100 50 -50 -100 0 Best % Change in Target Nodal Lesions Patients 100 50 -50 -100 0 Best % Change in Target Nodal Lesions Patients Overall Response Rate (Investigator Assessment per modified IWCLL/IWG Criteria) CI= confidence interval; CR= complete response; CRi = CR with incomplete marrow recovery; LNRR = lymph node response rate (i.e. >50% decrease in target nodal lesion); ORR= overall response rate; PR= partial response; PRwL = PR with lymphocytosis • For patients with 17p deletion treated with duvelisib (n=20), the ORR was 80% (95% CI: 63, 98), which included 2 (10%) CRi, 13 (65%) PR, and 1 (5%) PRwL Progression-Free Survival Per Investigator Assessment Growth & survival of malignant B cells Recruitment of malignant B cells Recruitment & differentiation of cells supporting B cell growth & survival Tumor-associated myeloid cell PI3K-γ PI3K-γ Tumor Microenvironment (TME) BCR Cytokine receptor Cytokines Cytokines Migration, activation, and M2 polarization signals Cytokine receptor CD40R CD40L Anti-tumor immune response CXCL13 CXCR5 CXCR4 CXCL12 CXCR4 CXCL12 CD4 + T cell PI3K-δ PI3K-γ Malignant B cell PI3K-δ PI3K-γ Category N = 89 Median Age (years) 68 Min, Max 39, 90 ≥ 65 years, % 61 Sex, % Male 63 Female 37 Race, % White 92 Other 5 Unknown 3 Background The Efficacy of Duvelisib Monotherapy Following Disease Progression on Ofatumumab Monotherapy in Patients with Relapsed/Refractory CLL or SLL in the DUO TM Crossover Extension Study Bryone Kuss 1 ; Matthew S. Davids 2 ; Peter Hillmen 3 ; Carol Moreno 4 ; James H. Essell 5 ; Nicole Lamanna 6 ; Zsolt Nagy 7 ; Ulrich Jaeger 8 ; Constantine Tam 9 ; Stephan Stilgenbauer 10 ; Paolo Ghia 11 ; Julio Delgado 12 ; Diep Le 13 ; Brenda Jeglinksi 13 ; Marco Montillo 14 1 Flinders Medical Centre, Bedford Park, AUS; 2 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 3 St. James’s Institute of Oncology, The Leeds Teaching Hospitals, Leeds, UK; 4 Hospital de la Santa Creu i Sant Pau, Barcelona,Spain; 5 Oncology Hematology Care, SCRI, Cincinnati, Ohio, USA; 6 New York Presbyterian, Columbia University Medical Center, New York, NY; 7 1st Department of Internal Medicine, Semmelweis University, Budapest, HUN; 8 Department of Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, Vienna, AUT; 9 Peter MacCallum Cancer Centre, St Vincent’s Hospital and University of Melbourne , Melbourne, AUS; 10 Department III of Internal Medicine, University Hospital Ulm, Ulm, GER; 11 Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, ITA; 12 Hospital Clinic, Barcelona, SPA; Flinders Medical Centre (FMC), Bedford Park, AUS; 13 Verastem Oncology, Needham, MA; 14 Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, ITA Demographics and Baseline Characteristics • Duvelisib is an oral dual inhibitor of PI3K-δ and PI3K-γ being developed for treatment of hematologic malignancies, including relapsed/refractory (R/R) CLL/SLL • The Phase 3 DUO TM Study (NCT02004522; Study IPI-145-07) in patients with R/R CLL/SLL met its primary endpoint, with duvelisib monotherapy demonstrating a statistically significant improvement in PFS vs ofatumumab monotherapy (Flinn ASH 2017) • In DUO, the most common ≥ Gr 3 AEs were hematologic and included neutropenia (30%), anemia (13%), and thrombocytopenia (8%); the most common severe non-hematologic AEs were diarrhea (15%), pneumonia (14%), and colitis (12%) Category Duvelisib monotherapy N=160 Ofatumumab monotherapy N=159 Median PFS (months) 13.3 * 9.9 95% CI 12.1, 16.8 9.2, 11.3 ORR, % 74 * 45 95% CI 66.9, 80.6 37.5, 53.0 LNRR, % 85 * 16 95% CI 79.5, 90.5 10.1, 21.4 DUO™ Study Study IPI-145-12 Crossover Study Ofatumumab IV Administration same as DUO N=8 Duvelisib 25 mg BID continuously N=89 Duvelisib 25 mg BID PO continuously N=160 Ofatumumab IV - 300 mg IV infusion on Day 1 - 2000 mg IV weekly (x7) then monthly (x4) N=159 Relapsed or Refractory CLL/SLL patients 319 Patients Randomized 1:1 Category N = 89 Diagnosis, % CLL 99 SLL 1 High-Risk Cytogenetics, % 17p deletion present (per central lab) 20 Years from Initial Diagnosis Median 7 Min, Max 0.5, 22.0 Current Stage – Rai, (n=38), % I 16 II 34 III 13 IV 37 Current Stage – Binet, (n=51), % A 0 B 74 C 26 Baseline Lymphocytes (×10 9 /L) Median 13.96 Min, Max 0.0, 273.2 Prior Treatment N = 89 Median number of prior anticancer therapies 3 Min, Max 2-8 Received ≥ 3 prior lines of therapy, % 61 Prior Therapies, % Purine Analog 73 Alkylator 96 Cyclophosphamide 72 Bendamustine 38 Chlorambucil 29 Monoclonal antibody 100 Ofatumumab 100 Rituximab 87 Obinutuzumab 2 Alemtuzumab 1 Baseline Characteristics Disease History Prior to DUO Entry Prior Anticancer Therapy Efficacy DUO Study Pre-crossover Ofatumumab N=89 % Study IPI-145-12 Post-crossover Duvelisib N=89 % ORR 28 73 95% CI 19, 37 64, 82 CR 1 0 CRi 0 5 PR 27 57 PRwL 0 11 LNRR 27 73 Percent Change in Nodal Target Lesions (Ofatumumab Pre-crossover) Percent Change in Nodal Target Lesions (Duvelisib Post-crossover) Safety Preferred Term All Grades % Grade 3 % Grade 4 % Hematologic Neutropenia 25 12 10 Nonhematologic Diarrhoea 38 17 0 Pyrexia 23 3 0 Rash 21 5 0 Colitis 11 9 0 Vomiting 11 0 0 Asthenia 11 0 0 Cough 11 0 0 Decreased appetite 10 0 0 Nausea 10 0 0 Pneumonia 10 9 0 0 10 20 30 40 50 60 70 80 90 100 Infection SOC Neutropenia Diarrhea Colitis Skin reaction SOC Pneumonia Transaminitis Pneumonitis % of Patients Adverse Events of Interest Treatment-Emergent AEs by Grade (>10% Overall) All Causalities Note: AEs coded using MedDRA version 16.1. Percentages are based on the number of treated patients. Abbreviation: SOC = system, organ, class • Few discontinuations due to AEs of interest • Three patients with severe opportunistic infections - Pneumocystis jirovecii pneumonia (PJP) (n=2): 1 not receiving prophylaxis at the time of onset - Pneumonia cytomegaloviral (n=1) • 1 AE on study leading to death assessed as related to duvelisib: PJP (noted above) • In this extension study, duvelisib monotherapy achieved robust responses in 89 R/R CLL/SLL patients who had disease progression following ofatumumab treatment on the DUO study - ORR: 73% on duvelisib (28% on prior ofatumumab) - Median PFS: 15 months on duvelisib (9 months on prior ofatumumab) - 83% of evaluable patients had >50% reduction in target nodal lesions • The safety profile of duvelisib monotherapy was manageable and consistent with what was observed in the Phase 3 DUO study • These data further support the potential clinical benefit of duvelisib monotherapy in patients with R/R CLL/SLL Conclusions Presented at the 2018 American Society for Clinical Oncology Annual Meeting • Chicago, Illinois, USA • June 1-5, 2018 Patient Enrollment and Disposition Poster # 170; Abstract 7533 Study Enrollment by Region/Country • 89 of 101 patients treated with ofatumumab with confirmed disease progression on DUO elected to enroll in Study IPI-145-12 • As of 19 July 2017, 60 (67%) patients have discontinued duvelisib, 32 (36%) due to AEs, 16 (18%) due to PD, 4 (5%) due to death, and 8 (9%) for other reasons (e.g. voluntary withdrawal) • 29 (33%) patients remain on duvelisib 17% 11% 12% 13% 8% 9% 6% 8% 5% 3% 9% US (n=7; 8%) Australia (n=5; 6%) New Zealand (n=4; 5%) Hungary (n=15; 17%) Italy (n=12; 13%) Spain (n=11; 12%) France (n=10; 11%) Belgium (n=8; 9%) UK (n=8; 9%) Austria (n=7; 8%) Germany (n=2; 3%) 28% (24/87 evaluable patients) had a >50% reduction in target nodal lesions 83% (65/78 evaluable patients) had a >50% reduction in target nodal lesions 100 Probability of Progression-Free Survival 89 65 55 42 25 20 10 5 2 1 0 89 82 63 54 31 13 4 3 2 1 0 Time (months) Number at Risk 80 60 40 20 0 3 6 9 12 15 18 21 24 27 30 0 Ofatumumab (N= 89) DUO Study Pre-crossover Duvelisib (N= 89) Study IPI-145-12 Post-crossover Treatment ≥ Grade 3 AEs AEs leading to discontinuation (any Grade) Median PFS (months) (95% CI) Ofatumumab (Pre-crossover): 9 (9, 11) Duvelisib (Post-crossover): 15 (10, 17) Key Efficacy Results from the DUO TM Study (Flinn ASH 2017) All results per blinded independent review committee *statistically significant vs ofatumumab: p<0.0001 LNRR = lymph node response rate (i.e. >50% decrease in target nodal lesion) • Study IPI-145-12 (NCT02049515) is an open-label, optional, crossover extension study where patients with radiologically confirmed disease progression on DUO were given the option to receive the opposite treatment • Herein we present data for the 89 patients who voluntarily crossed over f ollowing radiologically confirmed disease progression on ofatumumab on DUO and received duvelisib on Study IPI-145-12 • To further characterize duvelisib, an ad-hoc analysis was performed for ORR and PFS for the 89 patients while receiving ofatumumab pre-crossover in the DUO study • Eligible patients enrolled within 3 months of radiologically-confirmed disease progression on the DUO study (excluding Richter’s transformation or prolymphocytic leukemia) • Duvelisib 25 mg BID was administered until PD, intolerance, death, or study withdrawal • All patients received mandatory prophylaxis for PJP Study Design For more information +1-781-292-4200 [email protected] Copies of this poster obtained through Quick Response (QR) Code are for personal use only and may not be reproduced without permission from ASCO ® and the author of this poster.