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

– Obinutuzumab for CLL – Lenalidomide for MCL – Ibrutinib for MCL and CLL

• Horizon

– Idelalisib for indolent NHL – ABT-199 for CLL, NHL – CART therapy

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

“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

Proposed Mechanisms of Action of Rituximab B cell Rituximab

CD20 CD20 Macrophage, monocyte, or natural killer cell

ADCC

Fc g RI, Fc g RII, Fc g RIII Cell lysis

CDC

Complement activation (C1qC1rC1s) MAC 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.

MoAb’s for Lymphoma

FDA approved

• Rituximab (CD20) • Alemtuzumab (CD52) • Ofatumomab (CD20) • Obinutuzimab (CD20) • Zevalin (CD20) -Y 90 • Bexxar (CD20) -I 131 • Brentuximab vedotin (CD30) -MMAE

Dropped

• Lumiliximab (CD23) • Galiximab (CD80) • Epratuzumab (CD22) • Hu1D10 (HLA DR) • SGN-30 (CD30) • SGN-40 (CD40)

Under Study

• Biosimilars (CD20)

Type I (rituximab) vs Type II (obinutuzimab) ANTIBODY TYPE

LIPID RAFTS CDC ADCC DIRECT CYTOTOXICITY BINDING SITES HOMOTYPIC AGGREGATION

I

YES HIGH + WEAK 2 WEAK

II

NO LOW + STRONG 1 STRONG

FREE END TYPE I TYPE II

Adapted from Cragg MS Blood 2011

CLL11: Phase III Study of Chlorambucil (Chl) Alone vs Chl + Obinutuzumab vs Chl + Rituximab in Previously Untreated CLL Patients With Comorbidities R

1:2:2

GA101 + chlorambucil

×

6 cycles Rituximab + chlorambucil

×

6 cycles Primary endpoint: PFS

(investigator assessed)

Secondary endpoints: ORR DOR DFS OS MRD

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/m 2 d1 cycle 1; 500 mg/m 2 d1 cycles 2-6 q28d (GCLLSG CLL8)

DATA (from PI)

Stage I analysis, ASCO 2013 and FDA data, of G-Chl vs Chl Progression-Free Survival

11mos 23mos

Stage 2 analysis of G-Chl vs R-Chl, ASH PLENARY

Obinutuzumab

• FDA approval Nov 1

st – For use in combination with chlorambucil – First line CLL treatment

• Unknown if “FCO” or “BO” will be superior to FCR or BR

CLL: CART Therapy

CLL CD19 CART T Cell

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”

I wish it were this simple

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

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

Targeting Intracellular Pathways

Potential Targets

• Proteasome • RAS-RAF-MEK • Angiogenesis • Histones • mTOR • JAK-STAT • PI3 kinase • BTK • BCL-2

Agent (disease)

Bortezomib (MCL) Sorafenib (bust) Bevacizumab (bust) SAHA, romidepsin (CTCL) Temsirolimus (MCL) SB1518 (TBD) Idelalisib (TBD) Ibrutinib (MCL, CLL) ABT-199 (TBD)

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

Targets of B-Cell Receptor Signaling

Antigen

CK

B Cell Receptor

C D 7 9 B C D 7 9 A

P

SYK LYN

fostamatinib Cytokine Receptor

BTK

P

PI3K

P

C D 1 9 DAG

Cal 101

PIP 3 AKT PLCγ BLNK IP3--Ca++ PKCβ JAK1

TLR

MYD88 ERK Bcl10 MALT1 CARD11 IkB NFkB IkB Proteosomal Degradation

Transcriptional Activation

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 A Goy, 12 A Davies, 13 N Wagner-Johnston, 4 S Schuster, 5 K Blum, 6 PL Zinzani, 14 M Dreyling, 15 L Holes, 16 D Li, 16 W Jurczak, 7 R Dansey, 16 I Flinn, 8 C Flowers, Wayne Godfrey, 16 9 P Martin, 10 and G Salles A Viardot, 17 11 1 University of Washington School of Medicine, Seattle, WA, USA; 2 University of Wisconsin Carbone Cancer Center, Madison, WI, USA; 3 David Geffen School of Medicine at UCLA, Los Angeles, Los Angeles, CA, USA; 4 Washington University School of Medicine, St. Louis, MO, USA; 5 Abramson Cancer Center of the University of Pennsylvania, Philadelphia, PA, USA; 6 Ohio State University Wexner Medical Center, Columbus, OH, USA; 7 Jagiellonian University, Krakow, Poland; 8 Sarah Cannon Research Institute, Nashville, TN, USA; 9 Winship Cancer Institute of Emory University, Atlanta, GA, USA; 10 Weill Cornell Medical College, New York, NY, USA; 11 University Hospital of Ulm, Ulm, Germany; 12 Hackensack University Medical Center, Hackensack, NJ, USA; 13 University of Southampton, Southampton, United Kingdom; 14 University of Bologna, Bologna, Italy; 15 University Hospital Grosshadern, LMU Munich, Germany; 16 Clinical Research Oncology, Gilead Sciences, Seattle, WA, USA; 17 Hospices Civils de Lyon, University Claude Bernard, Pierre Benite, France

American Society of Hematology December 8, 2013 New Orleans, LA Oral No 85.

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

Expression EC 50 (nM)

a

Ubiquitous >10,000

b

Ubiquitous 1419

g

Leukocytes 2500

d

Leukocytes 9

♦ Promising activity in R/R iNHL in phase I study* *Benson D et al. ASCO 2013, abstr 8526 Slide 21

Study 101-09 Waterfall Plot Lymph Node Response +50 +25 0

•90% had improvement in lymphadenopathy •57% had ≥50% decrease from baseline

-25 -50 a -75 -100 Individual Patients (N=125)

a Criterion for lymphadenopathy response [Cheson 2007] b 3 subjects no post baseline evaluation: □ 2 subjects NE ■ 1 subject PD by Lymph Node biopsy Slide 22

Study 101-09: Duration Of Response (DOR) Median DOR = 12.5 months 100 75 50 25 0 0 (71) 3 (54) 6 (34) 9 (17) 12 (9) 15 (0) Time from Response, Months (N, Patients at Risk) 18 (0)

Analysis includes subjects who achieved a CR or PR (or MR for WM subjects) according to IRC assessments Slide 23

Study 101-09: Adverse Events > 10% AE Diarrhea Fatigue Nausea Cough Pyrexia Dyspnea Decreased appetite Abdominal pain Vomiting URI Decreased weight Rash Asthenia Night Sweats Pneumonia Any Grade N, % 54 (43%) 37 (30%) 37 (30%) 36 (29%) 35 (28%) 22 (18%) 22 (18%) 20 (16%) 19 (15%) 18 (14%) 17 (13%) 16 (13%) 14 (11%) 14 (11%) 14 (11%) Grade ≥ 3 N, % 16 (13%) 2 (2%) 2 (2%) None 2 (2%) 4 (3%) 1 (1%) 3 (2%) 3 (2%) None None 2 (2%) 3 (2%) None 9 (7%)

Slide 24

Idelalisib

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

Targets of B-Cell Receptor Signaling

Antigen B Cell Receptor

C D 7 9 B C D 7 9 A

P

SYK LYN

fostamatinib Cytokine Receptor

BTK

P

PI3K

P

C D 1 9 DAG

Cal 101

PIP 3 AKT PLCγ BLNK IP3--Ca++ PKCβ

ibrutinib

CK JAK1 ERK Bcl10 MALT1 CARD11 IkB NFkB

TLR

MYD88 IkB Proteosomal Degradation

Transcriptional Activation

PCI-32765:

First-in Class Inhibitor of BTK O N NH 2 N N N N

PCI-32765

O • • • • • • Forms a specific and irreversible bond with cysteine-481 in BTK Highly potent BTK inhibition at IC 50 = 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 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 27

Original Article Targeting 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

Best Response to Therapy.

Wang ML et al. N Engl J Med 2013;369:507-516

Duration of Response, Progression-free Survival, and Overall Survival.

Wang ML et al. N Engl J Med 2013;369:507-516

Backround • • • •

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

Figure 1: lymphocyte count vs. nodal response

Figure 1: Response over time

Figure 3: PFS and OS

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

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

BCL-2 targeting

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-x L and Bcl-w – Thrombocytopenia due to Bcl-x L inhibition is dose-limiting O O 2 S NH O N NO 2 H N N O N H N • ABT-199: a small molecule, orally-bioavailable second generation BH3-mimetic (Souers et al.,

Nature Medicine

in press) Cl

ABT-199

• >100-fold selectivity for Bcl-2 over Bcl-x L in tumor cell line assays

39

Adverse Events (AEs)

All Grades

Diarrhea Nausea Neutropenia Fatigue Upper respiratory tract infection Cough

Grades 3/4

Neutropenia Anemia Thrombocytopenia

≥20% of pts n (%)

29 (43) 27 (40) 25 (37) 22 (33) 22 (33) 15 (22)

≥ 3 pts n (%)

24 (36) 6 (9) 6 (9) Tumor lysis syndrome* Febrile neutropenia 6 (9) 5 (7) Hyperglycemia 5 (7) Hypophosphatemia 3 (4) *TLS includes 3 events from Cohort 1; 2 clinical events and 1 laboratory TLS occurred in Cohorts 4, 8, and 2

40

NHL Maximal % Reduction in Nodal Size

20 * = Confirmed Partial Remission** CR = Complete Remission 0 MCL MCL MCL DLBCL MCL WM MCL MCL WM FL MCL FL FL FL DLBCL WM FL FL DLBCL FL FL -20 -40 -60 -80 * CR * * Dose (cohort) 200 mg (1) 300 mg (2) 400 mg (3) 600 mg (4) 600 mg (5) -100 *

n = 21 evaluable (at minimum 6 week assessment) **Confirmed = response verified at 2 nd consecutive assessment

Median Time to 50% Reduction = 43 days (range 36 to 113; n=11)

Best Percent Change from Baseline in SPD of Nodal Mass by CT Scan • 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.

17p

del (17p)

FR

Fludarabine refractory

»

del(17p) and FR SPD = Sum of the product of diameters; SE = safety expansion.

N = 57 evaluable (at minimum, Week 6 assessment)

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

Efficacy in CLL/SLL • 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 2 nd 2013, began ABT-199 Feb 17, 2014

Baseline Week 6 Week 16

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 

Questions?