1. Relevance as Front Line Therapy
Owen A. O’Connor, M.D., Ph.D.
Professor of Medicine and Experimental Therapeutics
Director, Center for Lymphoid Malignancies
Columbia University Medical Center – College of Physicians and Surgeons
The New York Presbyterian Hospital
New York, N.Y.

2. Lenalidomide Restores Immune Compétence in FL
FL cells directly Immune Suppress their host
Express Multiple T-cell Inhibitory Molecules on their Surface that Inactivate T Cell Cytotoxicity
Lenalidomide restores Immune Competence
By down regulating the expression of these B7 inhibitory molecules on the FL cell surface restoring the T cells ability to kill the cancer cells
The “high expression” of these T cell inhibitory surface ligands is a general mechanism used for immune evasion by cancer
Ramsay A.G, et al Blood: Pre-published online April 30, 2012
Ramsay A G , et. al. Blood 2009;114: 2
Ramsay A G , Gribben J G Blood 2011;118:

3. Responses (1999 IWG) assessed every 3 cycles
ASH2012: Lenalidomide and Rituximab for Untreated Indolent Lymphoma: Final Results of a Phase II Study
Nathan Fowler, Sattva Neelapu, Frederick Hagemeister, Peter McLaughlin, Larry W Kwak, Jorge Romaguera, Michele Fanale, Luis Fayad, Robert Orlowski, Michael Wang, Francesco Turturro, Yasuhiro Oki, Linda Lacerte, Felipe Samaniego
Department of Lymphoma/Myeloma
MD Anderson Cancer Center, Houston, Texas
Phase II
Advanced stage, untreated iNHL; measurable disease (> 1.5 cm) (N = 110)
LEN 20 mg, days
Rituximab 375 mg/m2 day 1, q28d x 6 cycles (responders up to 12 cycles)
Responses (1999 IWG) assessed every 3 cycles

4. Phase II, Single-Arm Study of Lenalidomide and Rituximab in Untreated, Advanced-Stage iNHL: Patient Characteristics
Patient Characteristics
n (%)
Histology
SLL
30 (27%) FL
50 (45%)
MZL
Median age, years (range)
58 (34-84)
Male
58 (53%)
FLIPI score of ≥ 2
(of 46 evaluable FL patients)
36 (78%)
High tumor burden (GELF)
24 (52%)
Bulky disease (> 7 cm mass or 3 nodes > 3 cm)
25 (23%)
Fowler et al. ASH 2012, Abstract 901.

5. Phase II, Single-Arm Study of Lenalidomide and Rituximab in Untreated, Advanced-Stage iNHL: Efficacy
All (N = 103)
FL (N = 46)
SLL (N = 30)
MZL (N = 27)
ORR 90 98 80 89
CR/CRu 64 87 27 67 PR 26 11 53 22 SD 8 2 13
2-year PFS = 83% for all pts; 89% for FL
Molecular response in most FL patients with the absence of detectable BCL-2
93% of 45 FL PET+ pts attained complete metabolic response
Two episodes of neutropenic fever
Fowler et al. ASH 2012, Abstract 901.

6. PET Response: Follicular Lymphoma
Pre-Treatment
Post-Treatment
Positive
Negative N 45 1 3
43* %
98% 2% 7%
93%
* Includes 1 patient with PET positive lesion: biopsy = non-lymphoma
45 of 46 FL patients had PET imaging pre/post treatment.
Scans interpreted as +/- by visual assessment by IHP1 recommendations.
With equivocal or indeterminate findings, status determined by consensus by two nuclear medicine physicians in independent review.
Juweid, M. et al. JCO (5):

7. R2 for Untreated Indolent Lymphoma: Response According to GELF
FL response %
GELF Criteria
(n = 46)
Bulk of Disease
GELF (+) (n = 22)
GELF (−) (n = 24)
Bulky (n = 13)
Non-bulky (n = 33)
ORR
100%
96%
13%
97%
CR/CRu
95%
79%
92%
85% PR 5%
17% 8%
12% SD 0% 4% 3%
*Includes 1 patient with a PET-positive lesion: biopsy = non-lymphoma.
Fowler et al. Blood (ASH Annual Meeting Abstracts). 2012;120. Abstract 901.

8. Grade ≥ 3 Hematologic Toxicity
Five patients developed grade 3 neutropenic fever.

9. Lenalidomide Plus Rituximab (R2) in FL
CALGB 50401: A Randomized Trial of Lenalidomide Alone vs. Lenalidomide + Rituximab in Patients with Recurrent Follicular Lymphoma
John P. Leonard and Bruce D. Cheson
CALGB/Alliance for Clinical Trials in Oncology
ASCO 2012
Grade 1-3a relapsed FL after ≥1 rituximab-based regimen
Lenalidomide + Rituximab (n = 45)
Lenalidomide (n = 45)
RANDOMIZE
Lenalidomide: 15 mg/d d1-21/28 cycle 1, then d20 and 25 if tolerated; 12 cycles
Rituximab: 375 mg/m2 d8, 15, 22, 29 of cycle 1

10. Lenalidomide vs. R2 in Recurrent FL: Patient Characteristics
Median age, years (range)
63 (34-85)
62 (36-89)
FLIPI
Low
31%
49%
Intermediate
43%
30%
High
26%
21%
TTP since last rituximab dose
1.6 years
1.3 years
Stage
I/II
20%
III/IV
80%
70%
LDH > NL
16% 2%
Data not reported for 3 patients in rituximab only arm, 3 never treated, and 2 with insufficient data. Data were pending at presentation for FLIPI (n = 31), prior R (n = 3), stage (n = 1), and LDH (n = 4).
Leonard et al, ASCO, 2012

11. Lenalidomide vs. R2 in Recurrent FL: Efficacy
R2 (n = 44)
ORR, % (95% CI)
51% (36%–66%)
73% (52%–85%) CR
13%
36% PR
38%
Median EFS
1.2 years
2.0 years
2-year EFS
27%
44%
EFS for REV vs. R2
Unadjusted HR = 2.1 (P = 0.010)
Adjusted for FLIPI HR = 1.9 (P = 0.061)
No significant difference in OS (P = )
CI, confidence interval; HR, hazard ratio; PR, partial response; OS, overall survival
Leonard et al, ASCO, 2012

12. Lenalidomide vs. R2 in Recurrent FL: Safety
Grade 3/4 Adverse Events (AE) in > 1 Patient, %
Lenalidomide
(n = 45)
R2 (n = 44)
Grade 3
Grade 4
Heme
Neutropenia 16 14 5
Thrombocytopenia
Anemia
Fatigue 9 12 2
Thrombosis* 7
Rash 3
Infection 4
Myelosuppression was the most common grade 3/4 AE in L and R2 arms
Prior history of and risk factors for thrombosis or use of prophylaxis did not correlate with thrombosis
*Thrombosis observed in 9 patients overall, including 7 patients on lenalidomide (1 with no prophylaxis, 5 with acetylsalicylic acid [ASA] prophylaxis, and 1 missing) and 2 patients on R2 (1 with no prophylaxis, 1 with ASA prophylaxis + other antiplatelet agents).
Heme, hematologic toxicity.
Leonard et al, ASCO, 2012

13. Lenalidomide Clinical Activity in iNHL
Response Rates of Lenalidomide Monotherapy and R2 in Phase II Studies in iNHL CR PR
R2 in
untreated FL
R2 in
R/R FL
Lenalidomide monotherapy
in R/R NHL %

14. Rationale
R2 effectively eliminates FL tumor burden with a favorable safety profile
Lenalidomide reverses the FL induced immune suppression enabling host cells to kill the FL

15. RELEVANCE Organization
Lead – Lysarc (ex-Gelarc), French Cooperative group
Dual sponsorship for purpose of study conduct
Lysarc – France, Belgium, Spain, Canada, Italy, Portugal, Germany, Canada & Australia Will recruit up to 750 patients
Celgene – US, Japan Will recruit up to 250 patients
Considered as a single global study (total patients) and utilize single:
Database
SSC
DSMC

16. Relevance Study Design
R2 maintenance
(lenalidomide 1 yr + rituximab 2 yrs)
Rituximab maintenance
(2 yrs) R
24 mos. R2
R-Chemo
6 mos.
CR, CRu, PR
1st line FL
N=1000
Stratification: FLIPI (0-1 v 2 v 3-5), Age (>60 v ≤ 60), diameter of largest node (> 6 v ≤ 6 cm)
R-Chemo arm: Investigator choice of R-CHOP, R-CVP, R-B
Co-primary endpoints
Surrogate endpoint of CR/CRu rate at 30 months
PFS

17. Making the case for Relevance
R2 is an appropriate therapy for patients with FL irrespective of GELF criteria
Symptomatic disease can always be relieved with steroids prior to initiation of treatment, if worried about the kinetics of reponse
Burning valuable chemotherapy programs early is not a strategy that keeps future doors open to manage potential histologic transformation or even more aggressive disease.

18. THANK YOU