According to data published in The New England Journal of Medicine, the ORR in patients with FL (n = 72) was 54% (95% CI, 0.42-0.66). For patients with SLL, the ORR was 61% (95% CI, 0.41-0.79). For the entire population, the median time to response was 1.9 months, with a median duration of response of 12.5 months. The median PFS was 11 months and the median OS was 20.3 months.

In this study, the most common grade 3/4 adverse events were diarrhea (13%), decreased neutrophils (27%), and increased alanine transaminase (13%). Grade 3/4 diarrhea, colitis, or both developed in 16% of patients at a median of 6 months after the initiation of treatment. Adverse events that led to treatment discontinuation included colitis (3%), pneumonia and pneumonitis (2%), and diarrhea and neutropenia (2%). To address this, the initial dose was lowered to 100 mg or 75 mg twice daily.

“In clinical studies among patients with relapsed CLL, FL and SLL, Zydelig produced strong responses, including a significant improvement in progression-free survival in CLL. I believe it helps fill a significant unmet need for these patients,” Cheson said.



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