Shanghai, China March 24 th 2001 Xeloda Future Developments Mr. John Collins

 Metastatic breast cancer –monotherapy (taxane + anthracycline failure) first approved April 1998 in the USA now approved in >50 countries –Xeloda/Taxotere combination USA supplementary New Drug Application filed March 2001 European filing April/May 2001 (with monotherapy) Xeloda Registration Update

 First-line, monotherapy of metastatic colorectal cancer (CRC) Xeloda is now approved in 30 countries for CRC Hong Kong, Canada, Australia, Switzerland, Russia and Latin Americas European Union Countries USA: –Xeloda received a letter of approvability from the US FDA on 20 September 2000 Xeloda Registration Update

Enzymatic activation of Xeloda ® IntestineLiver Xeloda 5'-DFCR 5'-DFUR CyD 5'-DFCR 5'-DFUR 5-FU Tumour Xeloda Thymidine phosphorylase (TP) CyD CE 5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine; CyD = cytidine deaminase; CE = carboxylesterase

Thymidine phosphorylase (TP) activity in human tissues TP activity (µg 5-FU/mg protein/hour) Colorectal Gastric Breast Cervix Uterus Ovarian Renal Bladder Thyroid Liver Liver (metastasis) (n =) Healthy tissue Tumour tissue * * * * * * * * * *p<0.05Miwa M et al. Eur J Cancer 1998;34:1274–81 *

TP upregulation in tumour xenografts (mg/kg) Control Paclitaxel100 Docetaxel15 Vincristine1.5 Vinblastine3 Vindesine5 Mitomycin C5 Doxorubicin7.5 Cisplatin10 Control Methotrexate50 Cyclophosphamide200 TP activity (unit/mg protein) Gemcitabine and vinorelbine also upregulate TP Ishitsuka H. Invest New Drugs 2000;18:343–54

Xeloda Development Program Ph. II Taxane Failure NO15542 Ph. II Paclitaxel Failure Trial SO14697 Ph. II Breast Cancer, > 55 years: SO15179 Ph. II Anthracycline Failures SO14799 Ph. II CRC - SO14797 Ph. III CRC US - SO14695 Ph. III CRC EU - SO14796 Ph. I Paclitaxel Combo Ph. I Docetaxel Combo Ph. III BC Taxotere Combo Ph. 1 EU/US New Drug Application (NDA) 10/97 NDA 9/99 NDA 3/01

Xeloda Colorectal Cancer Monotherapy: Summary  Superior antitumor activity (26 % vs 17 %)  Equivalent time to progression (median 4.6 vs 4.7m)  Equivalent survival (median 12.9 vs 12.8 m)  Significantly less stomatitis/mucositis, diarrhea, nausea, alopecia and neutropenia leading to significantly less neutropenic fever/sepsis  Significantly fewer treatment-related hospitalizations  More convenient than cumbersome IV therapy

 Adjuvant monotherapy X-ACT phase III trial –Xeloda vs intravenous bolus 5-FU/LV –1956 patients –Dukes C colon cancer –Primary study endpoint disease free survival  Combination therapy –Xeloda / irinotecan phase II/III –Xeloda / oxaliplatin phase II –Xeloda / radiotherapy phase II/III Future Development for Xeloda in Colorectal Cancer

Xeloda/ Irinotecan Combination  Xeloda / irinotecan phase I/II –irinotecan 70 mg/m 2 weekly 6 weeks out of 7 with Xeloda 1000 mg/m 2 twice daily days 1-14 and every 7 weeks  Xeloda / irinotecan phase II –irinotecan 240 mg/m 2, day 1 (every three weeks) or 120 mg/m 2 days 1 and 8 every three weeks with Xeloda 1000 mg/m 2 twice daily days 1-14 with one week rest period –very promising anti-tumor activity –principal toxicities were diarrhea and neutropenia –trial is ongoing –ASCO 2001

Xeloda/Oxaliplatin and Xeloda/Radiotherapy Xeloda / oxaliplatin phase II –oxaliplatin 130 mg/m 2 day 1 every three weeks + Xeloda 1000 mg/m 2 twice daily days 1-14 with one week rest period –96 patients –trial has completed recruitment Xeloda / radiotherapy –RT 50.5 grays, 6 weeks (1.8 Gy fractions) + Xeloda (continuous) recommended dose 825 mg/m 2 twice daily first to last day of radiotherapy –excellent tolerability at recommended dose level –tumor downstaging and induction of pCR

Xeloda in Breast Cancer: summary  Excellent response rates (20%) and median overall survival (>12 months)  Patients with stable disease (43%) have similar survival to responders  Palliative properties  Favorable safety profile  Patients prefer oral therapy  Xeloda/ Taxotere first and only combination to show superior survival compared to a standard monotherapy in anthracycline failures

 Monotherapy –Xeloda vs vinorelbine post-taxanes –Xeloda intermitt vs Xeloda cont vs CMF first line –Xeloda vs ET combo vs ET sequ. first line  Combination –EORTC phase III Xeloda + epirubicin (E) + cyclophosphamide (C) vs EC –phase II - 3 weekly docetaxel + Xeloda –phase II - weekly docetaxel + Xeloda  Adjuvant –phase III doxorubicin + cyclophosphamide followed by docetaxel vs Xeloda / docetaxel Future Development for Xeloda in Breast Cancer

Xeloda All Oral Combination  Xeloda potential combinations with other oral agents –Colorectal Cancer oral irinotecan OSI 774 (tyrosine kinase inhibitor) Breast Cancer oral cyclophosphamide oral vinorelbine idarubicine oral taxanes

. Target tumors include –pancreatic –stomach –esophageal –head and neck –renal cell –cervical –hepatic/biliary tract Future Developments for Xeloda - Other Indications

Roche Oncology Portfolio TumorActivatedXelodaColorectal, Breast Cytotoxic Cancer Monoclonal antibodiesHerceptin Breast Cancer MabThera Lymphoma Novel Mechanism CCISolid tumors (phase I) OSI 774 InterferonsRoferon-A Melanoma, NHL, CML PegasysRCC, CML (phase I)

Cell DifferentiationVesanoid APL Supportive Care Neupogen Neutropenia, PBSC NeoRecormon Platinum-induced anemia, myeloma, lymphoma, H/N Ostac Hypercalcemia, osteolysis Bondronat Hypercalcemia, breast Roche Oncology Portfolio

Roche Oncology Portfolio - Vision  Continue to research novel agents –specifically targeting cancer cells, –increasing efficacy and safety –focusing on outpatient therapy  Patient stratification and selection through diagnostics research with your continued support and expertise for clinical development