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Idelalisib is a first-in-class oral inhibitor of phosphatidylinositol 3-kinase (PI3K) delta, an enzyme that is overexpressed in B-cell malignancies and has a role in the viability, proliferation and migration of these cancer cells.
Twice-daily dosing
The usual dose of Zydelig is 150mg twice daily continued until disease progression or unacceptable toxicity occurs. Treatment should be withheld if the patient develops severe diarrhoea/colitis, pneumonitis, rash or if liver enzymes are significantly raised. When the adverse reaction has suitably resolved, patients can restart Zydelig at a reduced dose of 100mg twice daily which can then be increased to 150mg twice daily if appropriate.
'Overwhelming efficacy'
Investigators assessed the efficacy and safety of idelalisib in refractory chronic lymphocytic leukaemia in a randomised, double-blind placebo-controlled phase III study. Patients (n=220) were eligible if they were unable to receive cytotoxic chemotherapy because of renal impairment, major co-existing illness or if they had developed myelosuppression from previous therapy.
Participants were randomised to receive 8 cycles of rituximab plus continuous idelalisib (150g twice daily) or placebo. The primary endpoint was progression-free survival (PFS).
At the first prespecified interim analysis, the study was terminated owing to evidence of overwhelming efficacy with idelalisib.
At 24 weeks, the PFS rate was 93% in the idelalisib group compared with 46% in the placebo group (adjusted HR for progression or death in the idelalisib group, 0.15, 95% CI 0.08-0.28, p<0.001). The median duration of PFS was 5.5 months in the placebo group but was not reached in the idelalisib group. The overall survival rate in patients treated with idelalisib was also superior to that in patients who received placebo (92% vs 80% at 12 months).
In a single-group, open label phase II study, 125 patients with indolent non-Hodgkin's lymphoma who had not responded to rituximab and an alkylating agent, or had relapsed following treatment, were given idelalisib 150mg twice daily as monotherapy until disease progressed or the patient withdrew from the study.
Patients had received a median of four prior therapies and had a median age of 64 years. The response rate (primary endpoint) was 57% (95% CI 48-66%), with 6% of patients meeting the criteria for a complete response. Responses lasted for a median of 12.5 months, and the median duration of PFS was 11 months.
Further information: Gilead
