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Advances in the Immunotherapy of Solid Tumors Malignant Melanoma (8 minutes)

Advances in the Immunotherapy of Solid Tumors Malignant Melanoma (8 minutes). Antoni Ribas, M.D., Ph.D. Professor of Medicine Professor of Surgery Professor of Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC)

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Advances in the Immunotherapy of Solid Tumors Malignant Melanoma (8 minutes)

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  1. Advances in the Immunotherapy of Solid Tumors Malignant Melanoma(8 minutes) Antoni Ribas, M.D., Ph.D. Professor of Medicine Professor of Surgery Professor of Molecular and Medical Pharmacology Director, Tumor Immunology Program, Jonsson Comprehensive Cancer Center (JCCC) University of California Los Angeles (UCLA) Chair, Melanoma Committee at SWOG

  2. Ipilimumab (anti-CTLA4) in melanoma 3 mg/kg x 4 doses q3w 10 mg/kg x 4 doses q3w, then q3mo + dacarbazine

  3. NEJM 2012; Jun 28; 366 (26): 2517-9

  4. Melanoma responds to T cell infiltration by expressing PD-L1 (adaptive immune resistance)

  5. PD-L1 PD-1 Interferons Adaptive resistance to immunotherapy Anti-PD-1 Anti-PD-L1 Melanoma cell MHC TCR

  6. PD-1/PD-L1 inhibiting reagents in clinical development

  7. 17% ORR 28% ORR 27% ORR 10% ORR 18% ORR BMS935559 Nivolumab

  8. ORR: 38% Highest dose ORR: 52% (by RECIST 1.1 with confirmation assessed by ICR) ORR: 40% Highest dose ORR: 53% (by investigator-assessed irRC with confirmation) Nivolumab + Ipilimumab Lambrolizumab

  9. Clinical activity of MK-3475 in a patient progressing to 3 prior lines of therapy Baseline: April 13, 2012 April 9, 2013 72-year-old male with symptomatic progression after bio-chemotherapy, HD IL-2, and ipilimumab A. Ribas, ASCO 2013

  10. Clinical activity in a patient with a metastatic desmoplastic melanoma Baseline Jan/2012 Apr/2012 54 yrs old male with desmoplastic melanoma after progressing on ipilimumab B. Chmielowski M.D., Ph.D. Paul Tumeh M.D. A. Ribas, ASCO 2013

  11. MK-3475 (lambrolizumab) single agent therapy: Maximum Change From Baseline in Tumor Size (Independent Central Review per RECIST 1.1) 160  100 IPI-Pretreated 80 IPI-Naive 60 40 20 Percent Change From Baseline in Longest Diameter of Target Lesion 0 ‒20 ‒40 ‒60 ‒80 ‒100 Individual Patients Treated with MK-3475 Ribas et al. ASCO 2013

  12. Time to Response and On-Study Duration (Independent Central Review per RECIST 1.1) Individual Patients Treated With MK-3475 IPI-Pretreated IPI-Naive Complete Response Partial Response On Study 0 10 20 30 40 50 60 70 Weeks The median duration of response had not been reached at the time of analysis, with median follow-up time of 11 months. Ribas et al. ASCO 2013

  13. Drug-Related Adverse EventsObserved in >5% of Patients (N = 135)

  14. Frequent development of vitiligo (skin depigmentation) in responding patients

  15. PD-1 blockade improving other skin conditions Before After

  16. PD-1 blockade leading to the disappearance of a pigmented birth mark After Before

  17. Comparison of key clinical data with anti-PD-1 or anti-PD-L1 antibodiesin patients with advanced melanoma *Includes 4 patients with UM without a response

  18. Conclusions • PD-1/PD-L1 blocking immunotherapy agents are the most promising new agents in clinical development for the treatment of cancer • PD-1 blockade works by: • Expanding an intratumoral infiltrate by effector T cells • The full potential of PD-1/PD-L1 blocking antibodies is only starting to be realized: • Range of indications • Improved patient selection • Combination therapies

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