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Gilead Sciences, Inc. has decided to voluntarily withdraw the indications of idelalisib in patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma who had received at least 2 prior systemic therapies.
Gilead Sciences, Inc. has decided to voluntarily withdraw the indications of idelalisib (Zydelig) in patients with relapsed follicular B-cell non-Hodgkin lymphoma and relapsed small lymphocytic lymphoma (SLL) who had received at least 2 prior systemic therapies.1
In July 2014, the FDA had granted an accelerated approval to the agent for use in combination with rituximab (Rituxan) based on findings from a phase 2 trial (Study 101-09; NCT01282424), which examined single-agent idelalisib in those refractory to rituximab and alkylating-containing chemotherapy. The agent elicited an independent review committee–assessed objective response rate (ORR) of 54% (95% CI, 42%-66%) in those with follicular lymphoma (n = 72), and of 58% (95% CI, 37%-77%) in those with SLL (n = 26).2
The continued approval of these indications was contingent upon providing evidence that supported confirmation of clinical benefit in these 2 diseases.
“As the treatment landscape for follicular lymphoma and SLL has evolved, enrollment into the confirmatory study has been an ongoing challenge,” according to the statement issued by the biopharmaceutical company. “As a result, Gilead Sciences, Inc. formally notified the FDA of its decision to voluntarily withdraw these indications from the US market.”
The first-in-class inhibitor of PI3K delta, was also approved by the FDA in 2014 for use in the treatment of adult patients with relapsed chronic lymphocytic leukemia (CLL), and has marketing authorization in the European Union, United Kingdom, Canada, Australia, New Zealand, and Switzerland for use in the treatment of patients with CLL and follicular lymphoma.
“None of these approvals are affected by the proposed withdrawal,” according to Gilead Sciences, Inc.
In the single-arm, multicenter Study 101-09, idelalisib was examined in a total of 72 patients with follicular B-cell non-Hodgkin lymphoma and 26 patients with SLL who had relapsed within 6 months after having been treated with rituximab and an alkylating agent. To be eligible for enrollment, patients must have received at least 2 prior treatments.3
Study participants were administered oral idelalisib at a twice-daily dose of 150 mg until progressive disease or intolerable toxicity. Investigators evaluated tumor response per the revised International Working Group response criteria for malignant lymphoma.
The median age of the patients with follicular lymphoma was 62 years (range, 33-84), 54% were male, and 90% were White. Moreover, most patients (92%) had an ECOG performance status of either 0 or 1 at baseline. The median time since diagnosis was 4.7 years, and the median number of previous therapies received was 4 (range, 2-12).
The most frequently received prior regimens in this subgroup included R-CHOP (rituximab, cyclophosphamide, doxorubicin, and vincristine; 49%), bendamustine (Bendeka) plus rituximab (BR; 50%), and R-CVP (rituximab, cyclophosphamide, vincristine, and prednisone; 28%). Additionally, 33% of patients had extranodal involvement and 26% had bone marrow involvement.
Among those with SLL, the median age was 65 years (range, 50-87), 73% were male, 81% were White, and 96% had an ECOG performance status of 0 or 1. The median time since diagnosis was 6.7 years, and the median number of prior therapies received was 4 (range, 2-9). The most common previous regimens included BR (81%), FCR (fludarabine, cyclophosphamide, and rituximab; 62%), and R-CHOP (35%). Twenty-seven percent of patients had extranodal involvement at baseline.
Additional data from the trial showed that among those with follicular lymphoma who responded to treatment, the complete response (CR) rate was 8%, and the partial response (PR) rate was 46%. The median duration of response (DOR) was not evaluable (range, 0.0+ to 14.8+), and the median time to response was 1.9 months (range, 1.6-8.3).
Among those with SLL who responded to idelalisib, the CR rate was 0% and the PR rate was 58%. The median DOR was 11.9 months (range, 0.0+ to 14.7+), and the median time to response was 1.9 months (range, 1.6-8.3).
The approval for the use of idelalisib in patients with CLL was primarily supported by findings from the phase 3 Study 116 trial (NCT01539512), which evaluated the agent in combination with rituximab in a total of 220 patients with relapsed disease who could not tolerate standard chemotherapy.
The study was stopped early, in October 2013, by an independent data monitoring committee after the agent demonstrated a significant progression-free survival (PFS) benefit vs rituximab monotherapy. The median PFS had not yet been reached (95% CI, 10.7–not reached) with the doublet vs 5.5 months (95% CI, 3.8-7.1) with single-agent rituximab (HR, 0.18; 95% CI, 0.10-0.32; P < .0001).
Idelalisib has a boxed warning on its product label detailing the risks of fatal and serious toxicities that could include the following: hepatic, severe diarrhea, colitis, pneumonitis, and intestinal perforation.
The most common adverse reactions reported with the agent, with or without rituximab, included diarrhea, pyrexia, fatigue, nausea, cough, abdominal pain, chills, and rash. The most common laboratory abnormalities observed in clinical studies comprised neutropenia, hypertriglyceridemia, hyperglycemia, and increased alanine/aspartate aminotransferase.
“Gilead continues to work collaboratively with the FDA to complete the withdrawal of the follicular lymphoma and SLL indications in the United States and with health care professionals to support those currently being treated with [idelalisib],” according to the statement.