TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS

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  • Moving to efficacy, this slide reflects best response to date across various histologies, according to standard response criteria. Evaluable patients had at least 1 on-study tumor assessment. SD=23%; PD=21%Of note, amongst patients with CLL or SLL, the response rate is 69%. In follicular lymphoma, the response rate is 31%. In 9 patients with mantle cell lymphoma, there have been seven objective responses, including 3 patients who achieved a complete response, and in Diffuse large B-cell lymphoma, two of seven patients achieved a partial response.CLL NE = 1 W/C after 15 days on study AND 1 SAE of failure to thrive had only 14 days on studyFL NE = 2 DLTs AND 1 W/C after 7 days on studyMALT NE = 1 W/C after 1 cycle on studyCLL evaluated by IWGNHL evaluated by ChesonWM evaluated by IgM level
  • TREATMENT OF NON-HIDGKIN'S LYMPHOMA IN ELDERLY PATIENTS

    1. 1. 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
    2. 2. 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
    3. 3. Novel Anti-CD20 MoAbs for Relapsed/Refractory Indolent Lymphoma MoAb Phase Efficacy Ofatumumab 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 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 I/II ORR: 38%; PFS: 11.4 mos in pts with FL GA101 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).
    4. 4. With permission from Chen R et al. Proc ASH 2010; Abstract 283. 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 MMAE disrupts microtubule network ADC-CD30 complex traffics to lysosome MMAE is released Apoptosis G2/M cell cycle arrest
    5. 5. • 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) 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 Brentuximab Vedotin (SGN-35) for Rel/Ref Systemic ALCL
    6. 6. 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.
    7. 7. Lenalidomide: Targeting the Tumor Cell and Its Microenvironment Chng. Cancer Control. 2005;12:91; Drach. Expert Rev Cancer. 2005;5:477. Tumor Cells Tumor Stroma Dendritic Cells IL-6 TNF IL-1 IL-2 IFN  CD8+ T Cells Blood Vessels ICAM-1 VEGF bFGF NK Cells PKC NFAT PI3K IL-2 CD28
    8. 8. Lenalidomide/Rituximab for Untreated Stage II-IV iNHL: Response Rates by Subtype
    9. 9. Rituximab Plus Lenalidomide 20 mg daily for 21 days, off 7 days X 6, and if CR, reduce to 10 mg
    10. 10. 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% 4% 24% Hernandez -Illizaliturri 2011
    11. 11. 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
    12. 12. 13 Lenalidomide vs Investigators Choice for Ref/Rel DLBCL: Study Design DLBCL Stratify by IHC GCB lenalidomide n=25 Inv. Choice n=25 R Non-GCB lenalidomide n=25 Inv. Choice n=25 R Stage 1 N = 100 Selected Type(s) lenalidomide n=74 Inv. Choice n=74 R Stage 2 N = 148 or 296 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. 13. Small Molecule Inhibitors: Responses for Various Lymphoma Subtypes Pathway Drug Target % Response Rate by Histology DLBCL FL MCL SLL/ CLL T-Cell HL PI3K/AKT /mTOR Everolimus mToR 30 50 32 18 63 53 Temsirolimus mToR 36 56 38 10 - - CAL-101 PI3K 0 55 67 30 - - B Cell Receptor (BCR) Fostamtinib Syk 22 10 11 55 0 - Ibrutinib Btk 17 23 69 67 - -
    14. 14. Results of Activation of the B-Cell Receptor and Targets for Manipulation bortezomib carfilzomib ? ? fostamatinib temsirolimus everolimus deferolimus CAL-101 enzastaurin PCI-32765
    15. 15. 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 • IC50 = 0.5 nM • Orally available • Once daily dosing results in 24- hr sustained target inhibition N N N N NH 2 O N O
    16. 16. Phase I PCI-32765 for Recurrent NHL and CLL: Response in 48 Evaluable Patients *2 CLL pts had nodal response with lymphocytosis 9/13* 7/9 2/3 1/3 4/13 2/7 0 20 40 60 80 100 BestResponseRate(%) CR PR CLL/SLL MCL WM MZL/Malt FL DLBCL ORR (evaluable) 52% ORR (ITT) 45%
    17. 17. 0 20 40 60 80 100 ↓HGB ↓ANC ↓PLT % Grade 4 % Grade 3 % Grade 2 % Grade 1 • No hepatic or renal toxicities • No evidence of cumulative hematologic toxicity Phase I PCI-32765 for Recurrent NHL and CLL: Hematologic Tolerability (N=56) Percent
    18. 18. 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 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
    19. 19. Best Response (Efficacy Population n=110, Median Follow-up 9.2 mo) 21 23 22 44 49 46 0 20 40 60 80 100 CR PR Percentofpatients(%) Bortezomib- naïve (n=63) Bortezomib- exposed (n=47) Total (n=110) 66% 72% 68%
    20. 20. 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
    21. 21. LYMPH NODE MALIGNANT B-CELL Class I PI3K Isoform Cellular 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 PI3K Promotes Survival/Growth of Cancer Cells
    22. 22. Best On-Treatment Change in Tumor Size (ITT Analysis) -100 -75 -25 0 -50* +25 +50 +75 +100 MCL (N=21) iNHL (N=30) CLL (N=54) Inevaluable (patients without a follow-up tumor assessment) * Criterion for response [Cheson 2007, Hallek 2008] %ChangeinLymphNodeArea Single-Agent CAL-101 for R/R MCL, iNHL, and CLL: Best Tumor Volume Response
    23. 23. ORR with CAL-101 for R/R iNHL Slide 24 Bortezomib (N=60) Fostamatinib (Syk inhibitor) (N=25) Lenalidomide (N=43) PCI-32765 (Btk inhibitor) (N=20) Rituximab (N=166) Bendamustine (N=123) CAL-101 (N=30) 12% Prior Therapies (median) 4 4 3 3 2 2 3 12% 23% 30% 48% 75% 63% ITT Response Rate [Exact Binomial 95% CI], % Overall Response Rate Compared to Those with Other Drugs PFS results are as good or better with CAL-101
    24. 24. • 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 CAL-101 for R/R NHL: Cumulative Adverse Events Fatigue Neutropenia Diarrhea Pneum onia Anorexia ALT/AST 0 20 40 60 80 100 10%8%8% 27% 6% 10% Grade 3-4 Adverse Events Occuring in 5% of Patients Regardless of Causality (N=51) Adverse Event Type Incidence,%
    25. 25. Department of Lymphoma/Myeloma Disease – specific Working Groups N. Fowler F. Samaniego S. Neelapu L. Fayad L. Kwak T cell lymphoma Multiple myeloma D. Weber J. Shah S. Thomas M. Wang R. Alexanian Q. Yi Michael Wang, M.D. Nathan Fowler, M.D. Co-Directors Lymphoma Clinical Research Robert Orlowski, M.D., Ph.D. Director Myeloma Clinical Research Burkitt HIV Brain Testicular M. Fanale N. Fowler M. Fanale N. Fowler J. Shah J. Westin Larry W. Kwak, M.D., Ph.D. Chairman, Lymphoma/Myeloma Low Grade lymphoma Large Cell lymphoma Mantle cell lymphoma Hodgkins L. Fayad A. Rodriguez F. Hagemeister J. Westin M. Wang J. Romaguera M. Fanale F. Hage- meister Phase I Y. Oki M. Fanale

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