Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

Abstract

In a phase 1 trial, idelalisib (GS-1101, CAL-101), a selective inhibitor of the lipid kinase PI3Kδ, was evaluated in 54 patients with relapsed/refractory chronic lymphocytic leukemia (CLL) with adverse characteristics including bulky lymphadenopathy (80%), extensive prior therapy (median 5 [range 2-14] prior regimens), treatment-refractory disease (70%), unmutated IGHV (91%), and del17p and/or TP53 mutations (24%). Patients were treated at 6 dose levels of oral idelalisib (range 50-350 mg once or twice daily) and remained on continuous therapy while deriving clinical benefit. Idelalisib-mediated inhibition of PI3Kδ led to abrogation of Akt phosphorylation in patient CLL cells and significantly reduced serum levels of CLL-related chemokines. The most commonly observed grade ≥3 adverse events were pneumonia (20%), neutropenic fever (11%), and diarrhea (6%). Idelalisib treatment resulted in nodal responses in 81% of patients. The overall response rate was 72%, with 39% of patients meeting the criteria for partial response per IWCLL 2008 and 33% meeting the recently updated criteria of PR with treatment-induced lymphocytosis.(1,2) The median progression-free survival for all patients was 15.8 months. This study demonstrates the clinical utility of inhibiting the PI3Kδ pathway with idelalisib. Our findings support the further development of idelalisib in patients with CLL. These trials were registered at clinicaltrials.gov as #NCT00710528 and #NCT01090414.

Figure 1

Dose-exposure evaluation. Steady-state (day 28) idelalisib plasma exposures by idelalisib dosing regimen (N = 50). AUC_0-6, area under the concentration-time curve over 6 hours; C_max, maximum concentration; C_trough, trough concentration; SEM, standard error of the mean.

Figure 2

Pharmacodynamic effects. Phospho-Akt³⁰⁸ concentrations in circulating B cells (from normal subjects, N = 6) or CLL cells (from patients receiving idelalisib at 100 mg/dose bid (N = 7) or ≥150 mg/dose bid (N = 20)).

Figure 3

Changes in disease-related parameters. (A) Best on-treatment changes in the SPD of measured lymph nodes, by patient(). denotes nonevaluable patients (without a follow-up on-treatment tumor assessment) and denotes the presence of a del17p or TP53 mutation. Forty-one patients were assessed by computed tomography scan and 9 by physical examination. Four patients did not have a follow-up assessment. (B) Rate of best on-treatment lymph node response (≥50% reduction in SPD of measured lymph nodes) and best on-treatment change from baseline in SPD of measured lymph nodes by dosing regimen (N = 50). (C) Mean changes in the SPD of measured lymph nodes and in the ALC by time during the primary study. (D) Hb concentration, platelet counts, and ANC by time during the primary study; includes only patients with baseline anemia (Hb <110 g/L), thrombocytopenia (platelets <100 × 10⁹/L), or neutropenia (ANC <1.5 × 10⁹/L). ALC, absolute lymphocyte count; LNRR, lymph node response rate.

Figure 4

Time-to-event endpoints. (A) TTR, (B) DOR, (C-D) PFS, and (E) OS. TTR, PFS, and OS are measured from the start of therapy, whereas DOR is measured from the start of response. TTR and DOR are composed of responding subjects only; PFS and OS represent ITT analyses. A tick on the curve (┴) denotes a censored time point. OS, overall survival; PFS, progression-free survival.