In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.
On July 23, 2014, idelalisib (Zydelig) was approved for use in combination with rituximab (Rituxan) for treatment of patients with relapsed chronic lymphocytic leukemia (CLL) in whom rituximab alone would be considered appropriate therapy due to other comorbidities. Idelalisib also received accelerated approval for the treatment of patients with relapsed follicular B-cell non-Hodgkin lymphoma or relapsed small lymphocytic lymphoma who have received at least two prior systemic therapies.1,2
The approval in CLL was based on results of a phase III trial in which 218 patients were randomly assigned to receive idelalisib 150 mg twice daily plus rituximab (n = 110) or rituximab plus placebo (n = 108).2,3 Rituximab was administered in eight doses (first dose at 375 mg/m2, subsequent doses at 500 mg/m2) every 2 weeks for four infusions and then every 4 weeks for four infusions. The trial was stopped early based on an interim analysis showing that median progression-free survival as assessed by an independent review committee was not reached in the idelalisib/rituximab group vs 5.5 months in the rituximab/placebo group (hazard ratio [HR] = 0.18, P < .0001).
Accelerated approval in relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma was based on results of a single-arm open-label trial in 123 patients with relapsed indolent non-Hodgkin lymphomas who were started on idelalisib 150 mg twice daily.2,4 The overall response rate as assessed by an independent review committee was 54% (95% confidence interval [CI] = 42%–66%) in patients with follicular lymphoma, with median response duration not evaluable, and 58% (95% CI = 37%–77%) in patients with small lymphocytic lymphoma, with median response duration of 11.9 months.
How It Works
Idelalisib is an inhibitor of the PI3K-delta kinase, which is expressed in both normal and malignant B cells. Idelalisib inhibits a number of cell signaling pathways, including B-cell receptor signaling and CXCR4 and CXCR5 signaling, which are involved in transit of B cells to lymph nodes and bone marrow. In preclinical studies, idelalisib induced apoptosis and inhibited proliferation in cell lines derived from malignant B cells and in primary tumor cells; treatment of lymphoma cells with idelalisib resulted in inhibition of chemotaxis and adhesion and reduced cell viability.
How It Is Given
The recommended maximum starting dose of idelalisib is 150 mg twice daily in CLL and in follicular lymphoma/small lymphocytic lymphoma, with treatment continued until disease progression or unacceptable toxicity. Optimal and safe dosing regimens for patients receiving treatment for longer than several months have not yet been characterized.
The full prescribing information provides details of idelalisib dose modifications for pneumonitis, ALT/AST elevation, bilirubin elevation, diarrhea, neutropenia, and thrombocytopenia. Idelalisib should be discontinued in patients developing intestinal perforation.
Idelalisib is a strong CYP3A inhibitor and increases exposure to sensitive CYP3A substrates (eg, aprepitant, budesonide, lovastatin, midazolam). Idelalisib exposure is reduced by concomitant treatment with strong CYP3A inducers (eg, carbamazepine, phenytoin, rifampin, St. John’s wort) and increased with strong CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole). Coadministration of idelalisib with strong CYP3A inducers and sensitive CYP3A substrates should be avoided.
In the CLL trial, the most common grade ≥ 3 clinical adverse events in patients receiving idelalisib/rituximab were pneumonia (16% vs 13% in patients receiving rituximab/placebo), sepsis (7% vs 4%), and diarrhea (5% vs 0%). The most common grade ≥ 3 laboratory abnormalities were neutropenia (37% vs 27%), increased lymphocyte count (18% vs 5%), lymphopenia (9% vs 4%), and increased AST (8% vs 1%). Serious adverse events occurred in 49% of idelalisib/rituximab patients, with the most common being pneumonia (17%), pyrexia (9%), sepsis (8%), febrile neutropenia (5%), and diarrhea (5%). Adverse events led to dose interruption in 35% of patients, dose reduction in 15%, and discontinuation in 10%, with the most common reasons for discontinuation being hepatotoxicity and diarrhea/colitis.
In the follicular lymphoma/small lymphocytic lymphoma trial, the most common grade ≥ 3 clinical adverse events were pneumonia (16%) and diarrhea (14%), and the most common grade ≥ 3 laboratory abnormalities were neutropenia (25%), increased ALT (19%), and increased AST (12%). Serious adverse events occurred in 50% of patients with the most common being pneumonia (15%), diarrhea (11%), and pyrexia (9%). Adverse events led to interruption or discontinuation of treatment in 53%, with the most common reasons being diarrhea (11%), pneumonia (11%), and elevated transaminases (10%).
Idelalisib carries boxed warnings for serious or fatal hepatotoxicity (observed in 14% of patients), diarrhea (14%), colitis, pneumonitis, and intestinal perforation. Hepatic function must be monitored prior to and during treatment. Patients should be monitored for pulmonary symptoms and bilateral interstitial infiltrates. Idelalisib also carries warnings/precautions for severe cutaneous reactions, anaphylaxis, neutropenia, and embryo-fetal toxicity. Blood counts should be routinely monitored.
Report Adverse Events
Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/medwatch/report.htm, by faxing (800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (800-FDA-1088). ■
1. U.S. Food and Drug Administration: Idelalisib. Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm406410.htm.
2. ZYDELIG® (idelalisib) tablets prescribing information, Gilead Sciences, Inc, July 2014. Available at www.accessdata.fda.gov/drugsatfda_docs/label/2014/206545lbl.pdf.
3. Furman RR, Sharman JP, Coutre SE, et al: Idelalisib and rituximab in relapsed chronic lymphocytic leukemia. N Engl J Med 370:997-1007, 2014.
4. Gopal AK, Kahl BS, de Vos S, et al: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008-1018, 2014.