Chronic lymphocytic leukemia Best of ASH 2016 in CLL. Anthony Mato, MD MSCE Director, Center for CLL University of Pennsylvania

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1 Chronic lymphocytic leukemia Best of ASH 2016 in CLL Anthony Mato, MD MSCE Director, Center for CLL University of Pennsylvania

2 Can we cure CLL with CIT? Can we minimize chemotherapy without compromising efficacy? Can we extend PFS with LEN maintenance strategies? Is there a role for chemotherapy as a backbone in a targeted world?

3 Thompson, P et al. MRD analysis after FCR Early achievement of MRD-negativity in IGHV-mutated (IGHV-M) Patients Portends Highly Favorable Outcomes after First-Line Treatment of CLL with FCR. Serial Monitoring for MRD in Blood Predicts Clinical Progression. Philip A. Thompson, 1 Paolo Strati, 1 Jeff Jorgensen, 2 Michael J. Keating, 1 Susan M. O Brien, 3 Alessandra Ferrajoli, 1 Jan A. Burger, 1 Stefan Faderl, 4 Zeev Estrov, 1 Nitin Jain, 1 Tapan M. Kadia, 1 Gautam Borthakur, 1 Courtney DiNardo, 1 Naval Daver, 1 Elias Jabbour 1 and William G. Wierda. 1 Departments of 1 and 2 Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, 3 Chao Family Comprehensive Cancer Center, University of California, Irvine, Orange, CA 4 John Theurer Cancer Center, Hackensack, NJ

4 Thompson, P et al. MRD analysis after FCR Background Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) is potentially curative therapy for CLL Particularly in Mutated IGHV, non del17p pts Minimal residual disease (MRD)-negative status at end of therapy (EOT) associated with superior PFS/OS in multiple studies

5 Thompson et al. Blood 2016 Thompson, P et al. MRD analysis after FCR MRD-negative patients with mutated IGHV have highly favorable PFS

6 Results Thompson, P et al. MRD analysis after FCR ORR 96%. 64% CR (but no CT scans) MRD negative 3: 41/236 (17%). Further 6 MRD-neg cases excluded for sensitivity >0.01% ( %) MRD negative 105/219 (48%). Further 17 excluded for sensitivity >0.01% ( %)

7 Thompson, P et al. MRD analysis after FCR MRD-negative strongly associated with PFS but modified by IGHV mutation status

8 Thompson, P et al. MRD analysis after FCR MRD-negative status after 3 courses associated with superior PFS

9 Thompson, P et al. MRD analysis after FCR Patients with mutated IGHV have very favorable outcomes, even with only 3 courses of FCR

10 Conclusions Mutated IGHV, negative FISH and trisomy 12 are associated with greater likelihood of achieving MRD-negative status Mutated IGHV is the only pre-treatment characteristic associated with superior PFS in MRD-negative patients Patients with mutated IGHV who are MRD-neg after 3 courses of FCR have favorable outcome, even with <6 courses of FCR

11 Updated Analysis of Overall Survival in Randomized Phase III Study of Idelalisib in Combination with Bendamustine and Rituximab in Patients with Relapsed/Refractory CLL Andrew D. Zelenetz 1, Jennifer R. Brown 2, Julio Delgado 3, Herbert Eradat 4, Paolo Ghia 5, Abraham Jacob 6, Wojciech Jurczak 7, Javier Loscertales 8, Donald MacDonald 9, Franck Morschhauser 10, Javier de la Serna 11, Mazyar Shadman 12,13, Christopher Pocock 14, Adeboye Henry Adewoye 15, Yeonhee Kim 15, Lyndah Dreiling 15, David Simpson 16, Stephan Stilgenbauer 17 1 Memorial Sloan Kettering Cancer Center, New York, NY; 2 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA; 3 Department d'hematologia, Hospital Clinic, Institut d'investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain; 4 David Geffen School of Medicine, UCLA, Los Angeles, CA; 5 Università Vita-Salute San Raffaele and IRCCS Istituto Scientifico San Raffaele, Milan, Italy; 6 Royal Wolverhampton Hospitals NHS Trust New Cross Hospital, Wolverhampton, UK; 7 Jagiellonian University, Kraków, Poland; 8 Hospital Universitario de La Princesa, IIS-IP, Madrid, Spain; 9 Dalhousie University and QEII Health Sciences Centre, Halifax, Nova Scotia, Canada; 10 Service des Maladies du Sang, Hôpital Huriez, Université de Lille, Unité Groupe de Recherche sur les formes Injectables et les Technologies Associées, Lille, France; 11 Servicio de Hematología, Hospital Universitario 12 de Octubre, Madrid, Spain; 12 Fred Hutchinson Cancer Research Center, Seattle, WA; 13 University of Washington, Seattle, WA; 14 East Kent Hospitals, Canterbury, UK; 15 Gilead Sciences, Inc., Foster City, CA; 16 North Shore Hospital, Auckland, New Zealand; 17 University Hospital Ulm, Munich, Germany ASH 2016, San Diego, CA

12 Randomization Phase 3 Study 115 Design Double-Blind Initial Combination Therapy Post-Study Therapy Arm A n=207 B (70 mg/m 2 D1,2 Q4 weeks, C1 6) R (375 mg/m 2 C1, 500 mg/m 2 C2 6) IDELA (150 mg BID) PD Arm B n=209 B (70 mg/m 2 D1,2 Q4 weeks, C1 6) R (375 mg/m 2 C1, 500 mg/m 2 C2 6) Placebo (BID) PD Investigator s choice (standard of care or investigational) Enrollment period June 2012 August 2014 Pre-specified interim analysis at 67% of events An improvement in median PFS from 15 months to 22.5 months (due to addition of IDELA to bendamustine/rituximab in Arm A, hazard ratio 0.67) Stratification Endpoints 17p deletion and/or TP53 mutation IGHV mutation status Refractory vs relapsed disease Primary: PFS Secondary: ORR, nodal response, OS, CR IGHV, immunoglobulin heavy chain variable region; CR, complete response; ORR, overall response rate; OS, overall survival, PD, disease progression; PFS, progression-free survival. 12

13 PFS Probability, % Results: IRC-Assessed PFS Primary Endpoint IDELA PBO Median PFS, mo Hazard Ratio, 95% CI 0.31 (0.24, 0.41) p-value < Median follow-up, mo % PFS probability N at risk (Events) IDELA + BR PBO + BR 207 (0) 209 (0) Months (6) (11) (25) (33) (44) (54) (64) (69) (78) (81) (82) (87) (89) (93) (93) (95) (95) (95) (95) (95) (95) (95) (7) (27) (46) (56) (85) (119)(128)(135) (146 (155)(160)(163)(164)(165)(165)(165)(165)(165)(165)(165)(165)(165) 13

14 Probability of Survival, % Results: Overall Survival (ITT Population) Secondary Endpoint IDELA PBO Median OS, mo NR 40.6 Hazard Ratio, 95% CI 0.67 (0.47, 0.96) p-value 0.04 (stratified) 0.06 (unstratified) Median follow-up, mo (range) 21 (0.1, 43.3) N at risk (Events) IDELA + BR PBO + BR Months 207 (0) 199 (6) 193 (10) 184 (14) 178 (19) 166 (27) 163 (30) 159 (33) 154 (38) 143 (43) 126 (46) 106 (47) (0) (5) (11) (21) (30) (31) (35) (43) (50) (56) (59) (64) 76 (48) 52 (66) 56 (50) 42 (67) 45 (52) 31 (68) 34 (53) 24 (68) 21 (53) 17 (69) 9 (53) 5 (69) 4 (53) 3 (69) 2 (53) 2 (69) 1 (53) 2 (69) 1 (53) 0 (70) 0 (53) 0 (70) 14

15 Results: Adverse Event Summary IDELA + BR n=207 BR + Placebo n=209 n (%) n (%) Any AE 207 (100) 203 (97) Grade (95) 163 (78) Any serious AE 147 (71) 94 (45) AE leading to Study drug dose reduction 34 (16) 13 (6) Study drug discontinuation 68 (33) 31 (15) Death 25 (12) 19 (9) 15

16 Conclusions IDELA in combination with BR is superior to BR alone with regard to OS in relapsed/refractory CLL Median OS: not reached (IDELA) vs 41 months (placebo); HR 0.67 (p=0.036) Improvement in OS was observed across all risk categories Overall safety profile was manageable Opportunistic infections (PJP, CMV) and SAEs were more frequent in the IDELA vs placebo arm Results of IDELA-containing regimens may be further improved with implementation of adequate PJP prophylaxis and CMV monitoring measures This regimen represents an important option for patients with relapsed/refractory CLL 16

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21 Open as part of Center for CLL, Pennsylvania Hospital. Doug Beach, MD PI

22 What can we learn from long-term follow up and real-world data from Ibrutinib-treated patients?

23 Five-Year Experience With Single-Agent Ibrutinib in Patients With Previously Untreated and Relapsed/Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Leukemia Susan O Brien, MD 1,2, Richard R. Furman, MD 3, Steven Coutre, MD 4, Ian W. Flinn, MD, PhD 5, Jan Burger, MD, PhD 1, Kristie Blum, MD 6, Jeff Sharman, MD 7, William Wierda MD, PhD 1, Jeffrey Jones MD, MPH 6, Weiqiang Zhao, MD, PhD 6, Nyla A. Heerema, PhD 6, Amy J. Johnson, PhD 6, Ying Luan, PhD 8, Danelle F. James, MD, MAS 8, Alvina D. Chu, MD 8, John C. Byrd, MD 6 1 Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 University of California, Irvine, CA; 3 Department of Medicine, Weill Cornell Medical College, New York, NY; 4 Stanford Cancer Center, Stanford University School of Medicine, Stanford, CA; 5 Sarah Cannon Research Institute, Nashville, TN; 6 The Ohio State University, Columbus, OH; 7 Willamette Valley Cancer Institute and Research Center, Springfield, OR; 8 Pharmacyclics, LLC, an AbbVie Company, Sunnyvale, CA.

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26 Ibrutinib Treatment Continued in 65% Disposition of TN and 30% of R/R Patients Median time on study, months (range) Duration of study treatment, n (%) 1 year >1 2 years >2 3 years >3 4 years 4 years TN (n=31) 62 (1 67) 5 (16%) 0 1 (3%) 1 (3%) 24 (77%) R/R (n=101) 49 (1 67) 24 (24%) 14 (14%) 9 (9%) 19 (19%) 35 (35%) Patients remaining on ibrutinib therapy, n (%) 20 (65%) 30 (30%) Primary reason for discontinuation, n (%) Progressive disease Adverse event Consent withdrawal Investigator decision Lost to follow-up 1 (3%) 6 (19%) 3 (10%) 0 1 (3%) 33 (33%) 21 (21%) 5 (5%) 11 (11%) 1 (1%) After ~5 years of follow-up, 65% of TN and 30% of R/R patients continue treatment on study.

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33 Phase II Study of TGR-1202 in Patients with CLL who are Intolerant to Prior BTK or PI3K Inhibitor Therapy BTK or PI3K Inhibitor Therapy Discontinuation for Intolerance < 9 months TGR-1202 (800 mg daily) Intolerance defined as unacceptable toxicity where in the opinion of the investigator, treatment should be discontinued in spite of the optimal supportive care as a result of one of the following: i. 2 Grade 2 non-hematological toxicities as a cause of discontinuation, and/or; ii. 1 Grade 3 non-hematological toxicity, and/or; iii. Grade 3 neutropenia with infection or fever, and/or; iv. Grade 4 hematological toxicities, AND the toxicities persistent to the point that the investigator chose to discontinue therapy due to toxicity / no progression. All toxicity must resolve to Grade 1 prior to TGR-1202 dosing

34 Beyond kinase inhibitor monotherapies Novel KI double / triple combinations Venetoclax after KI

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39 TGR-1202 in Combination with Ibrutinib in Patients with Relapsed or Refractory CLL or MCL: Preliminary Results of a Multicenter Phase I/Ib Study X X Matthew S. Davids, MD, MMSc 1, Haesook T. Kim, PhD 1, Alyssa Nicotra 1, Alexandra Savell 1, Karen Francoeur, RN 1, Jeffery M. Hellman, PA-C 1, Hari Miskin 2, Peter Sportelli 2, Asad Bashey, MD, PhD 3, Laura Stampleman, MD 4, Jens Rueter, MD 5, Adam Boruchov, MD 6, Jon E. Arnason, MD 7, Caron A. Jacobson, MD, MMSc 1, David C. Fisher, MD 1, and Jennifer R. Brown, MD, PhD 1 1 Dana-Farber Cancer Institute, Department of Medical Oncology, Boston, MA, USA, 2 TG Therapeutics, New York, NY, USA, 3 Bone Marrow Transplantation Group of Georgia, Atlanta, GA, USA, 4 Pacific Cancer Care, CA, USA, 5 Eastern Maine Medical Center, Bangor, ME, USA, 6 St. Francis Medical Center, Hartford, CT, USA, 7 Beth Israel Deaconess Medical Center, Department of Medical Oncology, Boston, MA, USA for the Leukemia & Lymphoma Society Blood Cancer Research Partnership (LLS/BCRP) 2016 ASH Annual Meeting San Diego, California December 5, 2016

40 Results Preliminary Efficacy Analysis (n=28) PFS OS Median follow-up time among survivors: 11 mo. (range ) 1-year PFS and OS for CLL is 94% (n=17) 1-year PFS and OS for MCL is 37% and 52%, respectively (n=11) 6 MCL patients have died (5 due to PD, 1 due to toxicity from subsequent therapy) 1 CLL patient had sudden death deemed unlikely due to study drugs 40

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44 First in Human at PENN Phase Ia: BTK Inhibitor DTRMWXHS-12 Phase Ib: Arm A, DTRM-505 (DTRMWXHS-12 & Everolimus); Arm B, DTRM-555 (DTRMWXHS-12, Everolimus & Pomalidomide)

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50 Sequencing Therapies

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52 2d PFS by first KI and complex karyotype median PFS = 9 months median PFS = not reached median PFS = 29 months median PFS = 12 months Months Ibrutinib / not complex Idelalisib / not complex Ibrutinib / complex Idelalisib / complex

53 3a PFS following KI discontinuation by alternate treatment choices median PFS = 5.1 months median PFS = not reached median PFS = not reached Months KI (Ibr / Ide) CIT / MoAbs composite Venetoclax

54 3b PFS with alternate KI: KI intolerance vs. CLL progression median PFS = 9 months median PFS = not reached Months KI intolerance CLL Progression

55 3c PFS by second novel agent in Ibr failures median PFS = not reached Median PFS = 9 months Months Idelalisib Venetoclax

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66 Screening Response Assessment Response Assessment UPCC 25415: Phase I/II study of pembrolizumab in combination with TG-1101 (ublituximab) and TGR-1202 in patients with RR CLL and RT Part 1- Induction (Cycles 1 & 2*) Part 2- Induction Cycles 3-6* TG-1101 (ublituximab): 900 mg Days 1, 8, 15 TGR-1202: 800 mg oral daily. (Cycle = 28 days) Pembrolizumab: 3+3 dose escalation Level 1: 100mg IV q 3 weeks Level 2: 200mg IV q 3 weeks TG-1101 (ublituximab): 900 mg on Day 15 of Cycles 4 & 6 *For Cycle 1, TG-1101 dosing will be split over two days to minimize the risk of tumor lysis syndrome and infusion related reactions (up to 150 mg on day 1 and 750 mg on day) TGR-1202: 800 mg oral daily. **Continue as maintenance until PD** (*Cycle = 21 days)