Idelalisib Monotherapy and Durable Responses in Patients with Relapsed or Refractory Small Lymphocytic Lymphoma (SLL)
Authors: Gopal Ajay K , Davies Andrew John , Flinn Ian W. , Ghia Paolo , Goy Andre , Salles Gilles A. , Abella Steve , Philip Betsy , Sorenson Bess , Wagner-Johnston Nina D. 
Published: October 2019

Abstract
Background: SLL, a subtype of indolent non-Hodgkin's Lymphoma (iNHL), is considered the tissue equivalent of chronic lymphocytic leukemia (CLL); each disease is considered a clinical variation of the same biological entity. SLL is characterized by the accumulation of small, mature lymphocytes in lymph nodes without elevation of peripheral blood lymphocytes. SLL is an uncommon disorder, comprising 6% of cases of NHL and 15% of cases of the CLL/SLL entity.SLL is often diagnosed at an advanced stage, and patients (pts) with relapsed or refractory (R/R) disease are at risk for poor prognosis. Idelalisib (IDL) is a selective oral PI3Kδ inhibitor. IDL monotherapy (IDL-mono) demonstrated considerable anti-tumor activity in pts with R/R iNHL in phase 1 Study 101-02 (Study 02; NCT00710528), and phase 2 Study 101-09 (Study 09; NCT01282424; Gopal et al. NEJM. 2014;370:1008-1018).
This post hoc analysis evaluated efficacy and safety in pts with SLL who were treated with IDL in Study 02 or Study 09.
Methods: Eligible pts with SLL included those with R/R disease treated with IDL-mono across 7 dose cohorts in Study 02, and those with double-refractory disease (to both rituximab and an alkylating agent) treated with IDL-mono in Study 09. The primary objectives for Study 02 were to evaluate the safety and pharmacokinetics of IDL in pts with R/R hematologic malignancies. The primary objectives for Study 09 were to evaluate the efficacy and safety of IDL in pts with R/R B-cell iNHL. In both studies, IDL was continued until disease progression (PD) or unacceptable toxicity. Clinical response was assessed with the use of standard criteria for lymphoma (Cheson et al. J Clin Oncol. 2007;25:579-586).
Results: A total of 39 pts with R/R SLL participated in the 2 trials.Study 02 enrolled 11 pts, (5 on IDL doses ˂100 mg BID; 6 on IDL doses ˃100 mg BID). Study 09 enrolled 28 pts who received IDL 150 mg BID.
Enrolled pts (Study 02 and Study 09) had a median age of 69 and 65 years [range 34-87], and 73% and 75% were male, respectively. In both studies, 82% of pts presented with Ann Arbor Stage IV disease at baseline and had received a median of 4 prior regimens [range 1-9]. In Study 02, 9 of the 11 pts (82%) had refractory disease; all 11 pts had received prior regimens containing fludarabine. In Study 09, 27 of the 28 pts (96%) were refractory to both rituximab and an alkylating agent; common previous therapy included: 28/28 rituximab, 25/28 cyclophosphamide, 21/28 bendamustine, 19/28 vincristine, and 18/28 fludarabine.
The clinical response rate by dose cohort is presented in Table 1. In Study 02 and Study 09, overall response rates (ORR) were 6/11 (55%) and 17/28 (61%), respectively; median time to minor or first response was 0.9 months and 1.9 months; median duration of response (DOR) was 2.3 months and 12.5 months. Median progression-free survival (PFS) was 3.7 months and 11.4 months, respectively. In Study 02, the most common Grade ≥3 adverse events included febrile neutropenia 3/11, and neutropenia, thrombocytopenia, pneumonia, and streptococcal bacteremia (each 2/11). In Study 09, the most common Grade ≥3 adverse events included neutropenia 8/28, pneumonia 7/28, and diarrhea 4/28.
Transient lymphocytosis occurred with IDL-mono, similar to other B-cell receptor targeted therapies. In Study 02, time to peak occurred at 4.1 weeks with a median ALC of 4.98x10ˆ9/L (361% above baseline); time to nadir occurred at 8.0 weeks with a median ALC of 1.9x10ˆ9/L. In Study 09, time to peak occurred at 6.1 weeks with a median ALC of 6.2x10ˆ9/L (426% above baseline); Time to nadir occurred at 11.1 weeks with a median ALC of 1.3x10ˆ9/L.
Conclusions: This pooled subset analysis suggests IDL-mono provides substantial clinical activity in the subset of pts with R/R SLL. IDL had a manageable safety profile in the SLL population subset. Confirmatory phase 3 clinical trials of IDL with combination therapy are in progress for pts with iNHL, including those with SLL. Clinical trial information: NCT01732913 and NCT01732926.
Table 1. Clinical Response Rate by Dose Cohort for Patients with SLL Study 02 (n=11) Study 09 (n=28)* Outcome, n 50 mg BID x 28 Days (n=2) 150 mg QD x 28 Days (n=1) 150 mg BID x 21 Days (n=2) 300 mg QD x 28 Days (n=0) 100 mg BID x 28 Days (n=1) 150 mg BID x 28 Days (n=2) 200 mg BID x 28 Days (n=1) 350 mg BID x 28 Days (n=2) 150mg BID (n=28) ORR 1 0 1 0 0 1 2 2 17 (61%) CR 0 0 0 0 0 0 0 0 1 (4%) PR 1 0 1 0 0 1 1 2 16 (57%) MR 0 0 0 0 0 0 0 0 0 SD 1 1 0 0 1 0 0 0 10 (36%) PD 0 0 1 0 0 0 0 0 0 NE 0 0 0 0 0 1 0 0 1 (4%) *IRC Assessment

Disclosures
Gopal: Gilead, Spectrum, Pfizer, Janssen, Seattle Genetics: Consultancy; Millennium, Seattle Genetics, Sanofi-Aventis: Honoraria; Spectrum, Pfizer, BioMarin, Cephalon/Teva, Emergent/Abbott. Gilead, Janssen., Merck, Milennium, Piramal, Seattle Genetics, Giogen Idec, BMS: Research Funding. Davies:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Flinn:Cephalon, Inc; Teva Pharmaceutical Industries Ltd; Genentech, inc; Gilead: Research Funding. Ghia:Pharmacyclics: Consultancy; Roche: Consultancy, Research Funding; Janssen: Consultancy; Acerta Pharma BV: Research Funding; AbbVie: Consultancy; Adaptive: Consultancy; Gilead: Consultancy, Research Funding, Speakers Bureau; GSK: Research Funding. Goy:Celgene: Consultancy, Research Funding, Speakers Bureau; Allos, Biogen Idec, Celgene, Genentech, and Millennium. Gilead: Speakers Bureau. Salles:Celgene Corporation; Roche and Gilead Sciences: Research Funding; Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche: Speakers Bureau. Abella:Gilead: Employment. Philip:Gilead: Employment. Sorenson:Gilead: Employment. Wagner-Johnston:Celgene: Research Funding; Gilead: Consultancy.