Idelalisib, a selective inhibitor of phosphatidylinositol 3-kinase-δ, as therapy for previously treated indolent non-Hodgkin lymphoma

Abstract

Idelalisib (GS-1101, CAL-101), an oral inhibitor of phosphatidylinositol 3-kinase-δ, was evaluated in a phase I study in 64 patients with relapsed indolent non-Hodgkin lymphoma (iNHL). Patients had a median (range) age of 64 (32-91) years, 34 (53%) had bulky disease (≥1 lymph nodes ≥5 cm), and 37 (58%) had refractory disease. Patients had received a median (range) of 4 (1-10) prior therapies. Eight dose regimens of idelalisib were evaluated; idelalisib was taken once or twice daily continuously at doses ranging from 50 to 350 mg. After 48 weeks, patients still benefitting (n = 19; 30%) enrolled into an extension study. Adverse events (AEs) occurring in 20% or more patients (total%/grade ≥3%) included diarrhea (36/8), fatigue (36/3), nausea (25/3), rash (25/3), pyrexia (20/3), and chills (20/0). Laboratory abnormalities included neutropenia (44/23), anemia (31/5), thrombocytopenia (25/11), and serum transaminase elevations (48/25). Twelve (19%) patients discontinued therapy due to AEs. Idelalisib induced disease regression in 46/54 (85%) of evaluable patients achieving an overall response rate of 30/64 (47%), with 1 patient having a complete response (1.6%). Median duration of response was 18.4 months, median progression-free survival was 7.6 months. Idelalisib is well tolerated and active in heavily pretreated, relapsed/refractory patients with iNHL. These trials were registered at clinicaltrials.gov as NCT00710528 and NCT01090414.

Figure 1

Dose-exposure relationship. Steady-state (day 28) idelalisib plasma exposures by idelalisib dosing regimen (total N = 64). AUC_τ indicates area under the concentration-time curve over 12 (BID) or 24 (QD) hours; C_max, maximum concentration; C_τ, trough concentration; SD, standard deviation.

Figure 2

Lymph node response. (A) Best on-treatment percent changes in the SPD of measured lymph nodes in 54 evaluable patients (blue bars). Graph excludes 10 nonevaluable patients (5 patients with LPL/WM who had no measurable lymphadenopathy and 5 patients without a follow-up, on-treatment tumor assessment). (B) Best on-treatment change from baseline in SPD of measured lymph nodes by dosing regimen in 54 evaluable patients. SEM, standard error of the mean; SPD, sum of the products of the perpendicular diameters (of measured lymph nodes).

Figure 3

Time-to-event endpoints. TTR (A), DOR (B), PFS overall (C), and PFS by higher or lower dosing regimen (D). TTR and PFS are measured from the start of therapy, whereas DOR is measured from the start of response. TTR and DOR comprise responding patients only; PFS is evaluated in all patients. A tick on the curve denotes a censored time point.