Patient Care and Cutting Edge Research in Hodgkin and Non-Hodgkin Lymphoma

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1 Patient Care and Cutting Edge Research in Hodgkin and Non-Hodgkin Lymphoma Julie M. Vose, M.D., M.B.A. Chief, Hematology/Oncology University of Nebraska Medicine Center

2 WHO Press World Health Organization From the USA Stylus Publishing Quicksilver Drive Herndon VA : WHO Classification 4 th edition revised Updates reflect: New insights into biology, pathology and natural history of disease Summaries of revisions published: Swerdlow et al. Blood epub. March 15, 2016 (Lymphoid)

3 Update: Classification of mature T-cell lymphomas Primary cutaneous T-cell lymphomas Small/medium CD4+ T-cell lymphoma in 2008 Localized, indolent T-follicular helper phenotype, admixed B cells Cutaneous CD4+ lymphoproliferative disorder in 2016 WHO Indolent CD8+ lymphoid proliferation of the ear in 2008 Localized, indolent treated with excision, radiation Primary cutaneous acral CD8+ lymphoma in 2016 WHO Grouping of nodal PTCL with T-follicular helper phenotype Includes angioimmunoblastic and follicular T-cell lymphomas PD1+, BCL6+, CD10+, CXCL13+, ICOS+, SAP+, and/or CCR5+ (at least 2) Share mutations more common in myeloid neoplasms TET2, IDH2, RHOA, DNMT3A

4 T-cell lymphoma progress: FDA Approvals 2009 Praltrexate approved for relapsed PTCL 2011 Romidepsin approved for relapsed PTCL 2011 Brentuximab vedotin approved for relapsed ALCL 2014 Belinostat approved for relapsed PTCL

5 Progression Free Survival: Relapsed/Refractory PTCL BCCA Med 3.7 months Romidepsin N=130 Pralatrexate N=109 Belinostat N=129 Mak V et al. JCO 2013;31: , O Connor OA, et al. J Clin Oncol. 2011;29: ,Coiffier B, et al. J Clin Oncol. 2012;30 : , O Connor OA et al ASCO 2013

6 Molecular subgroups within PTCL-NOS GATA3 TBX21 33% of cases 49% of cases TH2 Transcription factor TH1 Transcription factor Plasma celllike gene signature (good outcome) Poor clinical outcome PI3K and mtor pathways Cytotoxic cell-like gene signature (poor outcome) NFkB and STAT3 Javeed Iqbal et al; Blood Reviews, 18 August 2015

7 Mature B-cell lymphomas Chronic lymphocytic leukemia MBL, CLL-type MBL, non-cll type B-prolymphocytic leukemia Splenic marginal zone lymphoma Hairy cell leukemia Splenic B-cell lymphoma, unclassifiable Splenic diffuse red pulp small B-cell lymphoma Hairy cell leukemia variant Mantle cell lymphoma In-situ mantle cell neoplasia Lymphoplasmacytic lymphoma IgM MGUS Heavy chain diseases m heavy chain disease g heavy chain disease Plasma cell neoplasms Extranodal marginal zone lymphoma (MALT lymphoma) Nodal marginal zone lymphoma Pediatric NMZL Follicular lymphoma In-situ follicular neoplasia Duodenal-type FL Testicular FL Pediatric-type FL Primary cutaneous FL Large B-cell lymphomas Large B-cell lymphoma with IRF4 rearrangement Burkitt lymphoma Burkitt-like lymphoma with 11q aberration High-grade B-cell lymphoma High-grade BCL with MYC/BLC2/BCL6 double or triple hit High-grade BCL, NOS B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and classic Hodgkin lymphoma

8 WHO 2017 classification of B-NHL : Clinician's perspective Aggressive B-cell Lymphomas Distinguishes the cell of origin (COO) between germinal center B-cell-like (GCB) or activated B-cell-like (ABC/non-GCB) DLBCL with the use of either an immunohistochemical (IHC) algorithm or gene-expression profiling (GEP) Eliminates the category B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU) Recognizes a new category high grade B-cell lymphomas with MYC and BCL2 and/or BCL6 translocations which includes double hit (DHL) and triple hit (THL) lymphomas Recognizes a new category High grade B-cell lymphoma NOS (HGBL, NOS) that includes cases that would formerly be called BCLU but lack MYC and BCL2 or BCL6 translocations

9 Determining cell-of-origin Gene expression profiling (GCB vs ABC) Gold Standard Not practical in clinical practice Immunohistochemistry (GCB vs non GCB) Widely available Many algorithms 20-30% error rate compared to GEP Hans algorithm

10 Cell of Origin in real time: Using FFPE Tissue Digital gene expression-based assay using NanoString technology (Lymph2Cx) GEP heat map, 20 genes contribute Scott D W et al Blood 2014 Comparison of Lymph2Cx scores from 2 labs 98% concordance of ABC and GCB

11 Performance of the Lymph2Cx assay compared to gold standard GEP Independent validation cohort L2x L2x Gold standard GEP Gold standard GEP Scott D W et al Blood 2014

12 Tumor Heterogeneity in DLBCL Subsets myc + DLBCL Double/Triple Hit/Expresser DLBCL MYC BCL2 Dunleavey Hematology Am Soc Hematol Educ Program 2014 Mottock & Gascoyne Clin Cancer Res 2015

13 MYC rearrangement / translocation in DLBCL Associated with poor outcomes with RCHOP-based Therapy Survival of MYC rearranged disease Survival of Double Expression and Double Hit patients MYC-R MYC/BCL2 Johnson et al Blood 2009 Johnson et al JCO 2012

14 CNS Involvement Double Hit and Double Expression Lymphoma Double hit lymphoma Double expression lymphoma Median OS 45 months Median OS 14 months Petrich et al Blood 2014 Savage et al Blood 2016

15 WHO 2016: New diagnostic categories for aggressive B-NHL Eliminates the category B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and BL (BCLU). Recognizes a new category high grade B- cell lymphomas with MYC and BCL2 and/or BCL6 translocations which includes double hit (DHL) and triple hit (THL) lymphomas. Recognizes a new category High grade B- cell lymphoma NOS (HGBL, NOS) that includes cases that would formerly be called BCLU but lack MYC and BCL2 or BCL6 translocations. Swerdlow et al Blood 2016? Criteria for doing FISH: All or restrict to GCB types

16 Is R-CHOP still the standard of care for DLBCL?

17 CALGB 50303: R-CHOP vs. DA-EPOCH-R Event Free Survival* Overall Survival No clinical subgroup identified based on age/ipi that appears to benefit from DA-EPOCH-R Inadequate numbers to comment on PMBCL (n=28) Double MYC/BCL2 expresser, double hit analysis pending PET, pharmacogenomic, pathology, molecular correlates pending *Primary endpoint Wilson and Bartlett et al ASH 2016

18 Attempts to improve on R-CHOP in DLBCL R-CHOP-14 Upfront stem cell transplant Maintenance rituximab R-CHOP-etoposide R-CHOP-enzastaurin R-CHOP-everolimus R-CHOP-bevacizumab R-CHOP-bortezomib Obinutuzumab-CHOP DA-EPOCH-R FAIL FAIL FAIL FAIL FAIL FAIL FAIL FAIL FAIL FAIL RCHOP 21 remains the SOC for most patients with DLBCL

19 Possible reasons for equivalent outcomes Trials enrolled all-comers with DLBCL Not stratified for GC and non-gc Inadvertent inclusion of double hit lymphomas Mixture of DEL and non DEL Not powered to detect differences based on outcomes of subgroups Unexpectedly good outcomes for the control arm

20 Dose-Intensive Treatment Strategies for Double Hit Lymphoma Petrich, et al. Blood 2014 Oki et al BJH 2014 * Intensified induction therapy shows NO improvement in OS by multivariate analysis in either study

21 Moving forward in DLBCL Identify high-risk subgroups of patients who will not be cured with R-CHOP in real time Focus of trials needs to be based on biology Smaller patient numbers in subgroups underscores the need for collaboration/cooperation Biopsy at relapse important to identify targetable subsets

22 COO is indicative of distinctive biology which could influence therapy Pasqualucci Curr Opin Hematol 2013

23 Pathways with Therapeutic Potential in ABC DLBCL Roschewski et al Nat Rev Clin Oncol 2014

24 Lenalidomide Immunomodulatory agent (IMDs) Anti-angiogenesis Modulation of the microenvironment Direct anti-tumor activity Chanan-Khan JCO 2008 Author N. ORR CR Median PFS (months) Wiernik % 15% 2-3 ORR: Witzig non-gcb 10853% 28% vs GCB 7% 9% median 2.7 PFS: 2011~ 6 m vs 2 m REVEAL % 18% 3.5

25 PFS and OS in R2CHOP and RCHOP (Mayo Clinic) Case Match Control in non-gcb DLBCL Nowakowski et al JCO 2015

26 DLBCL ROBUST: Clinical Study Schema (NCT ) ABC Select by GEP real time GCB, unclassified Ineligible Newly diagnosed DLBCL of ABC type IPI 2; ECOG PS 2; Age Primary Endpoint = PFS N = 560 R 6 x R-CHOP21 + Lenalidomide 15 mg x 14* n=280 6 x R-CHOP21 + Placebo x 14* n=280 *Option for 2 additional rituximab doses after completing treatment regimen (if considered standard of care per local practice) Stratification: - Age ( 65 yrs) - Bulky disease ( 7 cm) - IPI (2 versus 3)

27 BCR Signaling Cascade Bruton s Tyrosine Kinase (BTK) is involved in the BCR signaling cascade Activated by phosphorylation via upstream kinases Lyn and Syk Propagates the activation signal via phosphorylation of the downstream PLCγ Ultimately activates ERK and NF-κB Inhibition of BTK terminates downstream signaling of the BCR pathway Prevents development of viable tumor microenvironment Reduces integrin-mediated cell adhesion, and induces apoptosis Davids & Brown Leukemia and Lymphoma 2012

28 Ibrutinib in relapsed/refractory DLBCL Median OS (months) 9.76 (3.88, NR) 3.35 (1.22, NR Wilson et al Nature Medicine 2015

29 33 patients Ibrutinib RCHOP (IR-CHOP) No MTD for Ibrutinib 560 mg PO q d with standard RCHOP-21 18% febrile neutropenia 18 pts with DLBCL in the extended phase 100% ORR in the DLBCL (18/18) 15 CR and 3 PR Non-GCB CR: 4/4 GCB CR: 5/7 GCB ABC Younes et al Lancet Oncol 2014 PK not affected for either ibrutinib or vincristine

30 PHEONIX (NCT ): Ibrutinib in Combination With R-CHOP in Subjects With Newly Diagnosed Non-GCB DLBCL Phase 3, double-blind, placebo-controlled DLBCL Non-GCB Select by IHC real time GCB Ineligible Newly diagnosed DLBCL of non-gcb type IPI 2; ECOG PS 2; Age >18 Primary Endpoint = EFS N = 800 R 6 to 8 x R-CHOP21* + Ibrutinib 560 mg daily N=400 6 to 8 x R-CHOP21 + Placebo daily N=400 *Option for 2 additional cycles if considered standard of care per local practice ACCURAL COMPLETE

31 Are new anti-cd20 any better? Rituximab Veltuzumab Ocrelizumab Ofatumumab Obinotuzuma b Murine Chimeric Humanized Fully human Engineere d

32 Two Types of anti-cd20 mabs Type I CD20 clustering in B-cell membrane Type I Type II ++ - Type II Induction of CDC ++ + Induction of ADCC Induction of apoptosis + ++ = no activity; + = some activity; ++ = significant activity Cragg MS, et al. Curr Dir Autoimmun 2005 Glennie MJ, et al. Mol Immunol 2007 Teeling JL, et al. Blood 2004

33 Phase III GALLIUM Study of Obinutuzumab (G)-Chemo vs Rituximab (R)-Chemo in Frontline inhl: Study Design Previously untreated CD20-positive inhl Age 18 years FL (grades 1-3a) or splenic/nodal/extranodal MZL Stage III/IV disease or stage II with tumor diameter 7 cm ECOG PS 0-2 Requiring treatment according to GELF criteria R A N D O M I Z E 1 : 1 Induction G-chemo G 1000 mg IV on D1, D8, D15 of C1 and D1 of C2-8 (q3w) or C2-6 (q4w) plus CHOP, CVP, or bendamustine R-chemo R 375mg/m2 IV on D1 of C1-8 (q3w) or C1-6 (q4w) plus CHOP, CVP, or bendamustine Primary endpoint: PFS in FL Maintenance If CR or PR at EOI visit, G 1000 mg IV every 2 months for 2 years or until PD If CR or PR at EOI visit, R 375 mg/m 2 IV every 2 months for 2 years or until PD Marcus RE, et al. Blood. 2016;128: Abstract 6. Secondary endpoints: PFS in the overall study population (investigator-assessed), IRC-assessed PFS, CR/ORR at EOI, OS, EFS, DFS, DOR, TTNT, safety

34 Kaplan Meier Estimates of Investigator-Assessed Progression-free Survival and Overall Survival among Patients with Follicular Lymphoma. NEJM 2017; 377(14): Marcus R et al. N Engl J Med 2017;377:

35 Phase III GALLIUM Study of G-Chemo vs R-Chemo in Frontline inhl: Safety in Patients With FL Adverse events (AEs), n (%) G-chemo (n = 595) R-chemo (n = 597) Adverse events, n (%) G-chemo (n = 595) R-chemo (n = 597) Any AE 592 (99.5%) 587 (98.3%) Serious AEs (SEAs) 274 (46.1%) 238 (39.9%) Grade 3 AEs ( 5% in either arm) 444 (74.6%) 405 (67.8%) Neutropenia 261 (43.9%) 226 (37.9%) AEs leading to treatment discontinuations 97 (16.3%) 85 (14.2%) Leucopenia 51 (8.6%) 50 (8.4%) Febrile neutropenia 41 (6.9%) 29 (4.9%) Grade 5 (fatal) AEs 24 (4.0%) 20 (3.4%) Infusion-related reactions (IRRs) 40 (6.7%) 22 (3.7%) Thrombocytopenia 36 (6.1%) 16 (2.7%) Grade 3 AEs ( 5% in either arm) of special interest Infections 119 (20.0%) 93 (15.6%) IRRs 74 (12.4%) 40 (6.7%) Second neoplasms 28 (4.7%) 16 (2.7%) Marcus RE, et al. Blood. 2016;128: Abstract 6.

36 MRD Analysis of Phase III GALLIUM Study of G-Chemo vs R-Chemo in Frontline inhl: MRD Status MRD-negative status, n (%) R-chemo (n = 342) G-chemo (n = 348) P value At mid induction (in PB) 304 (88.9) 328 (94.3) At end of induction (PB/BM) 293 (84.9) 323 (92.0) At end of induction (BM) 165 (82.5) 199 (93.0) At end of induction (PB/BM) B 190 (89.6) 186 (92.5) NR CHOP 84 (77.8) 105 (91.3) NR CVP 19 (76.0) 32 (91.4) NR BM, bone marrow; MRD. minimal residual disease; NR, not reported; PB, peripheral blood Pott C, et al. Blood. 2013;122: Abstract 613. Marcus RE, et al. Blood. 2016;128: Abstract 6.

37 Phase III GALLIUM Study of G-Chemo vs R-Chemo in Frontline inhl: Authors Conclusions In patients with previously-untreated advanced FL, G-chemo + maintenance resulted in a clinically meaningful improvement in PFS, with a 34% reduction in the risk of a PFS event relative to R-based therapy Frequency of some AEs (eg, IRRs, cytopenias, and infections) was higher with obinutuzumab Fatal AEs more common in patients on bendamustine in both arms MRD assessment: Consistently higher MRD response rates observed with Marcus RE, et al. Blood. 2016;128: obinutuzumab Abstract 6. across compartments and chemotherapy partners

38 Relapsed Non-Hodgkin Lymphoma

39 Updates in Lymphoma: Small molecule inhibitors

40 PI3K Class I Family Regulatory Subunit (p85 or p101) Catalytic subunit (p110) PI3K Class IA PI3K Class IB PI3K PI3K PI3K PI3K Idelalisib Umbralisib Duvelisib Copanlisib Copanlisib Buparlisib Figure 2: Organization of the Class I PI3K family into subclasses (IA and IB) as well as isoforms (. Class IA PI3K are tyrosine kinase (TKI) receptor activated while class IB PI3K is G-protein coupled receptor activated. Different PI3K inhibitors g allow targetin of different isoforms with varying specificity ranging from single isoform inhibitors such as idelalisib and umbralisib (TGR-1202) to pan-isoform inhibitors such as buparlisib.

41 Background Umbralisib (TGR-1202) is a next generation PI3Kδ inhibitor with a differentiated safety profile from other PI3Kδ inhibitors Fold-selectivity Isoform PI3Kα PI3Kβ PI3Kγ PI3Kδ TGR-1202 >1000 >50 >48 1 1Idelalisib >300 >200 >40 1 2IPI-145 >640 >34 >11 1 Safety In 165 patients treated with umbralisib (TGR- 1202) alone or with anti-cd20: 80 patients on study over 6 cycles, and 43 patients have been on study over 12 cycles Grade 3/4 AST/ALT increase was 3% (8% all grades) Diarrhea in 47%, mainly grade 1, with 5 patients (3%) with Grade 3/4 8% of patients off study due to an AE Efficacy O Connor et al, ASH 2015 Burris et al, ASCO Flinn et al. 2009, 2 Porter et al. 2012

42 Best Percent Change Reductions in Lymph Node Size Phase I Study of Venetoclax (ABT-199) in Lymphoma 100 WM MCL FL DLBCL MZL PMBCL /50 (54%) of patients had 50% reduction in nodal size Davids MS, et al. J Clin Oncol. 2014;32(5S): Abstract 8522.

43 Dosing Schedule of Venetoclax: Dose Escalation Schematic Dose Escalation Scheme *3 patients (1 each in cohorts 2, 3, & 5) received ABT mg as initial dose. **Step-up doses range from 100 to 400 mg. DCD = Designated Cohort Dose Lead-in to Designated Cohort Dose - Expanded Safety Cohort c Median time on study 10.9 months Seymour et al. EHA 2014

44 PD-1 (programmed cell death 1) inhibitors (PD-1) is a trans-membrane protein found on the surface of T cells, which, when bound to programmed T cell death ligand 1 (PD-L1) on tumor cells, results in suppression of T cell activity and reduction of T cell-mediated cytotoxicity

45 Nivolumab in Expansion Cohort of 23 Relapsed Hodgkin Lymphoma Patients Ansell et al, NEJM, 2015

46 Hodgkin Lymphoma - Response to Pembrolizumab (n=29) * *Patient became PET negative and was therefore declared to be in complete remission. Analysis cut-off date: November 17, Moskowitz et al. ASH 2014, abstract 290

47 Does Immune Checkpoint Blockade work? Blocking PD-1 42 year old female Hodgkin lymphoma 26 year old male Hodgkin lymphoma

48 Interim Results from a Phase 1/2 Study of Brentuximab Vedotin in Combination with Nivolumab in Patients with Relapsed or Refractory Hodgkin Lymphoma Alex F. Herrera 1, Alison J. Moskowitz 2, Nancy L. Bartlett 3, Julie M. Vose 4, Radhakrishnan Ramchandren 5, Tatyana A. Feldman 6, Ann S. LaCasce 7, Stephen M. Ansell 8, Craig H. Moskowitz 2, Keenan Fenton 9, Carol Anne Ogden 9, David Taft 9, Qu Zhang 9, Kazunobu Kato 10, Mary Campbell 9, Ranjana H. Advani 11 1 City of Hope National Medical Center, Duarte, CA, USA; 2 Memorial Sloan Kettering Cancer Center, New York, NY, USA; 3 Washington University School of Medicine, St. Louis, MO, USA; 4 University of Nebraska Medical Center, Omaha, NE, USA; 5 Karmanos Cancer Institute, Detroit, MI, USA; 6 Hackensack University Medical Center, Hackensack, NJ, USA; 7 Dana Farber Cancer Institute, Boston, MA, USA; 8 Mayo Clinic, Rochester, MN, USA; 9 Seattle Genetics, Inc., Bothell, WA, USA; 10 Bristol-Myers Squibb, Princeton, NJ, USA; 11 Stanford University Medical Center, Palo Alto, CA, USA International Conference on Malignant Lymphoma; Lugano, Switzerland, June 14 17, 2017

49 Methods Patients received treatment (tx) in 21-day cycles for up to 4 cycles (12 weeks) During Cycle 1, BV was administered on Day 1 and Nivo on Day 8 During Cycles 2-4, dosing of both drugs occurred on Day 1 After completion of the EOT response assessment, patients were eligible to undergo ASCT Adverse events (AEs) were recorded from the start of tx through 100 days post last dose of Nivo including the ASCT period, as applicable Responses were assessed using the 2014 Lugano classification a a Cheson et al., J Clin Oncol 2014;32(27):

50 Adverse Events N=61 Pre-ASCT treatment-emergent AEs occurred in 60 pts (98%): Gr 1: 25% Gr 2: 36% Gr 3: 33%, anemia as most frequent (8%) Gr 4: 5% Treatment-related SAEs in 5 pts (8%): pneumonitis and pyrexia (2 pts each) colitis, malaise, nausea, pneumonia, respiratory failure, and sepsis (1 pt each) No unusual post-asct toxicities were reported Systemic steroids for potential immune-mediated AEs were required in 4 pts (7%); 1 pt each experienced: Gr 4 pneumonitis and colitis a Gr 3 diarrhea and Gr 2 colitis b Gr 2 pneumonitis a Gr 3 AST elevation a a. Related to BV and Nivo b. Related to Nivo

51 Tumor Response 85% objective response rate with 63% complete responses SPD change from baseline Max SUV change from baseline N = 59 n (%) Complete response (CR) 37 (63) Deauville 2 29 (49) Deauville 3 7 (12) Deauville 5 a 1 (2) Partial response (PR) 13 (22) Deauville 4 7 (12) Deauville 5 6 (10) No metabolic response (SD) 5 (8) Deauville 5 5 (8) Progressive disease (PD) 3 (5) Deauville 5 2 (3) Missing 1 (2) Clinical Progression (CP) 1 (2) a. 1 pt had uptake in lymph node, but no evidence of disease was found on biopsy SPD, sum of the product of the diameters; SUV, standard uptake value

52 812, NCT ) Conclusions BV + Nivo was well tolerated in patients with RR chl: Although IRRs occurred frequently (41%), most were Gr 1 2, and only 5% were Gr 3 <10% of pts had potential immune-mediated AEs requiring systemic steroids Among patients with RR chl, BV + Nivo demonstrated a high objective response rate (85%) with 63% complete responses Increased levels of pro-inflammatory cytokines/chemokines and T cell subsets indicate activation of the innate immune system Part 3 of the study will enroll 30 additional patients to evaluate safety and efficacy of same-day BV + Nivo dosing in all cycles The encouraging activity of BV + Nivo will be further studied in a pivotal phase 3 trial in pts with advanced chl who are ASCT-ineligible or have RR disease (CheckMate

53 Efficacy and Safety of Pembrolizumab in Relapsed/Refractory Primary Mediastinal Large B-cell Lymphoma: Interim Analysis of the KEYNOTE-170 Phase 2 Trial P.L. Zinzani

54 Bes t change from baseline (%) Pembro in mediastinal DLBCL % tumor reduction % of patients (16/22) had reduction in target lesions

55 Patient Case Complete Response 28-year old woman PMBCL diagnosis Previously treated with: R-DA-EPOCH: 6 cycles ESHAP: 3 cycles Cyclophosphamide (4 g): 1 cycle Baseline After 12 cycles

56 CAR-T Strategies: Salvage

57 Daniyan et al. Journal of Leukocyte Biology 2016 CAR-T Mechanics Novartis Kite Juno Gamma-retrovirus vectors Transduce only replication cells Risk of insertional mutagenesis Lentiviral vectors Transduce non-dividing cells Reduced insertional mutagenesis

58 Patient with Refractory THL Pre-lymphodepletion 1-month Post CAR-T

59 CAR-T vs Historical Controls 80% 55% Crump et al. ASCO 2016

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61 Toward Precision Medicine Put more science into clinical trials Investigational drug Responders Non-responders Pharmaco dynamic measurements Molecular diagnostics: candidate approach Molecular diagnostics: unbiased approach Modified from American Association for CancerResearch

62 Precision Medicine Breast cancer Prostate cancer Molecular diagnostics Treatment A Treatment B Lung cancer Treatment C Standard TX Modified from American Association for Cancer Research

63 Drugs Available in TAPUR Pharmaceutical Company (Number of Drugs) Drug(s) Provided for TAPUR Study AstraZeneca (1) Bayer (1) Bristol-Meyers Squibb (1) Eli Lilly (1) Olaparib Regorafenib Dasatinib Cetuximab Genentech (6 Erlotinib, Trastuzumab + Pertuzumab, Vemurafenib + Cobimetinib, Vismodegib Merck (1) Pembrolizumab Pfizer (6) Axitinib, Bosutinib, Crizotinib, Palbociclib, Sunitinib, Temsirolimus

64 6 4 International Conference on Malignant Lymphoma (ICML) June 14-17, 2017 INTERIM REPORT FROM A PHASE 2 MULTICENTER STUDY OF TAZEMETOSTAT, AN EZH2 INHIBITOR: CLINICAL ACTIVITY AND FAVORABLE SAFETY IN PATIENTS WITH RELAPSED OR REFRACTORY B-CELL NON-HODGKIN LYMPHOMA Franck Morschhauser, Gilles Salles, Pamela McKay, Hervé Tilly, Anna Schmitt, John Gerecitano, Peter Johnson, Steven Le Gouill, Michael J. Dickinson, Christophe Fruchart, Thierry Lamy, Aristeidis Chaidos, Wojciech Jurczak, Stephen Opat, John Radford, Pier Luigi Zinzani, Sarit Assouline, Guillaume Cartron, Alicia Clawson, Natasha Picazio, Scott Ribich, Stephen J. Blakemore, John Larus, Harry Miao, Mark Woodruff, Peter T. Ho, Vincent Ribrag

65 6 5 TAZEMETOSTAT FOR THE TREATMENT OF B-CELL NHL PRC2 EZH2 is an epigenetic regulator of gene expression and plays a critical role in multiple forms of cancer Activating mutations of EZH2 can act as an oncogenic driver for cancers, especially in FL and GCB-DLBCL, present in ~20% of patients EZH2 Y646F/N/H/S/C A682G A692V Tazemetostat Tazemetostat K27me3 K27me3 K27me3 K27me3 First-in-class, potent and selective oral inhibitor of mutated and wild-type EZH2 Preclinical activity in DLBCL cells lines, with greater activity in EZH2 mutant models Monotherapy activity and favorable safety in phase 1 studies in patients with relapsed or refractory (R/R) NHL, as well as certain genetically defined solid tumors Compacted Chromatin Transcriptional Repression

66 TUMOR REDUCTION IN FOLLICULAR LYMPHOMA 75% of patients experienced reduction of tumor burden Data as of 6/1/

67 L e s i o n s i z e, S P D TUMOR RESPONSE IN DLBCL WITH MUTATED EZH2 61 y.o. male Baseline Week 24 T i m e p o s t t r e a t m e n t, w k R-CHOP Carmustine Etoposide Cytarabine Melphalan Rituximab Epratuzumab ha20 Rituximab Lenalidomide Obinutuzumab Bendamustine Tazemetostat: week CR 2003 PR 2005 PR PR PD 2014 SD PR at week 48 67

68 SUMMARY Tazemetostat shows efficacy in heavily pretreated relapsed/refractory FL and DLBCL Follicular Lymphoma 92% ORR in patients with mutated EZH2 26% ORR in patients with wild-type EZH2 with 22% of patients on-study in SD 48% overall with treatment ongoing DLBCL 29% ORR in patients with mutated EZH2 15% ORR with 8% CRs in WT patients Durable responses in both WT and mutants Late responses and conversion to CR in both subtypes Molecular profiling may help predict response Tazemetostat is safe Low incidence of treatment-related grade 3, mainly thrombocytopenia (6%) and neutropenia (6%) Enrollment of EZH2 mutated DLBCL and FLcontinues 19

69 Summary: NHL and HL Novel Biology/Therapies 1. WHO Classification better understanding of subtypes and biology 2. Pathway targeting 3. Immune therapies 4. Combination therapies 5. Personalized targeted therapies?

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