1. A Randomized, Double-blind, Placebo-controlled Phase III Study in Patients with Metastatic Colorectal Cancer Receiving First-line Chemotherapy with FOLFOX 4 and PTK/ZK or Placebo (CONFIRM-1) J R Hecht, T Trarbach, E Jaeger, J Hainsworth, R Wolff, K Lloyd, G Bodoky, M Borner, D Laurent, C Jacques

2. PTK/ZK: An Oral Multi-VEGF Receptor Inhibitor Potent inhibitor of all known VEGF receptors Also inhibits PDGFR and c-Kit Half life of 3 to 6 hours Oral once-daily dosing Fit of PTK/ZK (green) into the ATP binding site

3. 3 VEGF-A VEGF-C VEGF-D VEGF-A VEGF-B PlGF VEGF-C VEGF-D VEGFR-1/Flt-1VEGFR-2/KDRVEGFR-3/Flt-4 PTK/ZK Extracellular Intracellular Angiogenesis Lymphangiogenesis Tumor metastasis PTK/ZK Inhibits All Known Receptors of VEGF Endothelial Cell PTK/ZK

4. 4 Proof of Concept in mCRC Baseline Day 2 PTK/ZK Morgan B, et al. J Clin Oncol. 2003;21: 3955-3964 Steward W, et al. ASCO 2004 Baseline Tumor vascularity and permeability decreased rapidly with PTK/ZK and correlated with clinical benefit Subsequent PTK/ZK-FOLFOX combination showed promising activity

5. 5 1168 Patients Stratification Factors: PS: 0, 1-2 LDH: ≤, > 1.5 x ULN FOLFOX 4 + PTK/ZK 1250 mg po qd CONFIRM-1 Trial Design FOLFOX 4 + Placebo Multinational randomized phase III trial in previously untreated mCRC RANDOMIZEDRANDOMIZED

6. 6 Main Eligibility Criteria Metastatic colorectal cancer patients No prior chemotherapy for metastatic disease Prior adjuvant chemotherapy allowed (> 6 mo) Measurable disease per RECIST criteria WHO PS 0-2 Adequate hematological and organ function No exclusions for prior coagulopathy or bleeding

7. 7 Primary Study Objectives Progression-free survival  Independent central radiological review  Primary analysis  Investigator assessment  Statistical hypothesis  25% reduction in risk of progression (HR 0.75) Overall survival  Statistical hypothesis  One-year OS rate from 71% to 76% (HR 0.80)

8. 8 Patient Characteristics Characteristics FOLFOX 4 + PTK/ZK N=585 FOLFOX 4 + Placebo N=583 Median Age (yrs)5961 Male / Female (%)63 / 3760 / 40 WHO PS 0 / 1 / 2 (%)55 / 41 / 454 / 40 / 6 Colon / Rectum (%)71 / 2668 / 30 Liver Metastasis (%)8074 Lung Metastasis (%)2631 Number of Organs Involved (%) 14643 23334 > 31922 Median LDH at Baseline0.95 x ULN Prior Adjuvant Chemotherapy (%)2628

9. 9 Patient Disposition FOLFOX 4 + PTK/ZK N= 585 (%) FOLFOX 4 + Placebo N=583 (%) Patients ongoing2532 Patients discontinued due to: Progressive disease3342 Adverse event2111 Withdrawal of consent127 Other reasons9 8 1168 patients were randomized between February 2003 and May 2004

10. 10 Safety

11. 11 Grade 3/4 NCI Adverse Events in >5% of Patients Adverse Events FOLFOX 4 + PTK/ZK N=579 (%) FOLFOX 4 + Placebo N=574 (%) Grade 3Grade 4Grade 3Grade 4 Neutropenia17142111 Thrombocytopenia6<14 Diarrhea15<110<1 Nausea9N/A5 Vomiting7<16 Abdominal pain4<15 Peripheral neuropathy9<17

12. 12 Grade 3/4 NCI Adverse Events in >5% of Patients Adverse Events FOLFOX 4 + PTK/ZK N=579 (%) FOLFOX 4 + Placebo N=574 (%) Grade 3Grade 4Grade 3Grade 4 Hypertension21<16 Dizziness7<120 Venous thrombosis7<14 Pulmonary embolismN/A6 1

13. 13 Other Clinically Important Adverse Events Adverse Events FOLFOX 4 + PTK/ZK N=579 (%) FOLFOX 4 + Placebo N=574 (%) Bleeding (gr 3-4)2.92.8 Arterial thrombosis (gr 3-4)1.91.4 Bowel perforation0.20.7 Reversible posterior encephalopathy 0.50 Deaths of any cause within 28 days of last study drug administration 5 6

14. 14 Efficacy

15. 15 Response Rate FOLFOX 4 + PTK/ZK N=585 (%) FOLFOX 4 + Placebo N=583 (%) P-value CR33N.S. PR3943N.S. SD3733N.S. PD1615N.S. UNK66N.S.

16. 16 Progression-Free Survival: Central Assessment (Primary Analysis)* HR 0.88 (95% CI) (0.74, 1.03) P-value 0.118 PTK/ZK + FOLFOX4 Placebo + FOLFOX4 *If assessment is delayed or missed, date of PD is adjusted to previous planned assessment date

17. 17 Progression-Free Survival: Investigator Assessment HR 0.82 (95% CI) (0.69, 0.97) P-value 0.019

18. 18 PFS: Hazard Ratio 0.80.60.41.61.41.2 Overall 1.0 0.118 1.8 HR P-value In favor of PTK/ZK In favor of placebo 0.88 Central

19. 19 PFS: Hazard Ratio 0.80.60.41.61.41.2 Overall 1.0 0.118 0.026 1.8 HR P-value In favor of PTK/ZK In favor of placebo 0.88 0.83 Central Investigator

20. 20 High LDH, PS 1-2 PFS by Pre-Planned Stratum: Hazard Ratio 0.80.60.41.61.41.2 Low LDH, PS 0 Overall Population 1.0 High LDH, PS 0 Low LDH, PS 1-2 1.8 In favor of PTK/ZK In favor of placebo Central Investigator 0.118 0.026 HR P-value 0.88 0.83

21. 21 Progression-Free Survival: Exploratory Analysis in Patients with High LDH (n=316) Central AssessmentInvestigator Assessment PTK/ZK + FOLFOX4 Placebo + FOLFOX4 PTK/ZK + FOLFOX4 Placebo + FOLFOX4 HR 0.68 (95% CI) (0.50, 0.92) P-value 0.012 HR 0.60 (95% CI) (0.44, 0.82) P-value 0.001

22. 22 Future Directions CONFIRM 1 overall survival data expected second half 2006 CONFIRM 2 final results expected 2006  FOLFOX +/- PTK/ZK in second-line CRC Optimize dosing schedule to reduce early treatment discontinuation and improve efficacy Explore the biology and clinical relevance of predictive factors such as LDH in CRC

23. 23 Conclusions PFS based on central review showed a modest benefit of adding PTK/ZK to FOLFOX which did not reach statistical significance Preplanned secondary analysis of PFS based on investigator assessment showed a statistically significant improvement favoring PTK/ZK PTK/ZK in combination with FOLFOX is generally well tolerated High LDH levels may predict which patients are most likely to benefit from PTK/ZK

24. 24 Acknowledgments UCLA/TORI  Dennis Slamon  Nancy Ryba  David Reese  David Chan, Ravi Patel  NCCRA  Mike and Michele Richman University of Essen Krankenhaus Nordwest, Frankfurt Sarah Cannon Cancer Center MD Anderson Cancer Center Virginia Cancer Institute Szent Laszlo Hospital, Budapest Institute for Medical Oncology, Bern The Patients and Their Families The Investigators in Over 200 Medical Centers Worldwide Novartis  David Lebwohl  Andrea Kay  Bee-Lian Chen  Andrew Henry  Eric Masson Schering AG Germany  Andrea Wagner  Christine Gonschorek  Michael Kretschmann  Martina Poethig  Silke Zaun