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-CD20 MoAbs for Relapsed/Refractory Indolent Lymphoma MoAb 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 Veltuzumab I/II IV administration: ORR: 44%, CR: 27% DOR in pts with FL: 19.7 mos Subcutaneous administration: ORR: 53% CR: 20% in pts with indolent NHL Ocrelizumab GA101 I/II ORR: 38%; PFS: 11.4 mos in pts with FL I ORR: 69%, CR: 38% in 13 pts with FL 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-CD30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released G2/M cell cycle arrest MMAE disrupts microtubule network 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, MToR, PI3K FosD, PCI-32765, Enzastaurin, Temsirolimus, Cal-101 Insensitive to Growth Inhibition HDAC, DNMT Vorinostat, Romidepsin, Belinostat, Panabinostat, Vidaza Evading apoptosis BCL2/BCLX, MCL-1, Survivin ABT-263, Obatoclax, YM155 Limitless Replication CDK, PARP AT7519, AZD7762, AT9283 Neoangiogenesis VEGFR, FGFR Sorafenib, Imatinib, Sunitinib Invasion/Metastasis Src, Fak, TGF Dasatinib, LY2109761, XL228 Immune Evasion NK/T cells Lenalidomide, Pomalidomide Stress Response Proteasome Bortezomib, Carfilzomib Stromal Subversion SHh, Wnt, Notch GDC-0449, XL139, XAV939, MK-0752 Cytokine Response CXCR4, IL-21R AMD3100, BKT140, 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 IL-2 IFN VEGF bFGF PI3K Dendritic Cells CD28 CD8+ T Cells Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477. NK Cells Lenalidomide/Rituximab for Untreated Stage II-IV iNHL: 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 R Inv. Choice DLBCL n=25 Stratify by IHC GCB ? Selected Type(s) lenalidomide R n=25 Inv. Choice lenalidomide n=74 R 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 mToR 30 50 32 18 63 53 mToR 36 56 38 10 - - CAL-101 PI3K 0 55 67 30 - - Fostamtinib Syk 22 10 11 55 0 - Ibrutinib Btk 17 23 69 67 - - PI3K/AKT Everolimus /mTOR 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 cysteine481 in Btk • Potent Btk inhibition O NH 2 N • IC50 = 0.5 nM N N N N O • Orally available • Once daily dosing results in 24hr sustained target inhibition Phase I PCI-32765 for Recurrent NHL and CLL: Response in 48 Evaluable Patients Best Response Rate (%) 100 80 7/9 9/13* ORR (evaluable) 52% 2/3 ORR (ITT) 45% 60 CR PR 40 1/3 4/13 2/7 20 0 CLL/SLL MCL WM *2 CLL pts had nodal response with lymphocytosis MZL/Malt FL 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, MD1, Simon Rule, MD2, Peter Martin, MD3, Andre Goy, MD4, Rebecca Auer, MD5, Brad S. Kahl, MD6, Wojciech Jurczak, MD7, Ranjana Advani, MD8, Jorge Romaguera, MD1, Jesse McGreivy, MD9, Fong Clow, ScD9, Michelle Stevens-Brogan9, Lori Kunkel, MD9, Kristie A. Blum, MD10 1 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 MedicineHematology/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 Best Response (Efficacy Population n=110, Median Follow-up 9.2 mo) CR PR Percent of patients (%) 100 72% 80 68% 66% 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 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 R-CHOP PI3K Promotes Survival/Growth of Cancer Cells Class I PI3K Cellular Isoform Expression Primary Physiological Role Alpha Broad Insulin signaling and angiogenesis Beta Broad Platelet function Gamma Leukocytes Neutrophil and T-cell function Delta Lymphocytes B-cell signaling, development and survival LYMPH NODE MALIGNANT B-CELL Single-Agent CAL-101 for R/R MCL, iNHL, and CLL: Best Tumor Volume Response Best On-Treatment Change in Tumor Size (ITT Analysis) +100 % Change in Lymph Node Area +75 +50 +25 MCL iNHL CLL (N=21) (N=30) (N=54) 0 -25 -50* -75 -100 Inevaluable (patients without a follow-up tumor assessment) * Criterion for response [Cheson 2007, Hallek 2008] ORR with CAL-101 for R/R iNHL Overall Response Rate Compared to Those with Other Drugs Prior Therapies (median) 63% CAL-101 (N=30) 4 75% Bendamustine (N=123) 48% Rituximab (N=166) 30% PCI-32765 (Btk inhibitor) (N=20) 3 3 2 23% Lenalidomide (N=43) 2 Fostamatinib (Syk inhibitor) (N=25) 12% 4 Bortezomib (N=60) 12% 3 ITT Response Rate [Exact Binomial 95% CI], % Slide 24 PFS results are as good or better with CAL-101 CAL-101 for R/R NHL: Cumulative Adverse Events Grade 3-4 Adverse Events Occuring in 5% of Patients Regardless of Causality (N=51) 100 Incidence, % 80 60 40 27% 20 8% 6% 10% 8% 10% T AS AL T/ xia or e An Pn eu m on ia ea ar rh Di ni a tro pe Ne u Fa tig ue 0 Adverse Event Type • 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 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