Final Results of a Randomized, Phase III Study of Rituximab With or Without Idelalisib Followed by Open-Label Idelalisib in Patients With Relapsed Chronic Lymphocytic Leukemia

Abstract

Purpose: A randomized, double-blind, phase III study of idelalisib (IDELA) plus rituximab versus placebo plus rituximab in patients with relapsed chronic lymphocytic leukemia (CLL) was terminated early because of superior efficacy of the IDELA-plus-rituximab (IDELA/R) arm. Patients in either arm could then enroll in an extension study to receive IDELA monotherapy. Here, we report the long-term efficacy and safety data for IDELA-treated patients across the primary and extension studies.

Patients and methods: Patients were randomly assigned to receive rituximab in combination with either IDELA 150 mg twice daily (IDELA/R; n = 110) or placebo (placebo/R; n = 110). Key end points were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), and safety.

Results: The long-term efficacy and safety of treatment with IDELA was assessed in 110 patients who received at least one dose of IDELA in the primary study, 75 of whom enrolled in the extension study. The IDELA/R-to-IDELA group had a median PFS of 20.3 months (95% CI, 17.3 to 26.3 months) after a median follow-up time of 18 months (range, 0.3 to 67.6 months). The ORR was 85.5% (94 of 110 patients; n = 1 complete response). The median OS was 40.6 months (95% CI, 28.5 to 57.3 months) and 34.6 months (95% CI, 16.0 months to not reached) for patients randomly assigned to the IDELA/R and placebo/R groups, respectively. Prolonged exposure to IDELA increased the incidence of all-grade, grade 2, and grade 3 or greater diarrhea (46.4%, 17.3%, and 16.4%, respectively), all-grade and grade 3 or greater colitis (10.9% and 8.2%, respectively) and all-grade and grade 3 or greater pneumonitis (10.0% and 6.4%, respectively) but did not increase the incidence of elevated hepatic aminotransferases.

Conclusion: IDELA improved PFS and OS compared with rituximab alone in patients with relapsed CLL. Long-term IDELA was effective and had an expected safety profile. No new IDELA-related adverse events were identified with longer exposure.

FIG 1.

(A) Study flow. (B) Patient flow. (*)For all analyses in this report, the four patients who experienced PD during treatment with IDELA/R and received single-agent IDELA 300 mg twice a day in the double-blind part of the extension study were pooled together with patients treated with IDELA/R who did not experience PD, and, at study termination, transitioned to open-label IDELA 150 mg twice a day in the extension study. AE, adverse event; IDELA, idelalisib; PD, progressive disease; R, rituximab.

FIG 2.

Progression-free survival (PFS) for (A) placebo/R and IDELA/R (intent-to-treat [ITT] population, primary study), and patients were censored at the time of transition to open-label IDELA; (B) IDELA/R-to-IDELA (full analysis set (FAS) population, primary and extension studies); (C) the IDELA/R-to-IDELA arm stratified by presence or absence of del(17p)/TP53 mutation (either/or and neither/nor; FAS); (D) the IDELA/R-to-IDELA arm stratified by presence or absence of IGHV mutated versus unmutated status (FAS). IDELA/R-to-IDELA included all patients who received IDELA/R in the primary randomized study, including patients who did not enroll in open extension, as well as patients who experienced progressive disease and transitioned to the double-blind extension study and patients without PD who completed the primary study and enrolled in the open-label extension study. The ITT population included all randomly assigned patients with treatment assignments designated according to random assignment in the primary study. The FAS population included all patients in the ITT set who received at least one dose of idelalisib, with treatment assignments designated according to random assignment in the primary study. HR, hazard ratio; IDELA, idelalisib; NR, not reached; R, rituximab.

FIG 3.

Overall survival (OS) in (A) the intent-to-treat population with treatment assignments according to initial random assignment; (B) patients with either del(17p) or TP53 mutation; (C) patients with neither del(17p) nor TP53 mutation. Insets show median (95% Cl) OS for each treatment group. IDELA, idelalisib; NR, not reached; R, rituximab.

FIG 4.

Cumulative rates of all-grade and grade 3 or greater (A) diarrhea/colitis and (B) abnormal LFTs in the IDELA/R-to-IDELA group. Inset tables provide incidence rates by 12-week intervals. IDELA, idelalisib; LFT, liver function tests; R, rituximab.