Treatment approaches to nonHodgkins lymphoma in elderly patients

Treatment approaches to non-Hodgkin’s lymphoma in elderly patients Larry W. Kwak, M. D. , Ph. D. Chairman, Department of Lymphoma/Myeloma Justin Distinguished Chair in Leukemia Research Co-Director, Center for Cancer Immunology Research MD Anderson Cancer Center

Refractory/Relapsed DLBCL: Therapy for “Non-Transplant Candidates” • Poor disease control and substantial morbidity. • Goal is generally palliative • Gemcitabine based • Low dose oral chemotherapy • “hyperfractionated cytoxan” • Rituximab • Radiation • New drugs

Novel Anti-CD 20 Mo. Abs for Relapsed/Refractory Indolent Lymphoma Mo. Ab Phase Efficacy I/II Dose (ORR): 300 mg (63%); 500 mg (33%); 700 mg (20%); 1000 mg (50%) II ORR: 11%, 6 -mo PFS in 116 pts with rituximab-refractory FL Ofatumumab IV administration: ORR: 44%, CR: 27% DOR in pts with FL: 19. 7 mos Veltuzumab I/II Ocrelizumab I/II ORR: 38%; PFS: 11. 4 mos in pts with FL I ORR: 69%, CR: 38% in 13 pts with FL GA 101 Subcutaneous administration: ORR: 53% CR: 20% in pts with indolent NHL Morschhauser. Ann Oncol. 2010 (Epub ahead of print); Morschhauser. J Clin Oncol. 2009; 27: 3346; Negrea. ASH. 2009 (abstr 3757); Hagenbeek. ASH. 2009 (abstr 935); Hagenbeek. Blood. 2008; 111: 5486; Salles. ASH. 2009 (abstr 1704).

Brentuximab Vedotin: Mechanism of Action Brentuximab vedotin (SGN-35) antibody-drug conjugate (ADC) monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-CD 30 monoclonal antibody ADC binds to CD 30 ADC-CD 30 complex traffics to lysosome MMAE is released MMAE disrupts microtubule network G 2/M cell cycle arrest Apoptosis With permission from Chen R et al. Proc ASH 2010; Abstract 283.

Brentuximab Vedotin (SGN-35) for Rel/Ref Systemic ALCL n=58 Investigator Central Review ORR 81% 86% CR 59% 53% PD 22% 33% Median DR 36 weeks NR Median DR for CR NR NR Median PFS 41 weeks NR Median PFS for prior therapy 26 weeks • In terms of response, ALK (+) = ALK (–) • “B” symptom resolution = 82% • Peripheral neuropathy = 38% (median time to resolution 5. 4 weeks) Shustov, ASH 2010 # 961 (Oral)

Novel Therapeutics for NHLs Cancer Hallmark Therapeutic Target Treatment Proliferation Syk, Btk, PKCB, MTo. R, PI 3 K Fos. D, PCI-32765, Enzastaurin, Temsirolimus, Cal-101 Insensitive to Growth Inhibition HDAC, DNMT Vorinostat, Romidepsin, Belinostat, Panabinostat, Vidaza Evading apoptosis BCL 2/BCLX, MCL-1, Survivin ABT-263, Obatoclax, YM 155 Limitless Replication CDK, PARP AT 7519, AZD 7762, AT 9283 Neoangiogenesis VEGFR, FGFR Sorafenib, Imatinib, Sunitinib Invasion/Metastasis Src, Fak, TGF Dasatinib, LY 2109761, XL 228 Immune Evasion NK/T cells Lenalidomide, Pomalidomide Stress Response Proteasome Bortezomib, Carfilzomib Stromal Subversion SHh, Wnt, Notch GDC-0449, XL 139, XAV 939, MK-0752 Cytokine Response CXCR 4, IL-21 R AMD 3100, BKT 140, IL-21 Mahadavan and Fisher. JCO 29: 1876, 1884, 2011.

Lenalidomide: Targeting the Tumor Cell and Its Microenvironment Tumor Cells IL-6 TNF IL-1 Tumor Stroma ICAM-1 Blood Vessels NFAT PKC IL-2 IFN VEGF b. FGF PI 3 K Dendritic Cells CD 28 CD 8+ T Cells Chng. Cancer Control. 2005; 12: 91; Drach. Expert Rev Cancer. 2005; 5: 477. NK Cells

Lenalidomide/Rituximab for Untreated Stage II -IV i. NHL: Response Rates by Subtype

Rituximab Plus Lenalidomide 20 mg daily for 21 days, off 7 days X 6, and if CR, reduce to 10 mg

Lenalidomide + Rituximab for Ref/Rel DLBCL Group No. of Pt. ORR CRR Reference US 49 (various histology) 35% 12% Wiernik 2008 Italian 23 DLBCL 35% 4% Zinzani 2011 International 217 DLBCL 35% 13% Witzig 2011 Retrospective from 4 sites 40 DLBCL GCB 23 Non-GCB 17 9% 53% Hernandez 4% -Illizaliturri 24% 2011

Lenalidomide for Ref/Rel DLBCL: Response by Molecular Subtype • 40 patients – GCB 23 – Non-GCB 17 • PFS (p=0. 004) – Non-GCB 6. 2 months – GCB 1. 7 months Hernandez-Ilizaliturri et al. Cancer 2011

Lenalidomide vs Investigators Choice for Ref/Rel DLBCL: Study Design Stage 1 lenalidomide Stage 2 N = 100 n=25 N = 148 or 296 Non-GCB DLBCL R Stratify by IHC GCB R Inv. Choice ? lenalidomide n=25 Selected lenalidomide Type(s) n=25 Inv. Choice R n=74 Inv. Choice n=74 ? n=25 If lenalidomide is superior to investigator’s choice in either or both subtype(s) then that subtype(s) will be tested in Stage 2. 13

Small Molecule Inhibitors: Responses for Various Lymphoma Subtypes Pathway Drug % Response Rate by Histology DLBCL FL MCL SLL/ CLL T-Cell HL m. To. R 30 50 32 18 63 53 m. To. R 36 56 38 10 - - CAL-101 PI 3 K 0 55 67 30 - - Fostamtinib Syk 22 10 11 55 0 - Ibrutinib Btk 17 23 69 67 - - PI 3 K/AKT Everolimus /m. TOR Temsirolimus B Cell Receptor (BCR) Target

Results of Activation of the B-Cell Receptor and Targets for Manipulation CAL-101 fostamatinib PCI-32765 ? enzastaurin bortezomib carfilzomib ? temsirolimus everolimus deferolimus

PCI-32765: A Novel Small Molecule Inhibitor of Btk in the BCR Pathway • Forms a specific and irreversible bond with cysteine 481 in Btk • Potent Btk inhibition O NH 2 N • IC 50 = 0. 5 n. M N N O • Orally available • Once daily dosing results in 24 hr sustained target inhibition

100 ORR (evaluable) 52% 7/9 80 9/13* ORR (ITT) 45% 2/3 CR 60 PR 40 1/3 4/13 2/7 20 *2 CLL pts had nodal response with lymphocytosis MZL/Malt FL L D LB C WM M MCL ZL /M A FL LT M W M SL L LL / C CLL/SLL C L 0 * Best Response Rate (%) Phase I PCI-32765 for Recurrent NHL and CLL: Response in 48 Evaluable Patients DLBCL

Phase I PCI-32765 for Recurrent NHL and CLL: Hematologic Tolerability (N=56) • No hepatic or renal toxicities • No evidence of cumulative hematologic toxicity Percent 100 % Grade 4 % Grade 3 % Grade 2 % Grade 1 80 60 40 20 0 ↓HGB ↓ANC ↓PLT

Interim Results of an International, Multicenter, Phase 2 Study of Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI -32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability With Longer Follow-up Michael Wang, MD 1, Simon Rule, MD 2, Peter Martin, MD 3, Andre Goy, MD 4, Rebecca Auer, MD 5, Brad S. Kahl, MD 6, Wojciech Jurczak, MD 7, Ranjana Advani, MD 8, Jorge Romaguera, MD 1, Jesse Mc. Greivy, MD 9, Fong Clow, Sc. D 9, Michelle Stevens-Brogan 9, Lori Kunkel, MD 9, Kristie A. Blum, MD 10 Lymphoma/Myeloma, The University of Texas MD Anderson Cancer Center, Houston, TX; 2 Department of Haematology, Derriford Hospital, Plymouth, United Kingdom; 3 Division of Hematology-Oncology, Weill Cornell Medical College, New York, NY; 4 John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ 5 Department Haemato-oncology, Barts Health NHS Trust, London, United Kingdom ; 6 Department of Medicine. Hematology/Oncology, University of Wisconsin, Madison, WI; 7 Department of Haematology, Jagiellonian University, Krakow, Poland; 8 Department of Medicine, Division of Oncology, Stanford University Medical Center, Stanford, CA 9 Pharmacyclics, Inc. , Sunnyvale, CA; 10 The Ohio State University, Columbus, OH 1

Best Response (Efficacy Population n=110, Median Follow-up 9. 2 mo) CR PR Percent of patients (%) 100 80 72% 66% 68% 60 40 44 49 46 23 22 Bortezomibexposed (n=47) Total (n=110) 20 21 0 Bortezomibnaïve (n=63)

Current Active Trials with Ibrutinib Phase NCT# Combination DZ State Subtype I 01704963 Single Agent Rel/Ref B-Cell NHL I 01479852 Benda/Ritux Rel/Ref NHL I 01569750 R-CHOP Untreated LCL, MCL, Indolent II 01599049 Single Agent Rel/Ref MCL (after Bortez) II 01583902 Single Agent Rel/Ref SLL/CLL II 01614821 Single Agent Rel/Ref Waldenstrom’s III 01578707 vs Ofa Rel/Ref SLL/CLL III 01611090 BR Rel/Ref SLL/CLL

PI 3 K Promotes Survival/Growth of Cancer Cells Class I PI 3 K Cellular Isoform Expression Primary Physiological Role Alpha Broad Insulin signaling and angiogenesis Beta Broad Platelet function Gamma Leukocytes Neutrophil and T-cell function Delta LYMPH NODE Lymphocytes B-cell signaling, development and survival MALIGNANT B-CELL

Single-Agent CAL-101 for R/R MCL, i. NHL, and CLL: Best Tumor Volume Response

ORR with CAL-101 for R/R i. NHL Overall Response Rate Compared to Those with Other Drugs Slide 24 PFS results are as good or better with CAL-101

CAL-101 for R/R NHL: Cumulative Adverse Events • Grade 3 -4 events were usually related to underlying disease or prior therapy • Reversible Gr 3 -4 ALT/AST elevations were not associated with increased bilirubin or decreases in liver synthetic function • No obvious pattern of drug-related symptomatic adverse events

Department of Lymphoma/Myeloma Disease – specific Working Groups Larry W. Kwak, M. D. , Ph. D. Chairman, Lymphoma/Myeloma Michael Wang, M. D. Nathan Fowler, M. D. Co-Directors Lymphoma Clinical Research Low Grade lymphoma N. Fowler F. Samaniego S. Neelapu L. Fayad L. Kwak T cell lymphoma Y. Oki M. Fanale Large Cell lymphoma Robert Orlowski, M. D. , Ph. D. Director Myeloma Clinical Research Mantle cell lymphoma L. Fayad A. Rodriguez F. Hagemeister J. Westin Hodgkins M. Wang J. Romaguera Burkitt HIV M. Fanale F. Hagemeister Brain Testicular N. Fowler Phase I M. Fanale N. Fowler J. Shah J. Westin Multiple myeloma D. Weber J. Shah S. Thomas M. Wang R. Alexanian Q. Yi