Abstract IA18: Clinical validation of PI3Kδ as a therapeutic target in B-cell malignancy
Authors: Dansey Roger 
Published: October 2015

Abstract
Idelalisib (ZYDELIG®, GS-1101) is a first-in-class, targeted, highly selective, oral inhibitor of PI3Kδ that reduces proliferation, enhances apoptosis, and inhibits homing and retention of malignant B cells in lymphoid tissues (Lannutti et al, 2011). We studied idelalisib in 2 registrational trials, one in relapsed chronic lymphocytic leukemia (CLL) and one in refractory, indolent non-Hodgkin lymphoma (iNHL). In the Phase 3 CLL trial (Furman 2014), patients with relapsed disease and multiple co-morbidities precluding the use of chemotherapy were randomized to receive blinded idelalisib 150 mg BID plus rituximab intravenously (at a dose of 375 mg per square meter, followed by 500 mg per square meter every 2 weeks for 4 doses and then every 4 weeks for 3 doses) for a total of 8 infusions or an oral placebo plus rituximab. A total of 220 patients were randomized, with a median age of 71 yrs (78% ≥65 yrs), median time since diagnosis of 8.5 yrs, and median number of 3 prior therapies (range: 1-12). Of these, 44% of pts had del17p/TP53 mutation. The median progression-free survival was 5.5 months in the placebo group and was not reached in the idelalisib group (hazard ratio for progression or death in the idelalisib group, 0.15; P&lt;0.001). Patients receiving idelalisib versus those receiving placebo had improved rates of overall response (81% vs. 13%; odds ratio, 29.92; P&lt;0.001) and overall survival at 12 months (92% vs. 80%; hazard ratio for death, 0.28; P = 0.02). IDELA+R retained robust efficacy across all high-risk subpopulations and achieved 76.5% ORR and PFS HR 0.13 in the highest risk patients who were positive for both 17p deletion and TP53 mutation. The Phase 2 iNHL study (Gopal 2014) enrolled 125 heavily pretreated patients with disease refractory to rituximab and alkylating agents to receive single agent idelalisib 150 mg BID. The median age of the patients was 64 yrs (range, 33 to 87); patients had received a median of four prior therapies (range, 2 to 12). The predominate iNHL subtype was follicular lymphoma (72 patients), followed by small lymphocytic lymphoma (28), marginal-zone lymphoma (15), and Waldenström's macroglobulinemia (10). The overall response rate was 57%. Responses were rapid (median time to a response was 1.9 months) and the median duration of response was 12.5 months. Median progression-free survival was 11 months. Key safety findings across the idelalisib program include an early transient hepatotoxicity characterized by elevations in serum transaminases (≥ Grade 3) occurring in 14% of treated subjects, late onset (≥ Grade 3) severe diarrhea/colitis, also occurring in 14% of subjects, and pneumonitis of any grade, occurring in 3% of subjects. Additional trials of idelalisib in combination with other chemoimmunotherapy are ongoing in both CLL and iNHL, including studies in patients with previously untreated disease. Future development plans include establishing the role of PI3Kδ inhibition in solid tumors and testing the activity of idelalisib against a range of hematologic malignancies.
Citation Format: Roger Dansey. Clinical validation of PI3Kδ as a therapeutic target in B-cell malignancy. [abstract]. In: Proceedings of the AACR Special Conference: Targeting the PI3K-mTOR Network in Cancer; Sep 14-17, 2014; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(7 Suppl):Abstract nr IA18.