1. SCH 717454 in Subjects with Relapsed Osteosarcoma or Ewing’s Sarcoma Protocol P04720 CTOS Nov 2008

2. 2 Disclosure Neither I, nor my colleagues have any stock nor have we been paid consultants of Schering-Plough Investigators have received research funds for this study (P04720).

3. 3 Insulin Growth Factor Pathway IGF-II/IGF-I IGF-1R P P P ERK1/2 AKT

4. 4 SCH 717454: A Potent & Specific anti-IGF-1R Monoclonal Antibody High Affinity Fully Human IgG1 clone 19D12 Does Not Recognize Insulin Receptor Properties and Activities That May Contribute To Antitumor Effects: Inhibits IGF ligand binding and IGF-1R signaling Downregulation of IGF-1R protein level Antibody-dependent cellular cytotoxicity Enhances other agents in pre-clinical studies IGF-1RIGF-1R/ IR dimer Insulin Receptor (IR)

5. 5 SCH717454 & Osteosarcoma Xenografts Inhibits osteosarcoma, Ewing’s sarcoma & neuroblastoma xenografts Pediatric preclinical testing program: complete responses in 2 out of 6 osteosarcoma (OS1, OS9) & 1 Ewing’s sarcoma cell line (EW5). Improved Event Free survival in 4/6 osteosarcoma and 2/5 Ewing’s models. Kolb, Gorlick et al. 2008 SCH 717454 Inhibits SJSA-1 Growth in vivo Staged model, 2 x weekly SCH 717454 Causes Regression of OS-1 in vivo (PPTP / NCI) 1234560 4.0 3.0 2.0 1.0 0.0 Treatment Control Relative Tumor Volume Time (weeks) Staged model, starting tumor volume: 250 mm 3, 0.5 mg SCH 717454, 2 x weekly

6. 6 Endpoints  Primary: Response  Secondary: TTP, Safety, PK, PD Recurrent/refractory Osteosarcoma or Ewing’s Sarcoma (N  25-50 each) Recurrent/refractory Osteosarcoma or Ewing’s Sarcoma (N  25-50 each) SCH 717454 10 mg/kg Q 2 weeks SCH 717454 10 mg/kg Q 2 weeks Refractory Osteosarcoma or Ewing’s Sarcoma Cohorts

7. 7 Key Inclusion/Exclusion Criteria Key Inclusions –≥11 years of age –Osteosarcoma or Ewing’s sarcoma Key Exclusions –Diabetics: hemoglobin A1C >7.5% – Heart disease, hepatitis or active infection – Prior anti-IGF-1R drug

8. 8 Serum IGF-1 Concentrations During Treatment 0 100 200 300 400 500 600 700 Baseline2 wks after Single Dose (Trough Level) Subsequent Doses (at Trough) IGF-1 blood level (ng/ml)

9. 9 IGF-1R Occupancy On Peripheral Blood Mononuclear Cells 0 10 20 30 40 50 60 BaselineTwo Weeks Post-Dose (Obtained at Trough) % of IGF-1R un-occupied Flow cytometry assay measuring the percent of cells that bind labeled SCH 717454 at baseline (blue) versus 2 weeks post single dose of SCH 717454 (purple)

10. 10 Preliminary Response Data Osteosarcoma: stable disease in >5* (1 stable to >6 months; another ongoing response with both lung and bone metastases) Ewings: 3 PRs; some of subjects with mixed responses *Initial data on subject at 8 weeks on study

11. 11 Preliminary Ewing’s Response BeforeAfter Single Dose 11 year old female with recurrent/refractory Ewing’s Sarcoma s/p 3 prior therapies

12. 12 Responding Ewing’s Sarcoma BeforeAfter (8 weeks) 29 year old male with recurrent/refractory Ewing’s Sarcoma s/p 3 prior therapies

13. 13 Near Complete Response in Ewing’s Beforeat 8 week assessment 28 year old male with recurrent/refractory Ewing’s Sarcoma s/p 2 prior therapies

14. 14 Most Common Adverse Events Adverse Event Incidence Grade 1Grade 2Grade 3Grade 4 Headache5 (8%)1 (2%)00 Fatigue1 (2%)3 (5%)00 Hyperglycemia3 (5%)01 (2%)0 Pruritus3 (5%)1 (2%)00 Nausea3 (5%)1 (2%)00 Back Pain003 (5%)0 Constipation1 (2%) 0 Dyspnoea1 (2%) 0 Pneumothorax2 (3%)01 (2%)0

15. 15 Safety/Tolerability Summary Well tolerated –Most AEs mild or moderate Hyperglycemia –Generally mild if present –Only 1 moderate/severe event in an adult diabetic –No severe or life-threatening drug-related AEs

16. 16 P04720: Group 1 Recurrence TTP Resectable Disease Resectable Disease SCH 717454 Dose Level 1 SCH 717454 Dose Level 1 Prior Surgery Recurrence Surgery SCH 717454 Dose Level 2 SCH 717454 Dose Level 2 Tumor Proliferation TTP SCH 717454 Dose Level 1 SCH 717454 Dose Level 1 SCH 717454 Dose Level 2 SCH 717454 Dose Level 2  Primary Endpoint: tumor proliferation  Secondary Endpoint: TTP/Time to relapse

17. 17 Summary Potent in preclinical models Clinically well-tolerated –Hyperglycemia uncommon, mostly mild Clinically active in Ewing’s sarcoma Stable disease in Osteosarcoma Enrollment continuing- North America, Europe, and South America

18. 18 Acknowledgements Contributing Investigators –Drs. Anderson, Skubitz, Miller, Meyer, Arico, Mita, Chawla, Katzenstein, O’Day, Desai, Villarroel, Lopez, Van de Graaf, Mas, Sandoval, Marec-Berard, Jean- Gentet, Bielack, and Klingelbiel Schering Plough Personnel –Drs. Lu, and Wang; Ms. Whitman All the patients and their families ? Questions?