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A Look Forward: New and Emerging Therapies Brad S. Kahl, MD Skoronski Chair of Lymphoma Research

A Look Forward: New and Emerging Therapies Brad S. Kahl, MD Skoronski Chair of Lymphoma Research University of Wisconsin School of Medicine and Public Health Associate Director for Clinical Research UW Carbone Cancer Center. Changing Landscape. FDA approvals last 12 months

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A Look Forward: New and Emerging Therapies Brad S. Kahl, MD Skoronski Chair of Lymphoma Research

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  1. A Look Forward: New and Emerging Therapies Brad S. Kahl, MD Skoronski Chair of Lymphoma Research University of Wisconsin School of Medicine and Public Health Associate Director for Clinical Research UW Carbone Cancer Center

  2. Changing Landscape • FDA approvals last 12 months • Obinutuzumab for CLL • Lenalidomide for MCL • Ibrutinib for MCL and CLL • Horizon • Idelalisib for indolent NHL • ABT-199 for CLL, NHL • CART therapy

  3. Examples of How We Treat • Hodgkin lymphoma • ABVD + IFRT • Diffuse Large B-cell Lymphoma • R-CHOP + IFRT • Follicular Lymphoma • R-bendamustine or R-CHOP + maintenance rituximab • CLL/SLL • FCR or R-bendamustine Chemotherapy

  4. “Everything works better with R” • Rituximab added to CHOP increased cure rate in DLBCL by 15% (absolute difference) • Rituximab added to chemotherapy increased 5-yr PFS by 20% and OS by 5% in FL. • Major effort into development of new moAbs. • Target different Ags • New “improved” anti-CD20s

  5. Proposed Mechanisms of Action of Rituximab Macrophage,monocyte, ornatural killer cell ADCC Rituximab CD20 FcgRI, FcgRII, FcgRIII Cell lysis CDC Complement activation (C1qC1rC1s) B cell MAC CD20 Cell lysis Apoptosis Anderson et al. Biochem Soc Trans. 1997;25:705; Golay et al. Blood. 2000;95:3900; Reff et al. Blood. 1994;83:435; Clynes et al. Nat Med. 2000;6:443; Shan et al. Cancer Immunol Immunother. 2000;48:673; Silverman et al. Arthritis Rheum. 2003;48:1484.

  6. MoAb’s for Lymphoma FDA approved Dropped Lumiliximab (CD23) Galiximab (CD80) Epratuzumab (CD22) Hu1D10 (HLA DR) SGN-30 (CD30) SGN-40 (CD40) Under Study Biosimilars (CD20) • Rituximab (CD20) • Alemtuzumab (CD52) • Ofatumomab (CD20) • Obinutuzimab (CD20) • Zevalin (CD20) -Y90 • Bexxar (CD20) -I131 • Brentuximab vedotin (CD30) -MMAE

  7. Type I (rituximab) vs Type II (obinutuzimab)

  8. TYPE I TYPE II FREE END Adapted from Cragg MS Blood 2011

  9. CLL11: Phase III Study of Chlorambucil (Chl) Alone vs Chl + Obinutuzumab vs Chl + Rituximab in Previously Untreated CLL Patients With Comorbidities Primary endpoint: PFS (investigator assessed) Secondary endpoints: ORR DOR DFS OS MRD R GA101 + chlorambucil × 6 cycles Rituximab + chlorambucil × 6 cycles 1:2:2 Chlorambucil = 0.5 mg/kg d1, d15 q28d (based on GermanCLLSG CLL5 study) GA101=100 mg d1, 900 mg d2, 1000 mg d8, 15 cycle 1; 1000 mg d1 cycles 2-6 Rituximab=375 mg/m2 d1 cycle 1; 500 mg/m2 d1 cycles 2-6 q28d (GCLLSG CLL8)

  10. DATA (from PI) Stage I analysis, ASCO 2013 and FDA data, of G-Chl vs Chl Progression-Free Survival 23mos 11mos Stage 2 analysis of G-Chl vs R-Chl, ASH PLENARY

  11. Obinutuzumab • FDA approval Nov 1st • For use in combination with chlorambucil • First line CLL treatment • Unknown if “FCO” or “BO” will be superior to FCR or BR

  12. CLL: CART Therapy T Cell CLL CART CD19

  13. Targeted agents • Principle • Find the driver of growth for a particular cancer (in the lab) • Identify this driver in your patients (predictive biomarker) • Attack the pathway with the correct kinase inhibitor or other small molecule “disruptor”

  14. I wish it were this simple

  15. Figure 1A: B cell receptor pathway. Taken from http://www.cellsignal.com/reference/pathway/B_Cell_Antigen.html

  16. Challenges • Reality • Numerous agents with 20-30% response rates and median durations of 6 months • Identifying biomarkers is hard • Assay challenges, sample challenges, specificity challenges, • Running biomarker driven clinical trials is difficult • Regulatory overload

  17. Targeting Intracellular Pathways Potential Targets Agent (disease) Bortezomib (MCL) Sorafenib (bust) Bevacizumab (bust) SAHA, romidepsin (CTCL) Temsirolimus (MCL) SB1518 (TBD) Idelalisib (TBD) Ibrutinib (MCL, CLL) ABT-199 (TBD) • Proteasome • RAS-RAF-MEK • Angiogenesis • Histones • mTOR • JAK-STAT • PI3 kinase • BTK • BCL-2

  18. Targeting the B Cell Receptor • Pathway utilized by normal cells • Differentiation, proliferation • Appears some B cell malignancies have “tonic” signaling through pathway • Unclear what is source of signaling • Currently most promising area of research in B cell malignancies

  19. Targets of B-Cell Receptor Signaling Antigen CK B Cell Receptor Cytokine Receptor CD19 TLR CD79B CD79A Cal 101 PI3K PIP3 P JAK1 LYN BTK SYK P P DAG AKT PLCγ fostamatinib MYD88 IP3--Ca++ BLNK PKCβ CARD11 Bcl10 ERK MALT1 IkB IkB NFkB Proteosomal Degradation Transcriptional Activation

  20. Mature Response Data from a Phase 2 Study of PI3K-Delta Inhibitor Idelalisib in Patients with Double (Rituximab and Alkylating Agent)-Refractory Indolent B-Cell Non-Hodgkin Lymphoma (iNHL) A Gopal,1 B Kahl,2 S de Vos,3 N Wagner-Johnston,4 S Schuster,5 K Blum,6 W Jurczak,7 I Flinn,8 C Flowers,9 P Martin,10 A Viardot,11A Goy,12 A Davies,13 PL Zinzani,14 M Dreyling,15 L Holes,16 D Li,16 R Dansey,16 Wayne Godfrey,16 and G Salles17 1University of Washington School of Medicine, Seattle, WA, USA; 2University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3David Geffen School of Medicine at UCLA, Los Angeles, Los Angeles, CA, USA; 4Washington University School of Medicine, St. Louis, MO, USA; 5Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 6Ohio State University Wexner Medical Center, Columbus, OH, USA; 7Jagiellonian University, Krakow, Poland; 8Sarah Cannon Research Institute, Nashville, TN, USA; 9Winship Cancer Institute of Emory University, Atlanta, GA, USA; 10Weill Cornell Medical College, New York, NY, USA; 11University Hospital of Ulm, Ulm, Germany; 12Hackensack University Medical Center, Hackensack, NJ, USA; 13University of Southampton, Southampton, United Kingdom; 14University of Bologna, Bologna, Italy; 15University Hospital Grosshadern, LMU Munich, Germany; 16Clinical Research Oncology, Gilead Sciences, Seattle, WA, USA; 17Hospices Civils de Lyon, University Claude Bernard, Pierre Benite, France American Society of Hematology December 8, 2013 New Orleans, LA Oral No 85.

  21. Idelalisib • Selective, oral inhibitor of PI3K-delta • Inhibits proliferation and induces apoptosis in many B-cell malignancies • Inhibits homing and retention of malignant B-cells in lymphoid tissues reducing B-cell survival Class I PI3K Isoform a b d g • Promising activity in R/R iNHL in phase I study* *Benson D et al. ASCO 2013, abstr 8526

  22. Study 101-09 Waterfall Plot Lymph Node Response • 90% had improvement in lymphadenopathy • 57% had ≥50% decrease from baseline aCriterion for lymphadenopathy response [Cheson 2007] b 3 subjects no post baseline evaluation: □ 2 subjects NE ■ 1 subject PD by Lymph Node biopsy

  23. Study 101-09: Duration Of Response (DOR) Median DOR = 12.5 months Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments

  24. Study 101-09: Adverse Events > 10%

  25. Idelalisib • I think there is a good chance idelalisib will get FDA approval in this patient population

  26. Targets of B-Cell Receptor Signaling Antigen CK B Cell Receptor Cytokine Receptor CD19 TLR CD79B CD79A Cal 101 PI3K PIP3 P JAK1 LYN BTK SYK P P DAG AKT PLCγ fostamatinib MYD88 IP3--Ca++ BLNK PKCβ ibrutinib CARD11 Bcl10 ERK MALT1 IkB IkB NFkB Proteosomal Degradation Transcriptional Activation

  27. PCI-32765: First-in Class Inhibitor of BTK O N H 2 N N N N N O • Forms a specific and irreversible bond with cysteine-481 in BTK • Highly potent BTK inhibition at IC50 = 0.5 nM • Orally administered with once daily dosing resulting in 24-hr target inhibition • In CLL cells promotes apoptosis, inhibits ERK1/AKT phosphorylation, NF-κB DNA binding, CpG mediated proliferation • Inhibits CLL cell migration and adhesion • No cytotoxic effect on T-cells or NK-cells PCI-32765 Honigberg LA et al: Proc Natl Acad Sci U S A.107:13075, 2010 Herman SEM et al: Blood 117: 6287-6296, 2011 Ponader, et al., ASH Meeting Abstracts 116:45, 2010

  28. Original ArticleTargeting BTK with Ibrutinib in Relapsed or Refractory Mantle-Cell Lymphoma Michael L. Wang, M.D., Simon Rule, M.D., Peter Martin, M.D., Andre Goy, M.D., Rebecca Auer, M.D., Ph.D., Brad S. Kahl, M.D., Wojciech Jurczak, M.D., Ph.D., Ranjana H. Advani, M.D., Jorge E. Romaguera, M.D., Michael E. Williams, M.D., Jacqueline C. Barrientos, M.D., Ewa Chmielowska, M.D., John Radford, M.D., Stephan Stilgenbauer, M.D., Martin Dreyling, M.D., Wieslaw Wiktor Jedrzejczak, M.D., Peter Johnson, M.D., Stephen E. Spurgeon, M.D., Lei Li, Ph.D., Liang Zhang, M.D., Ph.D., Kate Newberry, Ph.D., Zhishuo Ou, M.D., Nancy Cheng, M.S., Bingliang Fang, Ph.D., Jesse McGreivy, M.D., Fong Clow, Sc.D., Joseph J. Buggy, Ph.D., Betty Y. Chang, Ph.D., Darrin M. Beaupre, M.D., Ph.D., Lori A. Kunkel, M.D., and Kristie A. Blum, M.D. N Engl J Med Volume 369(6):507-516 August 8, 2013

  29. Best Response to Therapy. Wang ML et al. N Engl J Med 2013;369:507-516

  30. Duration of Response, Progression-free Survival, and Overall Survival. Wang ML et al. N Engl J Med 2013;369:507-516

  31. Backround • Limited options for R/R CLL • Bruton’s tyrosine kinase • Essential component of B cell receptor signaling • Ibrutinib (PCI-32765) • 1st in class oral BTK inhibitor • Phase 1b-2 multicenter trial • 420 mg/day N = 51 • 840 mg/day N = 34

  32. Figure 1: lymphocyte count vs. nodal response

  33. Figure 1: Response over time

  34. Figure 3: PFS and OS

  35. Conclusions • Unprecedented single agent activity in relapsed MCL and CLL • Durable responses • Side effect profile tolerable • Lack of myelosuppression • Infection risk similar to background • FDA approval • Nov 2013 MCL • Feb 2014 CLL

  36. Ongoing Research • BCR pathway inhibitors are: • Most active: CLL/SLL, MCL • Moderate: FL, MZL, MALT, DLBCL • Extensive ongoing research • In other lymphoma types • In combination with chemotherapy and other targeted agents

  37. BCL-2 targeting

  38. N O H 2 N O S 2 O N H O O N N H N N C l Introduction • Bcl-2 overexpression is fundamental in the pathophysiology of NHL(Sawas et al, Curr Opin Hematol, 2011) • BH3 mimetic Navitoclax (ABT-263) is active in indolent NHL and CLL (Wilson et al, Lancet Oncology, 2010 and Roberts et al, J Clin Oncol, 2012) • Inhibits Bcl-2, Bcl-xL and Bcl-w • Thrombocytopenia due to Bcl-xL inhibition is dose-limiting • ABT-199: a small molecule, orally-bioavailable second-generation BH3-mimetic (Souers et al., Nature Medicine in press) • >100-fold selectivity for Bcl-2 over Bcl-xL in tumor cell line assays ABT-199

  39. Adverse Events (AEs) *TLS includes 3 events from Cohort 1; 2 clinical events and 1 laboratory TLS occurred in Cohorts 4, 8, and 2 40

  40. NHL Maximal % Reduction in Nodal Size FL MCL MCL MCL WM WM DLBCL DLBCL MCL MCL MCL FL DLBCL WM FL MCL FL FL FL FL FL * = Confirmed Partial Remission** CR = Complete Remission Dose (cohort) * * CR * * n = 21 evaluable (at minimum 6 week assessment) **Confirmed = response verified at 2nd consecutive assessment Median Time to 50% Reduction = 43 days (range 36 to 113; n=11)

  41. Best Percent Change from Baseline in SPD of Nodal Massby CT Scan del (17p) Fludarabine refractory del(17p) and FR 17p FR » SPD = Sum of the product of diameters; SE = safety expansion. N = 57 evaluable (at minimum, Week 6 assessment) • 50/57 (88%) patients had at least a 50% reduction in sum of the product of diameters (SPD) of nodal masses. • The median time to 50% reduction was Week 6. 42

  42. Conclusions for ABT-199 ABT-199 highly active, acceptable safety profile Once daily oral dosing Tumor lysis syndrome is a risk Response rate in CLL/SLL is 79% (84 patients) Phase II dose 400 mg/day Response rate in NHL is 48% (44 patients) Phase II dose 1200 mg/day ABT-199 is highly promising as a single agent and in should be studied in combination

  43. Efficacy in CLL/SLL February 8 2012 March 27 2012 May 9 2012 Baseline Week 6 Week 16 • 45 year old male with CLL/SLL, diagnosed in 2007 • Prior therapies: • FCR x 6 cycles (PR for 9 months) • Bendamustine-Rituximab x 6 cycles (PR for 12 months) • R-CHOP x 3 cycles (minor response. Stopped for toxicity) • BR for 3 cycles (minor response) • High dose steroids (minor response) • November 2nd 2013, began ABT-199 Oct 25, 2013 Dec 10, 2013 January 14 2013 Feb 17, 2014

  44. Conclusions • Not truly ready to discard chemotherapy… • However, • Targeted agents are finally showing highly promising results in B cell malignancies • BCR inhibitors, BCL-2 inhibitors • Challenge is to develop rational combinations of targeted agents • Disrupt several key survival pathways simultaneously • Delay/prevent emergence of resistance • I am optimistic 

  45. Questions?

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