General Information

Zydelig (idelalisib) is a small molecule inhibitor of phosphoinositide-3 kinase (PI3K) delta, an intracellular signaling component. PI3K-delta is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies.

Zydelig is specifically indicated for the following:

• Relapsed chronic lymphocytic leukemia in combination with rituximab, in patients for whom rituximab alone would be considered appropriate therapy due to other co-morbidities.

Zydelig was granted accelerated approval for relapsed follicular B-cell non-Hodgkin lymphoma in patients who have received at least two prior systemic therapies and relapsed small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. These indications were voluntarily withdrawn in 2022.

Zydelig is supplied as a tablet for oral administration. The recommended maximum starting dose of Zydelig is 150 mg administered orally twice daily. Zydelig can be taken with or without food. Tablets should be swallowed whole. Continue treatment until disease progression or unacceptable toxicity. 

Mechanism of Action

Zydelig (idelalisib) is a small molecule inhibitor of phosphoinositide-3 kinase (PI3K) delta, an intracellular signaling component. PI3K-delta is expressed primarily in blood-cell lineages, including cells that cause or mediate hematologic malignancies. Idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B-cells and in primary tumor cells. Idelalisib inhibits several cell signaling pathways, including B-cell receptor (BCR) signaling and the CXCR4 and CRCR5 signaling, which are involved in trafficking and homing of B-cells to the lymph nodes and bone marrow. Treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion, and reduced cell viability.

Side Effects

Adverse effects associated with the use of Zydelig may include, but are not limited to, the following:

• diarrhea
• pyrexia
• fatigue
• nausea
• cough
• pneumonia
• abdominal pain
• chills
• rash

Clinical Trial Results

Zydelig was granted regular approval for use in patients with relapsed chronic lymphocytic leukemia (CLL). Accelerated approval was granted for relapsed follicular B-cell non-Hodgkin lymphoma (FL) and relapsed small lymphocytic lymphoma (SLL) based on overall response rate. Improvement in patient survival or disease related symptoms has not been established. Continued approval for these indications may be contingent upon verification of clinical benefit in confirmatory trials. Gilead voluntarily withdrew the accelerated approval indications in 2022 after failing to complete confirmatory trials.

Relapsed chronic lymphocytic leukemia

Zydelig was evaluated in a randomized, double-blind, placebo-controlled study (Study 1) in 220 subjects with relapsed CLL who required treatment and were unable to tolerate standard chemoimmunotherapy. Subjects were randomized 1:1 to receive 8 doses of rituximab (first dose at 375 mg/m2, subsequent doses at 500 mg/m2 every 2 weeks for 4 infusions and every 4 weeks for an additional 4 infusions) in combination with either an oral placebo twice daily or with Zydelig 150 mg taken twice daily until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). The subjects who received Zydelig in combination with rituximab went approximately 11 months without disease pregression, compared to approximately 6 months for subjects given rituximab and a placebo (p < 0.0001).

Relapsed follicular B-cell non-Hodgkin lymphoma

A single-arm, multicenter clinical trial enrolled 72 subjects with follicular B-cell non-Hodgkin lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. Subjects received 150 mg of Zydelig orally twice daily until evidence of disease progression or unacceptable toxicity. The primary endpoint was Independent Review Committee-assessed overall response rate. Zydelig achieved an overall response rate of 54%; 8% were complete responses and 46% were partial responses. The median duration of response was not reached.

Relapsed Small Lymphocytic Lymphoma

A single-arm, multicenter clinical trial enrolled 26 subjects with small lymphocytic lymphoma who had relapsed within 6 months following rituximab and an alkylating agent and had received at least 2 prior treatments. Subjects received 150 mg of Zydelig orally twice daily until evidence of disease progression or unacceptable toxicity. The primary endpoint was Independent Review Committee-assessed overall response rate. Zydelig achieved an overall response rate of 58%; all responses were partial responses. The median duration of response was 11.9 months.