Steven O’Day 1 , F. Stephen Hodi 2 , David McDermott 3 , Robert Weber 4 , Jeffrey Sosman 5 , John Haanen 6 , Xiaoping Zhu 7 , Michael Yellin 7 , Axel Hoos 8 , Walter J. Urba 9 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 1 The Angeles Clinic and Research Institute, Santa Monica, CA; 2 Dana-Farber Cancer Institute, Boston, MA; 3 Beth Israel Deaconess Medical Center, Boston, MA, 4 Saint Mary's Medical Center, San Francisco, CA; 5 Vanderbilt-Ingram Cancer Center, Nashville, TN; 6 The Netherlands Cancer Institute, Amsterdam, The Netherlands; 7 Medarex Inc., Bloomsbury, NJ; 8 Bristol-Myers Squibb Co., Wallingford, CT; 9 Earle A. Chiles Research Institute, Portland, OR
28
Embed
Steven O’Day 1, F. Stephen Hodi 2, David McDermott 3, Robert Weber 4, Jeffrey Sosman 5, John Haanen 6, Xiaoping Zhu 7, Michael Yellin 7, Axel Hoos 8, Walter.
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
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
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
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)
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.