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85 Mature Response Data From a Phase 2 Study Of PI3K-Delta Inhibitor Idelalisib In Patients With Double (Rituximab and Alkylating Agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL)

Program: Oral and Poster Abstracts
Type: Oral
Session: 623. Lymphoma: Chemotherapy, excluding Pre-Clinical Models: Novel Agents in Lymphoma Therapy
Sunday, December 8, 2013: 5:00 PM
La Nouvelle Ballroom AB (Ernest N. Morial Convention Center)

Ajay K. Gopal, MD1, Brad S. Kahl, MD2, Sven de Vos, MD, PhD3, Nina D. Wagner-Johnston, MD4, Stephen J. Schuster, MD5, Kristie A. Blum, MD6, Wojciech Jurczak, MD, PhD7, Ian W. Flinn, MD, PhD8, Christopher R. Flowers, MD9, Peter Martin, MD10, Andreas Viardot, MD, PhD11*, Andre Goy, MD12, Andrew Davies, BM PhD13*, Pier Luigi Zinzani, MD14, Martin H. Dreyling, MD, PhD15, Leanne M. Holes16*, Daniel Li, PhD16*, Roger Dansey, MD16*, Wayne R. Godfrey, MD16 and Gilles A. Salles, MD, PhD17

1University of Washington School of Medicine, Seattle, WA
2University of Wisconsin Carbone Cancer Center, Madison, WI
3University of California at Los Angeles Medical Center, Los Angeles, CA
4Washington University School of Medicine, Saint Louis, MO
5Lymphoma Program, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
6Division of Hematology, The Ohio State University Comprehensive Cancer Center, Columbus, OH
7Jagiellonian University, Krakow, Poland
8Sarah Cannon Cancer Institute, Nashville, TN
9Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA
10Weill Cornell Medical College, New York, NY
11University Hospital of Ulm, Ulm, Germany
12The John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
13Cancer Sciences Division, University of Southampton, Southampton, United Kingdom
14University of Bologna, Bologna, Italy
15Department of Internal Medicine III, Ludwig-Maximilians University of Munich, Munich, Germany
16Gilead Sciences, Foster City, CA
17Centre Hospitalier Lyon-Sud, Pierre-Benite, France

Introduction: Alkylating agent-rituximab combinations are a current standard of care for patients with iNHL. Most iNHL will eventually become refractory to current therapies. Particularly, once iNHL becomes "double-refractory" to rituximab + alkylating agents, there are few data available on beneficial therapeutic options and development of novel therapies is essential for this patient population. PI3K-delta signaling is critical for activation, proliferation and survival of B cells, and is hyperactive in many B-cell malignancies. Idelalisib, a selective oral inhibitor of PI3Kd, demonstrated considerable activity in recurrent iNHL in a phase 1 trial (Kahl, ICML 2011). We thus evaluated idelalisib in a phase 2 trial for patients with double-refractory iNHL, an area of unmet medical need. We present mature response data and extended follow-up of this study.

Methods: Eligible iNHL patients (pts) included those with measurable disease who were refractory to both rituximab and an alkylating agent. Refractory status was defined as lack of response to, or progression of lymphoma within 6 months of completion of therapy, documented by imaging. Idelalisib 150 mg PO BID was administered continuously until disease progression or intolerance. Responses were evaluated by an independent review committee, using standard criteria (Cheson, 2007). The new data cutoff date for this analysis was June 2013, 8 months after the last patient enrolled.

Results: Enrolled pts (N=125) had a median age of 64 years [range 33-87] and were 64% male. Indolent NHL subtypes included follicular lymphoma (FL) n=72 (58%), small lymphocytic lymphoma (SLL) n=28 (22%), marginal zone lymphoma (MZL) n=15 (12%) and lymphoplasmacytic lymphoma (LPL)/Waldenstrom's macroglobulinemia (WM) n=10 (8%). The median number of prior therapies was 4 [range 2-12], most common regimens included bendamustine/rituximab (BR) (n=60) and rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) (n=56) and 14 pts (11%) had a prior autologous transplant. 81 pts (65%) had prior bendamustine, of which 61/81 (75%) were refractory. 112 pts (90%) were refractory to their last regimen, and 99 pts (79%) were refractory to ≥2 regimens. Median time since completion of last regimen was 3.9 months. At baseline, pts had elevated LDH (30%), bulky disease >7 cm (26%), anemia ≥grade 1 (51%), neutropenia ≥ grade 1 (24%), and thrombocytopenia ≥grade 1 (34%).

With a median follow up 9.4 months, the overall response rate (ORR) was 57% (95% CI = 47.6, 65.6) with 71 responders, comprising 7 CRs (6%), 63 PRs (50%), and 1 minor response (MR) in a WM pt. There were 42 pts with stable disease (SD) (33%). 90% of pts experienced some decrease in tumor burden (Figure 1). Median time to response was 1.9 months (range 1.6-8.3), median time to CR was 3.7 months (range 1.9-12). ORR for iNHL subtypes was: FL (54%), SLL (61%), LPL/WM (80%), and MZL (47%). ORR for bendamustine refractory pts was 59%. ORR for pts with <4 /≥4 prior therapies was 50%/62%, and for bulky disease <7cm/≥7cm was 57/57%. Among responders, median DOR was 12.5 months. Median PFS for all pts was 11.0 months and median overall survival was 20.4 months.

The most common adverse events were (total%/≥ grade 3%) diarrhea (43/13), fatigue (30/2), nausea (30/2), cough (29/0), pyrexia (28/2), dyspnea (18/3), rash (13/2), and pneumonia (11/7). Based on central laboratory measurements, Grade ≥3 ALT/AST elevations occurred in 16 pts (13%). Drug was held for these pts, and 11/14 pts (79%) were re-treated without recurrence of ALT/AST elevation. Grade ≥3 neutropenia occurred in 27%, thrombocytopenia in 6%, and anemia in 2%. 20% of pts have discontinued therapy due to adverse events.

Conclusions: Idelalisib was well tolerated, had an acceptable safety profile, and was highly effective in this double-refractory iNHL population with an ORR of 57%. The ORR was consistent across all subgroups, regardless of disease histology, number of prior regimens, refractoriness to bendamustine, or tumor bulk. With continued administration of idelalisib, responses were durable beyond one year, substantially exceeding the median DOR for the last prior therapy. Mature response data demonstrate that idelalisib can provide clinical benefit to patients with the unmet medical need of double-refractory iNHL.

Figure 1: Waterfall plot of best nodal response.


Disclosures: Gopal: Gilead Sciences: Research Funding . Off Label Use: Idelalisib is a PI3K-delta inhibitor currently in phase III trials for multiple hematologic malignancies.. Kahl: Gilead Sciences: Other: Advisory Board , Research Funding . de Vos: Gilead Sciences: Other: Advisory Board , Research Funding . Wagner-Johnston: Gilead Sciences: Research Funding . Schuster: Gilead Sciences: Research Funding . Blum: Gilead Sciences: Research Funding . Jurczak: Gilead Sciences: Research Funding . Flinn: Gilead Sciences: Research Funding . Flowers: Gilead Sciences: Research Funding . Martin: Gilead Sciences: Research Funding . Viardot: Gilead Sciences: Research Funding . Goy: Gilead Sciences: Research Funding . Davies: Gilead Sciences: Research Funding . Zinzani: Gilead Sciences: Research Funding . Dreyling: Gilead Sciences: Research Funding . Holes: Gilead Sciences: Employment . Li: Gilead Sciences: Employment . Dansey: Gilead Sciences: Employment . Godfrey: Gilead Sciences: Employment . Salles: Gilead Sciences: Research Funding .

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