Steven O’Day1, F. Stephen Hodi2, David McDermott3, Robert Weber4, Jeffrey Sosman5, John Haanen6, Xiaoping

Zhu7, Michael Yellin7, Axel Hoos8, Walter J. Urba9

A phase III, randomized, double-blind, multicenter study comparing monotherapy

with ipilimumab or gp100 peptide vaccine and the combination in patients with previously

treated, unresectable stage III or IV melanoma

Study MDX010-20

1The Angeles Clinic and Research Institute, Santa Monica, CA; 2Dana-Farber Cancer Institute, Boston, MA; 3Beth Israel Deaconess Medical Center, Boston, MA, 4Saint Mary's Medical Center, San Francisco, CA; 5Vanderbilt-Ingram Cancer Center, Nashville, TN; 6The Netherlands Cancer Institute, Amsterdam, The Netherlands; 7Medarex Inc., Bloomsbury, NJ; 8Bristol-Myers Squibb Co., Wallingford, CT; 9Earle A. Chiles Research Institute, Portland, OR

2

Disclosures

Bristol-Myers Squibb

– Non-paid Consultant

– Research Funding

– Advisory Board

– Speakers Bureau

3

Metastatic Melanoma

Rapidly rising global incidence

– Young age at onset

Poor prognosis, limited therapeutic options

– 1-year survival ~25%; 2-year survival ~10%1

No approved therapies for pretreated pts

No randomized clinical trial has ever demonstrated survival benefit

1Korn EL et al. J Clin Oncol. 2008;26:527-534

4

Ipilimumab in Treatment of Cancer

CTLA-4:

– Downregulates T-cell activation

Ipilimumab:

– Fully human monoclonal antibody

– Blocks CTLA-4 receptor

– Potentiates T cell activation

Korman, Peggs and Allison: Adv. In Immunol 2006;90:297-339

5

Ipilimumab: Mechanism of Action

T cell

TCRCTLA4

APC

MHCB7

T-cell inhibition

T cell

TCR

CTLA4

APC

MHC B7

T-cell activation

T cell

TCR

CTLA4

APC

MHC B7

T-cell potentiation

IPILIMUMABblocksCTLA-4

CD28CD28

6

Ipilimumab: Phase II Experience Ipilimumab monotherapy

– 20–30% durable disease control and 2-year survival1,2

Mechanism-based side effects– Immune-related Adverse Events (irAEs)– Onset predominantly in first 12 weeks– Management with vigilant follow-up and

early steroids required

Ipilimumab + vaccine combinations explored

1O’Day SJ et al. Ann Oncol 2010; Feb; 2Wolchok JD et al. Lancet Oncol 2010; 11(2):155-164

7

gp100 Vaccine Control

HLA-A*0201 restricted

T-cell specific immune responses

Rare objective clinical response

Combination with IL-2 in metastatic melanoma (ASCO, 2009)– Improved Response Rate, PFS

Active control arm for present study

8

MDX010-20: Patient Eligibility Inclusion

– Pre-treated stage III or IV melanoma– HLA-A*0201 positive– Pre-treated CNS metastases allowed– Any LDH level

Exclusion– No autoimmune disease– No prior therapy with anti-CTLA-4 antibody– No prior therapy with anti-cancer vaccine

9

MDX010-20: Study Design

RANDOMIZE

Pre-treatedMetastaticMelanoma

(N=676)(N=137)

(N=136)

(N=403)

gp100 + placebo

Ipilimumab + placebo

Ipilimumab + gp100

10

MDX010-20: Study Design Details

Accrual: September 2004 – July, 2008– 125 Centers in 13 Countries

Randomized (3:1:1), Double-Blind

Stratified for M-Stage and prior IL-2

Induction – Ipilimumab: 3 mg/kg q 3 weeks X 4 doses– gp100: 1mg q 3 weeks X 4 doses

Re-induction (same regimen) in eligible patients

11

Statistical Considerations Primary Endpoint

– Original: BORR (N=750)

– Changed to OS (Jan. 2009) before unblinding

Primary Comparison

– Ipilimumab + gp100 vs gp100 (3:1)

– 385 events required

– 90% power to detect: 10.8 vs 8.6 months OS

Secondary Comparison

– Ipilimumab vs gp100 (1:1)

– 219 observed events

– 80% power

12

Balanced Baseline Characteristics

Ipi + gp100N=403

Ipi + pboN=137

gp100 + pboN=136

Age (years)

  Mean 55.6 56.8 57.4

Gender (%)

  Male 61 59 54

  Female 39 41 46

M Stage (%)

  M0 1 0.7 3

  M1a 9 10 8

  M1b 19 16 17

  M1c 71 73 72

13

Ipi + gp100N=403

Ipi + pboN=137

gp100 + pboN=136

ECOG PS (%)

  0 58 53 52

  1 41 47 45

  2 1 0.7 3

  3 0.2 0 0

LDH (%)

≤ ULN 63 61 60

ULN 37 39 38

CNS metastases (%) 11 11 15

Balanced Baseline Characteristics

14

Kaplan-Meier Analysis of Survival

Ipi + gp100 (A)Ipi + gp100 (A)Ipi alone (B) Ipi alone (B)

gp100 alone (C)gp100 alone (C)

11 22 33 44YearsYears

Comparison HR Comparison HR pp-value-value   Arms A vs. C 0.68 0.0004Arms A vs. C 0.68 0.0004 Arms B vs. C 0.66 0.0026Arms B vs. C 0.66 0.0026

15

Ipi + gp100 gp100 + pbo P-value

Primary Comparison

N 403 136

0.0004

Number of deaths

306 119

Hazard ratio (95% CI)

0.68(0.55, 0.85)

Median OS,

Month (95% CI)

10.0

(8.5,11.5)

6.4

(5.5, 8.7)

Ipilimumab + gp100 Improves Overall Survival vs gp100 alone

16

Ipi + pbo gp100 + pbo P-value

Secondary Comparison

N 137 136

0.0026

Number of deaths 100 119

Hazard ratio

(95% CI)0.66 (0.51, 0.87)

Median OS,

Month (95% CI)10.1

(8.0,13.8)

6.4

(5.5, 8.7)

Ipilimumab alone Improves Overall Survival Compared to gp100

17

Addition of gp100 Vaccine Did Not Improve Overall Survival

Ipi + gp100 Ipi + pbo P-value

Secondary Comparison

N 403 137

0.7575

Number of deaths

306 100

Hazard ratio

(95% CI)1.04 (0.83, 1.30)

Median OS, Month (95% CI)

10.0

(8.5, 11.5)

10.1

(8.0,13.8)

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Survival Rate Ipi + gp100 N=403

Ipi + pbo N=137

gp100 + pbo N=136

1 year 44% 46% 25%

2 year 22% 24% 14%

Kaplan-Meier Analysis of SurvivalIpi + gp100 (A)Ipi + gp100 (A)Ipi alone (B) Ipi alone (B)

gp100 alone (C)gp100 alone (C)

1 2 3 4Years

19 = 1st tumor assessment as per protocol

PFS: Impact of Both Ipilimumab Regimens vs gp100

Ipi + gp100 (A)Ipi + gp100 (A)Ipi alone (B) Ipi alone (B)

gp100 alone (C)gp100 alone (C)

1 2 3 4Years

ComparisonComparison Hazard Ratio (C.I.) Hazard Ratio (C.I.) pp-value-value  Arms A vs Arms A vs C 0.81 (0.66–1.00) 0.0464 C 0.81 (0.66–1.00) 0.0464Arms B vs C 0.64 (0.50–0.83) 0.0007Arms B vs C 0.64 (0.50–0.83) 0.0007Arms A vs Arms A vs B 1.25 (1.01–1.53) 0.0371 B 1.25 (1.01–1.53) 0.0371

20

Ipilimumab Improves Best Objective Response Rate (BORR)

Arm AIpi + gp100

N=403

Arm BIpi + pbo

N=137

Arm Cgp100 + pbo

N=136

BORR, % 5.7 10.9 1.5

P-value: A vs C 0.0433

P-value: B vs C 0.0012

DCR‡, % 20.1 28.5 11.0

P-value: A vs C 0.0179

P-value: B vs C 0.0002

‡Disease control rate: percentage of patients with CR, PR, or SD

21

Summary of Safety Events

% of PatientsIpi + gp100

N=380Ipi + pbo

N=131gp100 + pbo

N=132

Any adverse event (AE) 98.4 96.9 97.0

Treatment - related

Any AE88.9 80.2 78.8

Treatment - related

Grade 3/4 AE17.4 22.9 11.4

Treatment - related Deaths

2.1 3.1 1.5

22

Most Common Immune-Related Adverse Events* (irAEs; All Grades)

% of Patients

irAEIpi + gp100

N=380Ipi + pbo

N=131gp100 + pbo

N=132

All grades

Any 58.2 61.1 31.8

Dermatologic 40.0 43.5 16.7

GI 32.1 29.0 14.4

Endocrine 3.9 7.6 1.5

Hepatic 2.1 3.8 4.5*Across entire study duration

23

Most Common Immune-Related Adverse Events* (Grades 3, 4 & 5)

% of Patients

irAEIpi + gp100

N=380Ipi + pbo

N=131gp100 + pbo

N=132Grade 3 Grade 4 Grade 3 Grade 4 Grade 3 Grade 4

Any 9.7 0.5 12.2 2.3 3.0 0

Dermatologic 2.1 0.3 1.5 0 0 0

GI 5.3 0.5 7.6 0 0.8 0

Endocrine 1.1 0 2.3 1.5 0 0

Hepatic 1.1 0 0 0 2.3 0

Death due to irAE

1.3 1.5 0

*Across entire study duration

24

Summary of MDX010-20 Data

First randomized phase III trial to show survival improvement in metastatic melanoma (HR=0.66, 0.68)

Superior OS in two independent comparisons of ipilimumab vs gp100

Survival rates in the ipilimumab arms– 1 year: 44%, 46% – 2 years: 22%, 24%

Consistent superiority of ipilimumab for all secondary efficacy endpoints– PFS, BORR, DCR

25

Summary of MDX010-20 Data

The addition of gp100 vaccine to ipilimumab:

– Reduced PFS, BORR & DCR

– No influence on safety

– No influence on OS

26

Summary of MDX010-20 Data

Ipilimumab related toxicity:– Mechanism-based, immune-related toxicity

• Management with vigilant follow-up and early steroids is required

– Rate of Grade 3/4 toxicity:• Treatment-related: 17%, 23%• Immune-related: 10%, 15%

– Deaths• Treatment-related: 2.1%, 3.1%• Immune-related: 1.3%, 1.5%

27

Conclusions

Ipilimumab represents a new class of T-cell potentiators and an important advance for the field of immuno-oncology

Further development of ipilimumab is ongoing

– Diversification to a variety of cancer types and settings

– Alternative combination regimens

– Refinements in dose and schedule

28

Acknowledgments Many Thanks to the 676 Patients Enrolled on Study MDX010-20!!

INVESTIGATORS:

Argentina:M. Chacón, L. Koliren, G.L. Lerzo, R.L. Santos

Belgium: A. Awada, V. Cocquyt, J. Kerger, J. Thomas, T. Velu;

Brazil: C. Barrios, C. Dzik, M. Federico, J. Hohmann, M. Liberrati, A. Lima, G. Schwartsmann, J. Segalla;

Canada: T. Baetz, T. Cheng, D. Hogg, W. Miller, I. Quart, S. Rorke, S. Verma, R. Wong;

Chile: H. Harbst, P. Gonzalez-Mella

France:

F. Cambazard, O. Dereure, B. Dreno, L. Geoffrois, J-J. Grob, C. Lebbe, T. Lesimple, S. Négrier, N. Penel, C. Robert, A. Thyss

Germany: J.C. Becker, J. Freise, C. Garbe, J. C. Hassel, U. Keilholz, H. Naeher, C. Peschel, D. Schadendorf G. Shuler, U. Trefzer, J. Welzel

Hungary: Z. Karolyi

Netherlands:

R.L.H. Jansen, Alfons J. M. van den Eertwegh

South Africa:

G.L. Cohen, J.I. Raats, D.A. Vorobiof

Switzerland:

R. Dummer, O. Michielin

United Kingdom: J. Barber, S. Danson, M. Gore, S. Houston, C.G. Kelly, P. Lorigan, M. Middleton, C. Ottensmeier, P.M. Patel, E. Rankin

United States of America: M. Adler, T. Amatruda, A. Amin, C. Anderson, L. Blakely, E. Borden, S. Burdette-Radoux, R. Chapman, J. Chesney, J. Clark, A. Cohn, F.A. Collichio, G. Daniels, J. Drabick, J.A. Figueroa, J. Fleagle, R. Gonzales, J. Goydos, N. Haas, E. Hersh, H.L. Kaufman, K.D. Khan, A. Khurshid, J.M. Kirkwood, J.J. Kirshner, H. Kluger, D. Lawrence, D. Lawson, P.D. Leming, G. Linette, J. Lutzky, K. Margolin, M. Mastrangelo, B. Mirtsching, W. Paroly, A.L. Pecora, D. Pham, R. Rangineni, N. Rothschild, D. Schwartzentruber, M. Scola, W.H. Sharfman, J.J. Stephenson, N.S. Tchekmedyian, J. Wade, A. Wallace, M. Wax, J. Weber, A. Weeks, J. D. Wolchok, J.L. Zapas.

SPONSORS:

BMS: R.W. Humphrey

MEDAREX:

G. Nichol, D. McDonald, S. Fischkoff, J. Tian

A. Bhattacharya (BMS: Medical Writing)