10 th EADO Congress Vilnius, 7-10 May Ipilimumab update. Michele Maio

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1 10 th EADO Congress Vilnius, 7-10 May 2014 Ipilimumab update Michele Maio Medical Oncology and Immunotherapy, Department of Oncology University Hospital of Siena, Istituto Toscano Tumori SIENA, ITALY

2 Evolving Therapeutic Options for Cancer Treatment Surgery Chemotherapy Radiotherapy

3 Evolving Therapeutic Options for Cancer Treatment Surgery Chemotherapy Radiotherapy Immunotherapy

4 Science, 2013 Science 2013

5 D E C E M B E R VO L N AT U R E T-cell costimulatory receptors

6 Melanoma as a tool for cancer Tissue samples readily accessible Adaptable to tissue culture Amenable to testing of novel therapies research

7 Immunotherapy in solid tumors with immunomodulating antibodies Brain Mesothelioma Lung cancer (NSCLC, SCLC) Melanoma Breast cancer Renal cancer Gastroesophageal cancer Prostate cancer Bladder cancer Pancreatic cancer Colorectal cancer

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9 Chemotherapy/Targeted Agents and Immuno-therapy Differ in Action and Outcome Response Chemotherapy and Targeted Therapies IMMUNOTHERAPY Time (months) Maio M. et al, unpublished

10 Overall survival rates EAP 10 mgs Time 1-year 2-year 3-year 4-year OS * SE% (9.6) (8.4) (8.0) (8.0) *Di Giacomo AM, et al. Cancer Immunol. Immunother. 2013

11 Survival Analysis with 5 Years of Follow-up in a Phase III Study of Ipilimumab and Dacarbazine in Metastatic Melanoma Michele Maio, 1 Igor Bondarenko, 2 Caroline Robert, 3 Luc Thomas, 4 Claus Garbe, 5 AlessandroTestori, 6 Haolan Lu, 7 Kevin Chin, 7 Jedd D. Wolchok 8 1 University Hospital of Siena, Siena, Italy; 2 Dnepropetrovsk State Medical Academy, Dnepropetrovsk, Ukraine; 3 Institute Gustave Roussy, Villejuif, France; 4 Lyon 1 University, Centre Hospitalier Lyon Sud Pierre Bénite France; 5 University Medical Center, Tuebingen, Germany; 6 Istituto Europeo di Oncologia, Milan, Italy; 7 Bristol-Myers Squibb, Wallingford, CT, USA; 8 Memorial Sloan-Kettering Cancer Center, New York, NY, USA Abstract Number 3704

12 Kaplan-Meier Plot of Overall Survival Proportion Alive Patients at Risk DTIC + Ipi DTIC + Placebo Months DTIC + 10 mg/kg Ipi Censored DTIC + Placebo Censored CONFIDENTIAL. Not for further distribution. Maio M, ESMO 2013

13 Pooled Analysis of Long-term Survival Data From Phase II and Phase III Trials of Ipilimumab in Metastatic or Locally Advanced, Unresectable Melanoma Schadendorf D, 1 Hodi FS, 2 Robert C, 3 Weber JS, 4 Margolin K, 5 Hamid O, 6 Chen TT, 7 Berman DM, 8 Wolchok JD 9 1 University Hospital Essen, Essen, Germany; 2 Dana-Farber Cancer Institute, Boston, MA, USA; 3 Institute Gustave Roussy, Villejuif, France; 4 Moffitt Cancer Center, Tampa, FL, USA; 5 University of Washington, Seattle, WA, USA; 6 The Angeles Clinic and Research Institute, Los Angeles, CA, USA; 7 Bristol-Myers Squibb, Wallingford, CT, USA; 8 Bristol-Myers Squibb, Lawrenceville, NJ, USA; 9 Memorial Sloan-Kettering Cancer Center, New York, NY, USA. Abstract Number 24LBA

14 Studies Included in OS Analyses* Study ID Phase N Population Dose Retreatment or Maintenance MDX Previously treated 3 mg/kg ± gp100 Retreatment CA Treatment-naive 10 mg/kg + DTIC Maintenance CA Previously treated 0.3, 3, 10 mg/kg Maintenance CA Previously treated 10 mg/kg Maintenance CA CA CA Treatment-naive or previously treated Treatment-naive or previously treated Melanoma with brain metastases NCI04C0083 1/2 88 Previously treated NCI02C0106 1/2 56 Previously treated NCI03C0109 1/2 36 Previously treated 10 mg/kg ± budesonide Maintenance 3, 10 mg/kg Maintenance 10 mg/kg Maintenance 3, 5, 9 mg/kg ± gp100 3 mg/kg + gp mg/kg + gp , 0.3, 1, 2, 3 mg/kg + IL-2 Not included Not included Not included CA Observational 160 Treatment-naive 3 mg/kg No (induction only) CA Observational 90 Treatment-naive 3 mg/kg No (induction only) Expanded Access CA ** 2985 Previously treated 3, 10 mg/kg Maintenance for 10 mg/kg Program (EAP) *Total of 1861 patients for primary analysis; N=4846 patients including EAP. **US EAP treatment protocol. Hodi S, ESMO 2013

15 Primary Analysis of Pooled OS Data: 1861 Patients Median OS, months (95% CI): 11.4 ( ) Proportion Alive year OS rate, % (95% CI): 22 (20 24) Ipilimumab CENSORED Patients at Risk Months Ipilimumab Hodi S, ESMO 2013

16 Pooled OS Analysis Including EAP Data: 4846 Patients 1.0 Proportion Alive Median OS, months (95% CI): 9.5 ( ) 3-year OS rate, % (95% CI): 21 (20 22) Ipilimumab CENSORED Months Patients at Risk Ipilimumab Hodi S, ESMO 2013

17 The European Ipilimumab Expanded Access Programme: Efficacy and Safety Data from the Italian Cohort of Patients with Pretreated Advanced Melanoma Maio et al. European Ipilimumab EAP, Italian Cohort of Patients.

18 OS for BRAF-mutation Positive (n=173) and BRAF Wild-Type (n=296) Patients AScierto PA et al, Cancer Invest. 2014

19 Elderly Patients (>70 years): OS Chiarion-Sileni V et al, J Exp Clin Cancer Res. 2014

20 Survival analysis in MM pts treated with IPI 10mg according to the circulating CD4+ICOS+ (w7) median OS = 118 wks log-rank test, p = median OS = 27 wks Di Giacomo AM, et al. Cancer Immunol. Immunother CD4+ICOS+ > 4 fold increase CD4+ICOS+ 4 fold increase

21 Can melanoma continue to serve as a model tumour for immunotherapy? To investigate Adjuvant treatment Might immunotherapies be more effective if used when disease burden is lower and the immune system less compromised by the tumour? Combination/Sequencing therapies Biomarker development (surrogate/predictive) 21

22 Therapeutic combinations Chemotherapy Surgery Immunotherapy Radiotherapy Target Melero I. et al Nat rev cancer (2007) modified