Shanghai, China

March 24th 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®

Intestine Liver

Xeloda

5'-DFCR

5'-DFUR

CyD

5'-DFCR

5'-DFUR

5-FU

TumourXeloda

Thymidinephosphorylase (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)0 100 200 300 400 500

115115291351309309

8131718142324371311363525271620

Colorectal

Gastric

Breast

Cervix

Uterus

Ovarian

Renal

Bladder

Thyroid

Liver

Liver (metastasis)

(n =)

Healthy tissue

Tumour tissue

*

*

*

*

*

*

*

*

*

*p<0.05 Miwa M et al. Eur J Cancer 1998;34:1274–81

*

TP upregulation in tumour xenografts

0 5 10 15 20

(mg/kg)Control

Paclitaxel 100Docetaxel 15

Vincristine 1.5Vinblastine 3

Vindesine 5Mitomycin C 5Doxorubicin 7.5

Cisplatin 10

ControlMethotrexate 50

Cyclophosphamide 200

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 - SO14797Ph. III CRC US - SO14695

Ph. III CRC EU - SO14796

Ph. I Paclitaxel Combo

Ph. I Docetaxel ComboPh. 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/m2 weekly 6 weeks out of 7 with Xeloda 1000

mg/m2 twice daily days 1-14 and 22-35 every 7 weeks Xeloda / irinotecan phase II

– irinotecan 240 mg/m2, day 1 (every three weeks)

or

120 mg/m2 days 1 and 8 every three weeks

with Xeloda 1000 mg/m2 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/m2 day 1 every three weeks +

Xeloda 1000 mg/m2 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/m2 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 PortfolioRoche Oncology Portfolio

• TumorActivated Xeloda Colorectal, Breast Cytotoxic Cancer

• Monoclonal antibodies Herceptin Breast Cancer MabThera Lymphoma

• Novel Mechanism CCI Solid tumors (phase I)

OSI 774

• Interferons Roferon-A Melanoma, NHL, CML

Pegasys RCC, CML (phase I)

• Cell Differentiation Vesanoid APL

• Supportive Care Neupogen Neutropenia, PBSC

NeoRecormon Platinum-induced anemia, myeloma, lymphoma, H/N

Ostac Hypercalcemia, osteolysis

BondronatHypercalcemia, breast

Roche Oncology PortfolioRoche Oncology Portfolio

Roche Oncology Portfolio - VisionRoche 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