1. Should DLBCL patients receive upfront treatment today based on “cell of origin”?
John P. Leonard, M.D.
Richard T. Silver Distinguished Professor of Hematology and Medical Oncology
Associate Dean for Clinical Research
Vice Chairman, Department of Medicine

2. Disclosures Consulting advice:
Seattle Genetics, Genentech, Pharmacyclics, Biotest, Celgene, Medimmune, Gilead

3. Germinal center vs activated B cell DLBCL
Rosenwald A et al. N Engl J Med. 2002;346:

4. Outcome by GCB vs non-GCB gene signatures in DLBCL
N=233 patients treated with R-CHOP
PFS OS
Lenz G, et al, NEJM November 27, 2008

5. Upfront DLBCL – Novel agent/regimen in specific clinical or molecular patient subsets Study design
CHOP-R
Other regimen
Subset 1
CHOP-R
DLBCL
Subset 2
Other regimen

6. Approaches that potentially could target a DLBCL COO subset (2014)
R-EPOCH
Bortezomib
Ibrutinib
Lenalidomide
Azacytidine
ABC subtype enriched for DLBCL with less favorable methylation profiles
Phase I completed win combination with R-CHOP
EZH2 inhibitors
GCB subtype
Phase I single agent

7. Key elements to targeting a subset
Presence of the target and activity of the drug are clearly linked
“Enrichment” vs “Precision”
Relevant to single agent vs combination therapy
Target assay is robust
Assay performed in clinically acceptable timeline
Target population has enough patients
Target (and targeting) relevant in untreated and relapsed/refractory setting
Appropriate drug is available and optimized

8. Outcome by cell of origin R-EPOCH in upfront DLBCL
CALGB multicenter single arm phase II trial, N=69
Wilson et al, Hematologica 2012

9. CALGB 50303: R-CHOP vs R-EPOCH in Newly Diagnosed DLBCL
R-CHOP every 3 wks for 6 cycles
Untreated patients with newly diagnosed
DLBCL
(N = 478)
R-EPOCH Doxorubicin, etoposide, vincristine Days 1-4;
cyclophosphamide Day 5;
prednisone Days 1-5
Primary endpoints: EFS, molecular predictors of outcome for each regimen
Secondary endpoints: RR, OS, toxicity, use of molecular profiling for pathological diagnosis
Clinical Trials.gov. NCT

10. Non-GCB DLBCL is associated with high expression of target genes of NF-kB transcription factors
Davis, et al, J Exp Med 2001

11. CHOP-R + bortezomib DLBCL PFS and OS by subtype (n = 40)
Ruan et al, JCO 2010

12. Upfront DLBCL – Novel agent/regimen in specific clinical or molecular patient subsets Study design
CHOP-R
Other regimen
Bortezomib +
GCB
CHOP-R
DLBCL
Non-GCB

13. Six treatment cycles q21 days Six treatment cycles q21 days
PYRAMID study design
DLBCL diagnosis & subtyping
Hans method
Non-GCB
GCB
Not enrolled R
Vc-R-CHOP
Bortezomib 1.3 mg/m2, d 1, 4
Rituximab 375 mg/m2, d 1
Cyclophosphamide 750 mg/m2, d 1
Doxorubicin 50 mg/m2, d 1
Vincristine 1.4 mg/m2, d 1
Prednisone 100 mg/d, d 1–5
Six treatment cycles q21 days
R-CHOP
Rituximab 375 mg/m2, d 1
Cyclophosphamide 750 mg/m2, d 1
Doxorubicin 50 mg/m2, d 1
Vincristine 1.4 mg/m2, d 1
Prednisone 100 mg/d, d 1–5
Six treatment cycles q21 days
Follow up every 3 months for 2 yrs

14. REMoDL-B study
Randomized evaluation of molecular guided therapy in DLBCL with Bortezomib
All patients undergo biopsy for profiling at diagnosis
All patients receive cycle #1 R-CHOP
Randomized from cycle #2-6 to receive bortezomib 1.3 mg/m2 d 1 and 8
All patients initially randomized, designed to close for GCB subjects if evidence of futility
Up to 940 subjects, minimum 260 ABC subtype

15. Key Pathway Related Mutations Contribute to BTK Signaling in ABC DLBCL
BCR
CD79
SYK
BTK P
PLCγ
PI3K
PIP2  PIP3
Lyn/Fyn A B
CARD11
MALT1
BCL10
IKKγ
IKKb
IKKα
NF-κB
pathway
Survival
MYD88
CD79A/B
ITAM
mutation
21%
MYD88
TIR domain
mutation
39%
CARD11
coiled-coil
mutation
10%
Davis  et al 2010, Nature 463:88; Ngo et al 2011 Nature 470:115
EHA 2013, PCYC-1106 de Vos et al.

16. The Bruton’s Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), has Preferential Activity in the Activated B Cell-like (ABC) Subtype of Relapsed/Refractory (R/R) DLBCL: Interim Phase 2 Results
Sven de Vos1, Wyndham H. Wilson2, John Gerecitano3, Andre Goy4, Vaishalee P. Kenkre5, Paul Barr6, Kristie A. Blum7, Andrei Shustov8, Ranjana H. Advani9, Nathan H. Fowler10, Julie M. Vose11, Chih-Jian Lih12, Mickey Williams12, Roland Schmitz2, Yandan Yang2, Stefania Pittaluga2, George Wright2, Lori A. Kunkel13, Jesse McGreivy13, Darrin Beaupre13, Sriram Balasubramanian13, Mei Cheng13, Davina Moussa13, Lipo Chang13, Joseph Buggy13, Louis M. Staudt2
1UCLA Medical Center, Los Angeles, 2National Cancer Institute, Bethesda, 3Memorial Sloan-Kettering Cancer Center, New York, 4John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, 5Department of Medicine - Hematology/Oncology, University of Wisconsin, Madison, 6University of Rochester Medical Center, Rochester, 7Ohio State University Medical Center, Columbus, 8Department of Medicine, Division of Hematology, University of Washington Medical Center, Seattle, 9Department of Medicine, Division of Hematology, Stanford University Medical Center, Stanford, 10Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, 11Oncology/Hematology Division, University of Nebraska Medical Center, Omaha, 12SAIC Frederick National Laboratory for Cancer Research, Frederick, 13Pharmacyclics, Inc., Sunnyvale, United States

17. Phase II Study Design Ibrutinib: 560 mg/d, PO Eligibility (N = 70)
Relapsed/refractory de novo DLBCL
Progressive disease (PD) after ASCT or ineligible for ASCT
Archival tissue for central review
No primary mediastinal DLBCL, transformed DLBCL or CNS involvement
Ibrutinib:
560 mg/d, PO
ASCT = autologous stem cell transplant
Gene expression profiling of biopsy tissues using Affymetrix arrays to identify DLBCL subtype (ABC, GCB, unclassifiable)
Mutations in tumor samples analyzed by PCR and DNA sequencing
ABC DLBCL tumors analyzed for mutations in CD79B, MYD88 and CARD11 genes
Wilson WH et al. Proc ASH 2012;Abstract 686.

18. Waterfall Plot of Maximum Decrease in Bidimensional Measurements
ABC (N = 23)
GCB (N = 12)
Unclassifiable (N = 8)
Unknown (N = 3)
% Change from Baseline SPD
Only includes pts with post baseline LN measurements
* Best response was PD due to clinical progression
With permission from Wilson WH et al. Proc ASH 2012;Abstract 686.

19. Phase 1b Ibrutinib + R-CHOP in CD20+B-Cell NHL
Younes et al. ASH 2013, Abstract 852

20. Upfront DLBCL – Novel agent/regimen in specific clinical or molecular patient subsets Study design
CHOP-R
Other regimen
Ibrutinib +
GCB
CHOP-R
DLBCL
Non-GCB

21. Response to Lenalidomide in Relapsed and Refractory DLBCL Based on Subtype
RCHOP - inferior results in non-GCB
Retrospective analysis of patients with relapsed DLBCL treated with lenalidomide as a single agent or in combination with rituximab/steroids at several institutions (N=56) suggests activity in the non-GCB subset
Hernandez-Illizaliturri et al. Cancer 2011

22. Lenalidomide + R-CHOP-21
Author
FIL Chiappella, et al.1
MAYO Nowakowski, et al.2
LYSA Tilly, et al.3
Phase I
NHL subtype
DLBCL or FLgIIIb,
age 60-80
DLBCL or FLgIII,
age >18
DLBCL, FL, MCL, iNHL
age 18-80
N of patients 21 24 27
MTD
15 mg days 1-14
no DLT
LR-CHOP regimen
6 R-CHOP21 +
lenalidomide 15 mg
days 1–14
lenalidomide 25 mg
days 1–10
days 1-14
1. Chiappella et al, Haematol 2013; 2. Nowakowski et al, Leukemia 2011; 3. Tilly et al, Leukemia 2013

23. Newly diagnosed DLBCL or FL grade IIIb, Age FIT according to CGA , Ann Arbor stage II-IV, IPI 2-5
CNS prophylaxis according to Italian Society of Hematology guidelines
Pegfilgrastim or G-CSF as neutropenia prophylaxis
Low Molecular Weigh Heparin as DVT prophylaxis
Lenalidomide at MTD:
15 mg daily on days 1-14
Pre-treatment screening: CT/CT-PET, BM Bx, Tissue Bx
Chiappella et al, ASH 2013

24. ORR, PFS, EFS BY COO (IHC) GC. ORR: 88%, CR 81% Non-GC. ORR/CR: 88%
74%
71%
61%
2-yrs EFS GC: 61% (95% CI: 33-80)
2-yrs EFS non-GC: 74% (95% CI: 45-90)
2-yrs PFS GC: 71% (95% CI: 40-88)
2-yrs PFS non-GC: 81% (95% CI: 51-93)
p 0.789
p 0.806

25. Mayo Phase 2 R2CHOP vs RCHOP Case-matched Controls
Nowakowski et al. ASH 2013

26. PFS by GCB vs. non-GCB Subtype* in Case-matched RCHOP cohort vs R2CHOP
DLBCL subtype (Hans)*
GCB
non-GCB
unknown
12 (42%)
11 (40%)
5 (18%)
p=0.004
p=NS
Nowakowski et al. ASH 2013
* As defined by Hans et al. Blood 2004

27. E1412: R2CHOP vs. RCHOP RCHOP N=100 evaluable pts DLBCL DLBCL
Stratification
Age
IPI
10% path ineligibility rate total ~220 pts#
DLBCL
DLBCL
R 1:1
R2CHOP
N=100 evaluable pts
#up to 300 patients can be enrolled to meet a goal of 50 ABC DLBCL patients per arm as defined by GEP

28. Treating based on COO in DLBCL
Can you identify subsets reliably and quickly?
A 50% subset ends up being 30% of those screened
Is the drug activity specific to a subset?
Maybe
Is the drug specificity relevant in combination with standard therapy?
If not, is single agent activity robust?
Not usually in DLBCL
Are there enough patients to enroll just a subset?
2014: Studies of COO subsets are appropriate, but not ready for routine therapy selection in practice