steven o’day 1, f. stephen hodi 2, david mcdermott 3, robert weber 4, jeffrey sosman 5, john...
TRANSCRIPT
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
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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
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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
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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
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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
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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
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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
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MDX010-20: Study Design
RANDOMIZE
Pre-treatedMetastaticMelanoma
(N=676)(N=137)
(N=136)
(N=403)
gp100 + placebo
Ipilimumab + placebo
Ipilimumab + gp100
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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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
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Summary of MDX010-20 Data
The addition of gp100 vaccine to ipilimumab:
– Reduced PFS, BORR & DCR
– No influence on safety
– No influence on OS
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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%
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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
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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)