A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp 100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma Study MDX 010 -20 Steven O’Day 1, F. Stephen Hodi 2, David Mc. Dermott 3, Robert Weber 4, Jeffrey Sosman 5, John Haanen 6, Xiaoping Zhu 7, Michael Yellin 7, Axel Hoos 8, Walter J. Urba 9 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
Disclosures l Bristol-Myers Squibb – Non-paid Consultant – Research Funding – Advisory Board – Speakers Bureau 2
Metastatic Melanoma l Rapidly rising global incidence – Young age at onset l Poor prognosis, limited therapeutic options – 1 -year survival ~25%; 2 -year survival ~10%1 l No approved therapies for pretreated pts l No randomized clinical trial has ever demonstrated survival benefit 1 Korn EL et al. J Clin Oncol. 2008; 26: 527 -534 3
Ipilimumab in Treatment of Cancer l CTLA-4: – Downregulates T-cell activation l Ipilimumab: – Fully human monoclonal antibody – Blocks CTLA-4 receptor – Potentiates T cell activation Korman, Peggs and Allison: Adv. In Immunol 2006; 90: 297 -339 4
Ipilimumab: Mechanism of Action T-cell activation T-cell inhibition T-cell potentiation CTLA 4 T cell CD 28 TCR MHC APC T cell CD 28 TCR B 7 MHC APC CTLA 4 B 7 CTLA 4 TCR MHC APC B 7 IPILIMUMAB blocks CTLA-4 5
Ipilimumab: Phase II Experience l Ipilimumab monotherapy – 20– 30% durable disease control and 2 -year survival 1, 2 l Mechanism-based side effects – Immune-related Adverse Events (ir. AEs) – Onset predominantly in first 12 weeks – Management with vigilant follow-up and early steroids required l Ipilimumab + vaccine combinations explored 1 O’Day SJ et al. Ann Oncol 2010; Feb; 2 Wolchok JD et al. Lancet Oncol 2010; 11(2): 155 -164 6
gp 100 Vaccine Control l HLA-A*0201 restricted l T-cell specific immune responses l Rare objective clinical response l Combination with IL-2 in metastatic melanoma (ASCO, 2009) – Improved Response Rate, PFS l Active control arm for present study 7
MDX 010 -20: Patient Eligibility l Inclusion – – Pre-treated stage III or IV melanoma HLA-A*0201 positive Pre-treated CNS metastases allowed Any LDH level l Exclusion – No autoimmune disease – No prior therapy with anti-CTLA-4 antibody – No prior therapy with anti-cancer vaccine 8
MDX 010 -20: Study Design Pretreated Metastati c Melanom a (N=676) R A N D O M I Z E Ipilimumab + gp 100 (N=403) Ipilimumab + placebo (N=137) gp 100 + placebo (N=136) 9
MDX 010 -20: Study Design Details l Accrual: September 2004 – July, 2008 – 125 Centers in 13 Countries l Randomized (3: 1: 1), Double-Blind l Stratified for M-Stage and prior IL-2 l Induction – Ipilimumab: 3 mg/kg q 3 weeks X 4 doses – gp 100: 1 mg q 3 weeks X 4 doses l Re-induction (same regimen) in eligible patients 10
Statistical Considerations l Primary Endpoint – Original: BORR (N=750) – Changed to OS (Jan. 2009) before unblinding l Primary Comparison – Ipilimumab + gp 100 vs gp 100 (3: 1) – 385 events required – 90% power to detect: 10. 8 vs 8. 6 months OS l Secondary Comparison – Ipilimumab vs gp 100 (1: 1) – 219 observed events – 80% power 11
Balanced Baseline Characteristics Ipi + gp 100 N=403 Ipi + pbo N=137 gp 100 + pbo N=136 55. 6 56. 8 57. 4 Male 61 59 54 Female 39 41 46 M 0 1 0. 7 3 M 1 a 9 10 8 M 1 b 19 16 17 M 1 c 71 73 72 Age (years) Mean Gender (%) M Stage (%) 12
Balanced Baseline Characteristics Ipi + gp 100 N=403 Ipi + pbo N=137 gp 100 + pbo N=136 0 58 53 52 1 41 47 45 2 1 0. 7 3 3 0. 2 0 0 ≤ ULN 63 61 60 ULN 37 39 38 11 11 15 ECOG PS (%) LDH (%) CNS metastases (%) 13
Kaplan-Meier Analysis of Survival Ipi + gp 100 (A) Ipi alone (B) gp 100 alone (C) Comparison HR p-value Arms A vs. C 0. 68 0. 0004 Arms B vs. C 0. 66 0. 0026 1 2 Years 3 4 14
Ipilimumab + gp 100 Improves Overall Survival vs gp 100 alone Ipi + gp 100 Primary Comparison N Number of deaths Hazard ratio (95% CI) Median OS, Month (95% CI) gp 100 + pbo P-value 403 136 306 119 0. 68 (0. 55, 0. 85) 10. 0 6. 4 (8. 5, 11. 5) (5. 5, 8. 7) 0. 0004 15
Ipilimumab alone Improves Overall Survival Compared to gp 100 Ipi + pbo gp 100 + pbo P-value Secondary Comparison N 137 136 Number of deaths 100 119 Hazard ratio (95% CI) Median OS, Month (95% CI) 0. 66 (0. 51, 0. 87) 10. 1 (8. 0, 13. 8) 0. 0026 6. 4 (5. 5, 8. 7) 16
Addition of gp 100 Vaccine Did Not Improve Overall Survival Ipi + gp 100 Ipi + pbo P-value Secondary Comparison N 403 137 Number of deaths 306 100 Hazard ratio (95% CI) Median OS, Month (95% CI) 1. 04 (0. 83, 1. 30) 10. 0 (8. 5, 11. 5) 0. 7575 10. 1 (8. 0, 13. 8) 17
Kaplan-Meier Analysis of Survival Ipi + gp 100 (A) Ipi alone (B) gp 100 alone (C) 1 2 Years 3 4 Survival Rate Ipi + gp 100 N=403 Ipi + pbo N=137 gp 100 + pbo N=136 1 year 44% 46% 25% 2 year 22% 24% 18
PFS: Impact of Both Ipilimumab Regimens vs gp 100 Ipi + gp 100 (A) Ipi alone (B) gp 100 alone (C) Comparison Hazard Ratio (C. I. ) p-value Arms A vs C 0. 81 (0. 66– 1. 00) 0. 0464 Arms B vs C 0. 64 (0. 50– 0. 83) 0. 0007 Arms A vs B 1. 25 (1. 01– 1. 53) 0. 0371 1 2 = 1 st tumor assessment as per protocol Years 3 4 19
Ipilimumab Improves Best Objective Response Rate (BORR) Arm A Ipi + gp 100 N=403 BORR, % 5. 7 Arm B Arm C Ipi + pbo gp 100 + pbo N=137 N=136 10. 9 P-value: A vs C 0. 0433 P-value: B vs C 1. 5 0. 0012 DCR‡, % 20. 1 28. 5 P-value: A vs C 0. 0179 P-value: B vs C 11. 0 0. 0002 ‡Disease control rate: percentage of patients with CR, PR, or SD 20
Summary of Safety Events % of Patients Ipi + gp 100 N=380 Any adverse event (AE) Treatment - related Any AE Treatment - related Grade 3/4 AE Treatment - related Deaths Ipi + pbo N=131 gp 100 + pbo N=132 98. 4 96. 9 97. 0 88. 9 80. 2 78. 8 17. 4 22. 9 11. 4 2. 1 3. 1 1. 5 21
Most Common Immune-Related Adverse Events* (ir. AEs; All Grades) % of Patients Ipi + gp 100 Ipi + pbo ir. AE N=380 N=131 All grades Any 58. 2 61. 1 Dermatologic 40. 0 43. 5 GI 32. 1 29. 0 Endocrine 3. 9 7. 6 Hepatic 2. 1 3. 8 gp 100 + pbo N=132 31. 8 16. 7 14. 4 1. 5 4. 5 *Across entire study duration 22
Most Common Immune-Related Adverse Events* (Grades 3, 4 & 5) % of Patients ir. AE Ipi + gp 100 N=380 Ipi + pbo N=131 gp 100 + pbo N=132 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 ir. AE 1. 3 1. 5 0 *Across entire study duration 23
Summary of MDX 010 -20 Data l First randomized phase III trial to show survival improvement in metastatic melanoma (HR=0. 66, 0. 68) l Superior OS in two independent comparisons of ipilimumab vs gp 100 l Survival rates in the ipilimumab arms – 1 year: 44%, 46% – 2 years: 22%, 24% l Consistent superiority of ipilimumab for all secondary efficacy endpoints – PFS, BORR, DCR 24
Summary of MDX 010 -20 Data l The addition of gp 100 vaccine to ipilimumab: – Reduced PFS, BORR & DCR – No influence on safety – No influence on OS 25
Summary of MDX 010 -20 Data l 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% 26
Conclusions l Ipilimumab represents a new class of T-cell potentiators and an important advance for the field of immuno-oncology l Further development of ipilimumab is ongoing – Diversification to a variety of cancer types and settings – Alternative combination regimens – Refinements in dose and schedule 27
Acknowledgments Many Thanks to the 676 Patients Enrolled on Study MDX 010 -20!! INVESTIGATORS: Argentina: M. Chacón, L. Koliren, G. L. Lerzo, R. L. Santos Belgium: A. Awada, V. Cocquyt, J. Kerger, J. Thomas, T. Velu; 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 Brazil: C. Barrios, C. Dzik, M. Federico, J. Hohmann, M. Liberrati, A. Lima, G. Schwartsmann, J. Segalla; Netherlands: Canada: T. Baetz, T. Cheng, D. Hogg, W. Miller, I. Quart, S. Rorke, S. Verma, R. Wong; G. L. Cohen, J. I. Raats, D. A. Vorobiof Chile: H. Harbst, P. Gonzalez-Mella United Kingdom: J. Barber, S. Danson, M. Gore, S. Houston, C. G. Kelly, P. Lorigan, M. Middleton, C. Ottensmeier, P. M. Patel, E. Rankin France: F. Cambazard, O. Dereure, B. Dreno, L. Geoffrois, J-J. Grob, C. Lebbe, T. Lesimple, S. Négrier, N. Penel, C. Robert, A. Thyss R. L. H. Jansen, Alfons J. M. van den Eertwegh South Africa: Switzerland: R. Dummer, O. Michielin 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: A. Bhattacharya (BMS: Medical Writing) G. Nichol, D. Mc. Donald, S. Fischkoff, J. Tian 28
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