Results from the Phase 3 DUO. of Duvelisib vs Ofatumumab in Relapsed/Refractory CLL/SLL

Transcription

1 Results from the Phase 3 DUO TM Study of Duvelisib vs Ofatumumab in Relapsed/Refractory CLL/SLL Ian Flinn 1, Peter Hillmen 2, Marco Montillo 3, Zsolt Nagy 4, Árpád Illés 5, Gabriel Etienne 6, Julio Delgado 7,Bryone Jean Kuss 8, Constantine Tam 9, Zoltán Gasztonyi 10, Fritz Offner 11, Scott Lunin 12, Francesco Bosch 13,Matthew Davids 14, Nicole Lamanna 15, Ulrich Jaeger 16, Paolo Ghia 17, Florence Cymbalista 18, Craig Portell 19, Alan Skarbnik 20, Amanda Cashen 21, Virginia Kelly 22, Barry Turnbull 22, Stephan Stilgenbauer 23 1 Sarah Cannon Research Institute, Nashville, USA; 2 St. James's Institute of Oncology, The Leeds Teaching Hospitals, Leeds, UK; 3 Niguarda Cancer Center, ASST Grande Ospedale Metropolitano Niguarda, Milan, ITA; 4 1st Department of Internal Medicine, Semmelweis University, Budapest, HUN; 5 Department of Hematology, Institute for Medicine, U. of Debrecen, Debrecen, HUN; 6 Hematology Department, Institut Bergonie, Bordeaux, FRA; 7 Hospital Clinic, Barcelona, SPA; 8 Flinders Medical Centre (FMC), Bedford Park, AUS; 9 Peter MacCallum Cancer Centre, Melbourne, AUS; 10 Dep. of Internal Medicine and Hematology, Petz Aladár County Hospital, Győr, HUN; 11 Hematology, University Hospital Ghent, Gent, BEL; 12 Florida Cancer Specialists, Venice, USA; 13 Department of Hematology, University Hospital Vall d Hebron, Barcelona, SPA; 14 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, USA; 15 New York Presbyterian, Columbia University Medical Center, New York, USA; 16 Medical University of Vienna, Vienna, AUT; 17 Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, ITA; 18 Laboratoire d'hématologie, Hôpital Avicenne, Paris, FRA; 19 Division of Hematology and Oncology, University of Virginia, Charlottesville, USA; 20 John Theurer Cancer Center, Hackensack Meridian Health, Closter, USA; 21 Siteman Comprehensive Cancer Center, Washington University, St. Louis, USA; 22 Verastem Inc., Needham, USA; 23 Department III of Internal Medicine, University Hospital Ulm, Ulm, GER

2 Duvelisib is an Oral Dual Inhibitor of PI3K-δ and PI3K-γ Duvelisib targets both malignant B cells (PI3K-δ) and the supportive tumor microenvironment (PI3K-γ) Promising clinical activity (56% ORR per investigator assessment) in a Phase 1 study in advanced CLL/SLL (O Brien ASH 2014) 2

3 DUO: A Phase 3 Randomized Study in Relapsed/Refractory CLL/SLL Optional Crossover Study Relapsed or Refractory CLL/SLL patients 319 patients Randomized 1:1 Duvelisib 25 mg BID continuously * N=160 Ofatumumab IV mg IV infusion on Day mg IV weekly (x7) then monthly (x4) N=159 Ofatumumab IV Administration same as DUO N=8 Duvelisib 25 mg BID continuously N=89 Response per modified iwcll/iwg Criteria ** Assessed by independent review committee (IRC) Cycle 3 (C3), C5, C7, C11, C15, C19, every 6 months thereafter CT scan, CBC, disease related symptoms, BM biopsy *** Survival assessment every 6 months Endpoints PFS (primary) ORR, DOR, OS (secondary) Safety (AEs and lab abnormalities) * Patients may have stopped treatment at C18 for CR/PR >3 months at discretion of Investigator ** Lymphocytosis not considered disease progression; PR = 2 Group A and 1 Group B Criteria *** Required for confirmation of CR/CRi 3

4 Eligibility and Prophylaxis Key Eligibility Criteria - Progressed on or relapsed after 1 prior anticancer therapy - Measurable lymph node disease (> 1.5 cm) per CT scan - Hemoglobin 8.0 g/dl and platelet count 10,000 μl with or without transfusion support - No minimum ANC required - Richter s transformation and prolymphocytic leukemia excluded - Prior treatment with BTK or PI3K inhibitors excluded - Patients with prior, current, or chronic hepatitis B infection excluded Prophylaxis - All patients required to receive Pneumocystis prophylaxis while on treatment - Prophylaxis for CMV infection/reactivation recommended but not required 4

5 Study Enrolled Patients Worldwide US (n=51; 16%) Australia (n=21; 7%) New Zealand (n=12; 4%) Hungary (n=65; 20%) Italy (n=41; 13%) Spain (n=40; 13%) France (n=30; 9%) Belgium (n=27; 9%) UK (n=17; 5%) Austria (n=11; 3%) Germany (n=4; 1%) 5

6 Baseline Characteristics and Prognostic Features Characteristic DUV N = 160 OFA N = 159 CLL/SLL, % 97 / 3 99 / 1 Median age (range), years 69 (39-90) 69 (39-89) Male, % ECOG PS 2, % 7 10 Rai stage 3 / Binet Stage C, % 56 / / 34 Bulky disease ( 5 cm target lesion), % Grade 4 Cytopenia(s), % Molecular features (per central laboratory), % 17p deletion TP53 mutation p deletion and/or TP53 mutation Unmutated IGHV ZAP70 Positive ( 20%)

7 Prior Anticancer Regimens Characteristic DUV N = 160 OFA N = 159 Median prior therapies (range) 2 (1-10) 2 (1-8) Median months from prior therapy (range) 22 (1-149) 18 (1-106) Purine Analog, % Alkylator, % Cyclophosphamide Chlorambucil Bendamustine Monoclonal antibody, % Rituximab Ofatumumab 2 3 Obinutuzumab 1 2 Alemtuzumab 8 3 7

8 Patient Disposition Characteristic DUV OFA Randomized, n Treated, n Median exposure (weeks) Discontinued Treatment, n (%) 124 (79) 155 (100) AE 55 (35) 6 (4) Disease progression 35 (22) 31 (20) Subject withdrawal 13 (8) 7 (5) Death 12 (8) 3 (2) Investigator decision 3 (2) 4 (3) Completed treatment per protocol 1 (1)* 103 (67)* Other 5 (3) 1 (1) On Treatment, n (%) 34 (22) 0 Received opposite treatment on optional crossover study, n (%) 8 (5) 89 (57) *completed treatment for OFA = 7 cycles and for duvelisib = 18 cycles (duvelisib patients permitted to receive duvelisib 18 cycles) 8

9 DUO Met Primary Endpoint of PFS Significantly Longer Median PFS with Duvelisib per IRC DUV OFA Median PFS (Months) % CI 12.1, , 11.3 Hazard ratio 0.52 p-value < Number at Risk 9

10 Significantly Longer PFS with Duvelisib per Investigator Assessment DUV OFA Median PFS (Months) % CI 15, 22 9, 11 Hazard ratio 0.40 p-value < Number at Risk 10

11 Significantly Longer PFS with Duvelisib in Patient with 17p Deletion per IRC DUV OFA Median PFS (Months) % CI 8.9, , 10.8 Hazard ratio 0.41 p-value Number at Risk 11

12 Duvelisib Maintained PFS Advantage in All Subgroups Analyzed 12

13 Percent Significantly Higher ORR with Duvelisib per IRC Overall Response Rate Lymph Node Response Rate % DUV OFA CR 0.6% 0.6% PRwL 0.6% 0 PR 72.5% 44.7% p-value < % Lymph node response: 50% decrease in the SPD of target lymph nodes from baseline % % 10 0 DUV OFA DUV OFA ORR in patients with 17p deletion: duvelisib 70% vs OFA 43% (p=0.0182) 13

14 Overall Survival Similar Between Treatment Arms DUV OFA Median OS (Months) NE NE 95% CI 31, NE 29, NE Hazard ratio 0.99 p-value Number at Risk NE = Not estimable Many patients received a subsequent anticancer therapy 89 patients on OFA arm received duvelisib in crossover study, achieving an ORR of 73% and a median PFS of 15 months per Investigator assessment 14

15 Adverse Events (Percent of Patients) All Grades Grade 3 DUV N=158 OFA N=155 DUV N=158 OFA N=155 Median Observation Period (Weeks) Hematologic Neutropenia Anemia Thrombocytopenia Nonhematologic Diarrhea Pyrexia Nausea Cough Pneumonia Constipation Upper resp. tract infection Vomiting Bronchitis Colitis Decreased appetite Weight decreased Asthenia Abdominal pain Dyspnea Rash

16 AEs of Special Interest Infrequently Led to Duvelisib Discontinuation Rash Pneumonitis Transaminitis Colitis Pneumonia Diarrhea Neutropenia Severe opportunistic infections (6%): bronchopulmonary aspergillosis (n=4), fungal infection (n=2), PJP (n=2)*, and cytomegalovirus colitis (n=1) - No severe Herpes zoster infections All Grade 3 AEs AEs leading to discontinuation (any Grade) Percent of Patients Percent of Patients Treatment-related AEs leading to death (n=4): general health deterioration (n=1); pneumonia staphylococcal (n=2); sepsis (n=1) * Neither patient on prophylaxis at the time of the event 16

17 DUO Study Conclusions DUO met the primary endpoint for PFS: duvelisib monotherapy achieved significant improvement in PFS vs OFA (13.3 m vs 9.9 m; HR = 0.52; p < ) per IRC PFS per investigator response assessment significantly favored duvelisib vs OFA (17.6 m vs 9.7 m; p < ) Similar benefit in CLL/SLL patients with 17p deletion Duvelisib achieved significant improvement in ORR vs OFA (74% vs 45%; p < ) per iwcll/iwg Duvelisib significantly reduced lymph node burden > 50% in most patients vs OFA (85% vs 16%) With a median exposure of 50 weeks, the AE profile of duvelisib was manageable and consistent to what has been previously observed AEs of interest (neutropenia, diarrhea, pneumonia, colitis, transaminase elevations, pneumonitis, rash) infrequently led to discontinuation DUO results support duvelisib oral monotherapy as a potential new and convenient treatment option for previously treated CLL/SLL patients 17

18 THANK YOU We would like to acknowledge the participating institutions, their study investigators and clinical staff, for the successful conduct the study. Most importantly, we sincerely thank our patients and their families for their participation in this clinical study.