Click here to view presentations

Xeloda ® in the spotlight: oral, tumour- activated chemotherapy Colorectal cancer A discussion of sequential versus combination therapyDavid Cunningham (UK) Review of Xeloda ® in combination with oxaliplatin, irinotecan or radiotherapyDavid Kerr (UK) Xeloda ® in oesophagogastric cancerDavid Cunningham (UK) Breast Cancer Xeloda ® in combination with Taxotere or as monotherapyJoyce O’Shaughnessy (USA) Xeloda ® combinations in metastatic breast cancer and Xeloda ® in adjuvant trials David Cameron (UK) Use the navigation keys to browse the slides

A discussion of sequential versus combination therapy David Cunningham Head of Gastrointestinal Unit The Royal Marsden Hospital London and Surrey, UK

First-line therapy for colorectal cancer (CRC): what we know  50% of patients still receive fluoropyrimidine monotherapy first line –oral or i.v. 1  In terms of efficacy –infused 5-FU/LV plus irinotecan (FOLFIRI regimen) is similar to FOLFOX 2  In terms of both efficacy and safety –FOLFOX is better than bolus 5-FU/LV plus irinotecan (IFL-Saltz regimen) 3 –Xeloda is better than i.v. 5-FU/LV 4 1 ISIS market research, October Achille E et al. Eur J Cancer 2001;37(Suppl. 6):289 (Abst 1067) 3 Goldberg R et al. Proc Am Soc Clin Oncol 2002;21:128a (Abst 511) 4 Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20

When we use first-line monotherapy...  The decision is based on –data? –patient characteristics –disease characteristics –physician/patient preference –funding/reimbursement issues... should it be Xeloda?

Significantly superior tumour response rate with Xeloda ® Confirmed by Independent Review Committee (p=0.0001)  Equivalent progression-free and overall survival Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20

Improved safety profile with Xeloda ® Xeloda (n=596) 5-FU/LV (n=593) Patients (%) Hand-footStomatitisDiarrhoeaVomitingNeutro-Neutropenic syndromepeniafever + sepsis * * * *p< * Grade 3/4 treatment-related adverse events Cassidy J et al. Ann Oncol 2002;13:566–75

Oral Xeloda ® : a convenient, patient-oriented therapy  The majority of cancer patients prefer oral chemotherapy, as long as efficacy is not sacrificed 1,2  QoL is significantly (p=0.001) improved in patients receiving chemotherapy at home versus in hospital 3  Oral Xeloda provides convenient, patient- oriented therapy 1 Liu G et al. J Clin Oncol 1997;15:110–15 2 Borner MM et al. Eur J Cancer 2002;38:349–58 3 Payne SA. Soc Sci Med 1992;35:1505–9

A rational choice: Xeloda ® as first-line monotherapy for CRC  When a sequential approach is used, Xeloda should be the first-line therapy of choice based on –the superior antitumour activity of oral Xeloda versus i.v. 5-FU/LV observed in two randomised, phase III trials 1 –its improved safety profile 2 –patients’ preference for oral therapy over i.v. therapy, as long as efficacy is not sacrificed 3 1 Twelves C. Eur J Cancer 2002;38(Suppl. 2):S15–S20 2 Cassidy J et al. Ann Oncol 2002;13:566–75 3 Liu G et al. J Clin Oncol 1997;15:110–15

When we use first-line combination...  The decision is based on –data? –patient characteristics –disease characteristics –physician preference –patient preference... should Xeloda be the preferred fluoropyrimidine partner?

Irinotecan and oxaliplatin improve outcomes in metastatic CRC  Irinotecan improves survival –in first line (with 5-FU/LV) 1,2 –in second line (as monotherapy) 3,4  Addition of oxaliplatin to 5-FU/LV –improves response rate and TTP in first line 5,6 –is effective in 5-FU-resistant disease 7 1 Douillard JY et al. Lancet 2000; 2 Saltz LB et al. N Engl J Med 2000; 3 Rougier P et al. Lancet 1998; 4 Cunningham D et al. Lancet 1998; 5 de Gramont A et al. J Clin Oncol 2000; 6 Giacchetti S et al. J Clin Oncol 2000; 7 André T et al. Ann Oncol 1999

FOLFIRI has similar efficacy to FOLFOX Achille E et al. Eur J Cancer 2001;37(Suppl. 6):289 (Abst 1067) *First-line therapy

TTP is similar with FOLFIRI and FOLFOX regimens Months Probability Log-rank p=0.21 Median (months) FOLFIRI8.5 FOLFOX 8.1 Achille E et al. Eur J Cancer 2001;37(Suppl. 6):289 (Abst 1067)

FOLFOX and FOLFIRI have distinct safety profiles Achille E et al. Eur J Cancer 2001;37(Suppl. 6):289 (Abst 1067) *Specific modified Levy scale NS = not significant

FOLFOX is better than the IFL-Saltz regimen Goldberg R et al. Proc Am Soc Clin Oncol 2002;21:128a (Abst 511)

In combination therapy: protracted infusion 5-FU is better than bolus 5-FU  Protracted infusion regimens appear to be safer and more effective –with irinotecan 1,2 –with oxaliplatin 3 1 Douillard JY et al. Lancet 2000;355:1041–7 2 Saltz LB et al. N Engl J Med 2000;343:905–14 3 Morton RF et al. Proc Am Soc Clin Oncol 2001;20 (Abst 495)

BUT: protracted infusion of 5-FU is inconvenient  Tumour-activated Xeloda was rationally designed to mimic continuous infusion 5-FU  New data on Xeloda in combination is coming up next should Xeloda be the preferred fluoropyrimidine partner in first-line combination therapy?

Review of Xeloda ® in combination with oxaliplatin, irinotecan or radiotherapy David Kerr Rhodes Professor of Therapeutic Sciences and Clinical Pharmacology University of Oxford, Oxford, UK

How can Xeloda ® replace 5-FU in colorectal cancer (CRC) therapy?  Trial results show that oral Xeloda has the potential to replace i.v. 5-FU as a convenient and highly effective combination partner for –oxaliplatin –irinotecan –radiotherapy

Xeloda ® plus oxaliplatin (XELOX): highly active, first-line combination therapy for metastatic CRC

XELOX trial in first-line metastatic CRC  Large, international, phase II trial (n=96): first-line therapy for metastatic CRC 1  Regimen recommended from phase I trial 2 1 Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531) 2 Díaz-Rubio E et al. Ann Oncol 2002;13:558– Oxaliplatin 130mg/m 2 (2-hour infusion) Oral Xeloda 1,000mg/m 2 twice daily Days 1–14Rest Repeat cycle at day 22 Day

Impressive response rate with XELOX Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)  Response rate was consistently >50% in all patient subgroups: prior adjuvant chemotherapy, liver or lung metastases, KPS  80 or age  or <60 years  Stable disease was prolonged (lasting >3 months) in all patients achieving this outcome (n=31) *WHO criteria

Long treatment duration with XELOX  Total number of treatment cycles administered –median = 10 cycles –range = 1–23  This includes –median of 8 cycles (range 1–16) with combination –median of 2 cycles (range 1–7) of Xeloda monotherapy, in 30 patients (31%) who continued to receive Xeloda monotherapy after discontinuing oxaliplatin Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

XELOX achieves median progression- free survival (PFS) of 7.6 months (n=96) Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531) Median:7.6 months (95% CI: 6.4–8.6) 20 months after study start (12 months after last inclusion):  13 patients (14%) progression free  3 patients remain on treatment Estimated probability Time (months)

XELOX achieves median overall survival of >16 months (n=96) 20 months after study start (12 months after last inclusion):  1-year survival = 72%  57 patients (59%) are still alive Estimated probability Time (months) Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

XELOX: favourable safety profile compared with FOLFOX4 1 de Gramont A et al. J Clin Oncol 2000;18:2938–47 2 Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

XELOX with Xeloda 1,000mg/m 2 twice daily offers the best therapeutic profile  Phase II trials evaluated different Xeloda doses: oxaliplatin 130mg/m 2 every 3 weeks plus –Xeloda 1,250mg/m 2 twice daily days 1–14 1 disadvantage: high incidence of grade 3/4 diarrhoea (33–50% of patients) –Xeloda 750mg/m 2 twice daily days 1–14 2 disadvantage: lower response rates (34–38%)  Offering both high efficacy and favourable safety, XELOX with Xeloda 1,000mg/m 2 twice daily is the preferred regimen 3 and is moving into phase III 1 Borner MM et al. J Clin Oncol 2002;20:1759–66 2 Shields AF et al. Proc Am Soc Clin Oncol 2002;21:143a (Abst 568) 3 Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)

Xeloda ® plus irinotecan: under intensive investigation in metastatic CRC

Xeloda ® plus 3-weekly irinotecan: an active and convenient regimen Day Irinotecan 250mg/m 2 as a 30-minute i.v. infusion Oral Xeloda 1,000mg/m 2 twice daily Days 1–14Rest Repeat cycle at day 22 Kerr DJ et al. Proc Am Soc Clin Oncol 2002;21:161a (Abst 643)

Xeloda ® plus 3-weekly irinotecan: identification of recommended dose *Twice daily dose of Xeloda † Two patients did not receive appropriate loperamide treatment Kerr DJ et al. Proc Am Soc Clin Oncol 2002;21:161a (Abst 643)

Xeloda ® plus 3-weekly irinotecan: promising antitumour activity Kerr DJ et al. Proc Am Soc Clin Oncol 2002;21:161a (Abst 643)

Xeloda ® plus 3-weekly irinotecan: French trial confirms results of UK/NL study  No PK interaction between Xeloda and irinotecan Delord JP et al. Proc Am Soc Clin Oncol 2002;21:100a (Abst 397) *Twice daily dose of Xeloda

Planned randomised, phase III trial in metastatic CRC (EORTC 40015)  2 x 2 factorial design (target n=692) Placebo twice daily Celecoxib 400mg/m 2 twice daily Xeloda 1,000mg/m 2 twice daily, days 1–14 + irinotecan 250mg/m 2 day 1, q21 Biweekly infused 5-FU/LV (de Gramont) + irinotecan 180mg/m 2 day 1, q14 RANDOMISATIONRANDOMISATION RANDOMISATIONRANDOMISATION +

QUASAR 2: phase III adjuvant trial in stage II/III CRC Xeloda 1,000mg/m 2 twice daily, days 1–14 + irinotecan 250mg/m 2 day 1, q21 3 months RANDOMISATIONRANDOMISATION Bolus 5-FU 370mg/m 2 /LV 20mg/m 2, weekly OR Bolus 5-FU 370mg/m 2 /LV 20mg/m 2, days 1–5, q28 6 months Xeloda 1,000mg/m 2 twice daily, days 1–14 + irinotecan 250mg/m 2 day 1, q21 6 months (target n=3,450)

Xeloda ® : simplifying chemoradiation for rectal cancer

Oral Xeloda ® : feasible and active in combination with radiotherapy  Phase I trial –DLT: hand-foot syndrome –well tolerated: no grade 4 adverse events, grade 3 events were very rare –clinically active: one pCR, nine PRs in 10 patients treated in neo-adjuvant setting Dunst J et al. J Clin Oncol. Submitted Radiotherapy 1.8Gy/day plus presacral boost (3 x 1.8Gy) Oral Xeloda 825mg/m 2 twice daily Continuous (days 1–37) Day

NSABP R-04 trial to open late 2002 Stratification Age (<50,  50) Gender Stage (T3, T4) Mobility (fixed, non-fixed) RT (45Gy in 28 fractions)* Xeloda 825mg/m 2 b.i.d. continuously during RT RT (45Gy in 28 fractions)* CI 5-FU 225mg/m 2 /day during RT Epoetin alphaPlacebo Surgery/APR/sphincter-saving surgery *Plus 5.4Gy boost for non-fixed tumours, 10.8Gy for fixed tumours Operable rectal adenocarcinoma: macroscopic T3/T4, N0–2, M0, located <12cm from anal verge Epoetin alpha

New combinations: Xeloda ® with oxaliplatin and radiotherapy  Recommended regimen from phase I/II study of pre-operative chemoradiation for rectal cancer Radiotherapy 1.8Gy/day plus presacral boost (3 x 1.8Gy) Oral Xeloda 825mg/m 2 twice daily Days 1–14Days 22–35 Oxaliplatin 50mg/m 2 Sauer R et al. (personal communication) Day

New combinations: Xeloda ® with irinotecan and radiotherapy  Phase I study of pre-operative chemoradiation for rectal cancer: MTD has not been reached  Tumours downstaged in all patients treated to date (n=9) Kennedy AS et al. Proc Am Soc Clin Oncol 2002;21:300b (Abst 3021) Radiotherapy 54Gy total dose Oral Xeloda 500– 1,000mg/m 2 twice daily Monday to Friday Weekly irinotecan 50mg/m 2 Day

Goal for Xeloda ® : to replace i.v. 5-FU as the backbone of combination therapy for CRC  Oral Xeloda is an effective and convenient combination partner for oxaliplatin, irinotecan and radiotherapy  Ongoing and planned phase III trials should further confirm the ability of Xeloda to replace 5-FU in combination therapy

Xeloda ® in oesophagogastric cancer David Cunningham Head of Gastrointestinal Unit The Royal Marsden Hospital London and Surrey, UK

Capecitabine monotherapy is active and safe 1 st -line therapy for gastric cancer  Phase II trial in Korea (n=60)  Treatment: capecitabine 1,250mg/m 2 twice daily, days 1–14, every 21 days  Antitumour activity: –ORR 34% (15/44 evaluable patients) –SD 36% (14/44)  Most common adverse events (AEs): –hand-foot syndrome (only 7% grade 3) –gastrointestinal AEs (<5% grade 3/4) Hong YS et al. Proc Am Soc Clin Oncol 2002;21:156a (Abst 623)

Xeloda ® /cisplatin: a promising new combination for advanced gastric cancer Kim TW et al. Ann Oncol. Submitted Day Cisplatin 60mg/m 2 as a 1-hour i.v. infusion Oral Xeloda 1,000mg/m 2 twice daily Days 1–14Rest Repeat cycle at day 22  Phase II study as first-line therapy (n=42)  Highly active: ORR = 55%; median TTP = 5.8 months; median OS = 9.7 months  Well tolerated: grade 3/4 neutropenia (32%), thrombocytopenia (10%), HFS (8%), diarrhoea (5%) and stomatitis (3%)

REAL-2: randomised, phase III trial in oesophagogastric carcinoma ECFECX EOF EOX Epirubicin50mg/m 2 i.v. 3 weekly Cisplatin 60mg/m 2 i.v. 3 weekly 5 FU 200mg/m 2 /day i.v. continuously Epirubicin 50mg/m 2 i.v. 3 weekly Cisplatin 60mg/m 2 i.v. 3 weekly Xeloda500mg/m 2 twice daily po continuously Epirubicin 50mg/m 2 i.v. 3 weekly Oxaliplatin130mg/m 2 i.v. 3 weekly 5 FU 200mg/m 2 /day i.v. continuously Epirubicin 50mg/m 2 i.v. 3 weekly Oxaliplatin130mg/m 2 i.v. 3 weekly Xeloda500mg/m 2 twice daily po continuously Planned duration of treatment: 24 weeks (8 cycles)

REAL-2: promising results for Xeloda ® vs 5-FU at planned interim analysis  Due to good tolerability, future patients will receive capecitabine 625mg/m 2 twice daily, continuously  Full update: Monday May 20, 10.00–10.15, level 4, Valencia Ballroom Tebbutt N et al. Proc Am Soc Clin Oncol 2002;21:131a (Abst 523)

Xeloda ® : replacing 5-FU in gastric cancer  Xeloda has the potential to replace i.v. 5-FU in regimens for advanced gastro-oesophageal cancer showing –high antitumour activity –favourable safety profile –improved convenience compared with CI 5-FU  Phase III trials are comparing Xeloda combinations versus standard combinations in Europe and Asia

Xeloda ® in combination with Taxotere ® or as monotherapy Joyce O’Shaughnessy, MD Co-Director of Chemoprevention Research Baylor-Sammons Cancer Center and US Oncology Research Dallas, Texas, USA

Xeloda ® : powerful, oral chemotherapy for metastatic breast cancer (MBC)  Thymidine phosphorylase (TP)-activated Xeloda is a highly effective treatment for MBC  Xeloda monotherapy is the reference treatment for patients with taxane-pretreated MBC and is registered in >50 countries in this setting  Addition of Xeloda to Taxotere improves survival over Taxotere monotherapy in patients with anthracycline-pretreated MBC

Xeloda ® /Taxotere ® (XT) improves survival in anthracycline-pretreated MBC

Xeloda ® /Taxotere ® (XT) versus Taxotere ® : phase III study design Randomization (3-weekly cycles) Xeloda 1,250mg/m 2 twice daily, days 1–14 plus Taxotere 75mg/m 2, day 1 Taxotere 100mg/m 2, day 1  Patients responding or with stable disease after 6 weeks of treatment continued until disease progression or unacceptable toxicity  Primary objective: to demonstrate superior TTP* O’Shaughnessy J et al. J Clin Oncol 2002;20(12). In press *Time to disease progression or death

Xeloda ® /Taxotere ® (XT) : significantly superior TTP and response rate Time (months) Estimated probability of TTP XT Taxotere Response rates: XT = 42% Taxotere = 30% p=0.006 Hazard ratio = Log-rank p=0.0001

Xeloda ® /Taxotere ® (XT) : significantly superior overall survival (OS) Time (months) XT Taxotere Hazard ratio = Log-rank p= O’Shaughnessy J et al. J Clin Oncol 2002;20(12). In press Estimated probability of OS

Survival update* for Xeloda ® Investigator Meeting, ASCO Time (months) (1 year)(2 years)(3 years)(4 years) *Minimum follow up = 27 months XT Taxotere Hazard ratio = Log-rank p<0.01 Estimated probability of OS

Most common treatment-related clinical adverse events (AEs) (all grades) XT (n=251) Taxotere (n=255) Diarrhea Hand-foot syndrome Nausea Fatigue/ asthenia Neutropenic fever VomitingAlopeciaPyrexiaMyalgia Arthralgia Stomatitis Patients (%)

Xeloda ® /Taxotere ® (XT) has set a new standard in anthracycline-pretreated MBC  The addition of Xeloda to Taxotere leads to –superior OS (3 months’ median improvement) –superior TTP and response rates –manageable safety profile  The survival benefit was clearly due to the addition of Xeloda, as patients in the combination arm received a lower dose of Taxotere

US Oncology: what are our next steps with Xeloda ® /Taxotere ® (XT) combination therapy?  Evaluation in the adjuvant setting

A = doxorubicin T = Taxotere C = cyclophosphamide X = Xeloda Patients with ER+ or PR+ tumors will receive tamoxifen or anastrozole for 5 years Eligibility criteria (n=1,830) N 1–2 N 0, T >2cm N 0, ER–/PR– XT x 4 RANDOMIZATIONRANDOMIZATION AC x 4 T x 4 Evaluation of Xeloda ® /Taxotere ® (XT) as adjuvant therapy: phase III trial design (US Oncology)

 Evaluation in the adjuvant setting  Optimization of the XT regimen –reducing the Xeloda dose to 950mg/m 2 twice daily instead of 1,250mg/m 2 twice daily should improve the safety profile while maintaining high efficacy –the rationale for lowering the Xeloda dose to 950mg/m 2 twice daily is as follows... US Oncology: what are our next steps with Xeloda ® /Taxotere ® (XT) combination therapy?

Safety summary and issues: Xeloda ® /Taxotere ® (XT) versus Taxotere ® alone  With XT, there was a higher incidence of –dose reductions (65 vs 36%) –treatment-related withdrawals (25 to 18%) –grade 3 treatment-related AEs, especially hand-foot syndrome (incidence peaked in cycle 2)  But with XT, there was a lower incidence of –neutropenic fever, myalgia, arthralgia and pyrexia –fewer grade 4 treatment-related AEs  Similar number of treatment-related hospitalizations in both treatment arms  QoL was at least similar in patients receiving XT

Starting the 2nd cycle with a lower Xeloda ® dose has no impact on TTP Time (months) nd cycle, full dose of Xeloda 2nd cycle, reduced dose of Xeloda Taxotere 100mg/m 2 Estimated probability of TTP

Received versus planned * dose: Xeloda ® and Taxotere ® in the XT arm Received vs planned dose –34–67–910–1213–1516–1819–2122–2425–2728–30Overall Time interval (weeks) Xeloda Taxotere *First dose x 28 per expected 3-week cycle, excluding dose reductions, interruptions or delays

Argument for lowering the Xeloda ® starting dose in combination with Taxotere ® 75mg/m 2  To reduce the incidence of –dose reductions –treatment-related withdrawals –grade 3 treatment-related AEs, especially hand-foot syndrome  Starting the second cycle with a lower Xeloda dose had no impact on TTP or overall survival  Median dose intensity in the second cycle was approximately Xeloda 950mg/m 2 twice daily  therefore, US Oncology will move forward with Xeloda 950mg/m 2 twice daily + Taxotere 75mg/m 2 in our adjuvant programme

Xeloda ® monotherapy: the reference therapy for taxane-pretreated MBC

Xeloda ® : the most extensively evaluated agent in taxane-pretreated MBC  Four separate trials in 500 patients have evaluated Xeloda monotherapy –pivotal US trial (n=163) 1 –confirmatory US/French trial (n=75) 2 –German trial (n=136) 3 –French trial (n=126): updated at ASCO  Treatment: Xeloda 1,250mg/m 2 twice daily for 14 days, followed by a 7-day rest period 1 Blum JL et al. J Clin Oncol 1999;17:485–93 2 Blum JL et al. Cancer 2001;92:1759–68 3 Reichardt P et al. Eur J Cancer 2001;37(Suppl. 6):S191 (Abst 699) 4 Fumoleau P et al. Proc Am Soc Clin Oncol 2002;20:62a (Abst 247)

Xeloda ® in taxane-pretreated MBC: consistently high efficacy 1 Blum JL et al. Eur J Cancer 2001;37:S190 (Abst 693) 2 Blum JL et al. Cancer 2001;92:1759–68 3 Reichardt P et al. Eur J Cancer 2001;37(Suppl. 6):S191 (Abst 699) 4 Fumoleau P et al. Proc Am Soc Clin Oncol 2002;20:62a (Abst 247)

Xeloda ® in taxane-pretreated MBC: TTP Time (months) Pivotal US trial (n=162) US/French trial (n=74) German trial (n=136) French trial (n=126) Estimated probability of TTP

Xeloda ® in taxane-pretreated MBC: favorable OS Time (months) Estimated probability of OS Pivotal US trial (n=162) US/French trial (n=74) German trial (n=136) French trial (n=126)

Favorable safety profile of Xeloda ® monotherapy Hand-footNausea Diarrhea VomitingStomatitisFatigue syndrome Patients (%) *Two patients did not receive study drug Treatment-related AEs (n=498*) Grade 1/2 Grade 3 Grade 4

Xeloda ® monotherapy: myelosuppression* is rare (n=498) Leukopenia Neutropenia Anemia Thrombo- cytopenia Grade 3 Grade 4 *Recorded as grade 3/4 laboratory adverse events

Xeloda ® in taxane-pretreated MBC: summary  Xeloda is the reference treatment and is registered in >50 countries in this setting  Oral Xeloda fulfills patients’ preference for convenient, highly active therapy  No other agent has consistently demonstrated such high efficacy in a large population of patients (n=500) in this setting  Xeloda has a reasonable safety profile with a particularly low incidence of grade 4 AEs, alopecia and myelosuppression

Xeloda ® : powerful, oral chemotherapy for MBC (summary)

Oral Xeloda ® has set a new standard in the treatment of MBC  XT is the first cytotoxic combination to improve survival over Taxotere monotherapy in patients with anthracycline-pretreated MBC  Xeloda monotherapy is the reference treatment for patients with taxane-pretreated MBC

Future of Xeloda ® in metastatic breast cancer and in adjuvant trials David Cameron Senior Lecturer in Medical Oncology Western General Hospital Edinburgh, UK

Moving Xeloda ® forward: alone and in combination  High activity, good safety profile and a convenient oral agent  Ongoing trials aim to define the role of Xeloda –as a single agent –in combination with other agents  Potential to improve outcomes in early and metastatic breast cancer (BC)  AIM to ensure every woman who can benefit will receive this novel agent

Xeloda as monotherapy…

Xeloda ® monotherapy: highly promising as second- or first-line therapy for MBC 1 Talbot D et al. Br J Cancer 2002;86:1367–72 2 O’Shaughnessy J et al. Ann Oncol 2001;12:1247–54 NR = not reported

Further evaluation of Xeloda ® as first-line therapy: randomised, phase III trial ANZBCTG Xeloda 1,000mg/m 2 b.i.d. days 1–14 q21d Continuous Xeloda 666mg/m 2 b.i.d. Classical Bonadonna CMF q28d RANDOMISATIONRANDOMISATION 1° endpoint: QoL-adjusted TTP Planned n=465

Ongoing CALGB trial: adjuvant Xeloda ® for high-risk breast cancer in the elderly  Randomised phase III trial in women  65 years with early-stage breast cancer –Xeloda versus CMF or AC (depending on patient’s cardiac history)  1° endpoint: 5-year relapse-free survival  2° endpoints: overall survival, QoL, physical function  Assessment of compliance, tolerability and biological markers of response

Xeloda in combination...

Rationale for Xeloda ® in combination: TP upregulation Paclitaxel100 Docetaxel15 Vinblastine3 Vindesine5 Mitomycin C5 Doxorubicin7.5 Cisplatin10 Cyclophosphamide200 Gemcitabine90 Vinorelbine * * * * * * * † *p<0.05 † p value not available TP upregulation (x control activity) Ishitsuka H. Invest New Drugs 2000;18:343–54 Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388) (mg/kg)

XT: moving forward Planned NSABP B27 replacement trial in patients with operable BC R AC x 4 Surgery AC x 4 Taxotere + Xeloda x 4 Surgery Taxotere x 4  Phase III data: the addition of Xeloda to Taxotere leads to superior OS, TTP and RR

Xeloda ® plus paclitaxel: effective with a favourable safety profile in phase II studies *Includes 23% chemonaïve patients † Not reached >22 months after study initiation 1 Pérez-Manga G et al. Breast Cancer Res Treat 2000;64:124 (Abst 535) 2 Meza L G et al. Breast Cancer Res Treat 2001;69:271 (Abst 358)  Safety profile: favourable with a low incidence of grade 3/4 clinical adverse events

TEX: promising therapy for locally advanced/metastatic BC  ORR: 94% in 34 patients with LABC (stage III) 70% in 33 patients with MBC (stage IV)  Predictable safety profile: febrile neutropenia (16%) was the most common adverse event  Recruitment for phase III trial (TEX vs TE) is underway Rosso R et al. Breast Cancer Res Treat 2001;69:270 (Abst 353) Docetaxel 75mg/m 2 plus Epirubicin 75mg/m 2 Xeloda 1,000mg/m 2 twice daily Days 1–14Rest 21-day cycle, repeated at day 22 TEX phase II study

CEX has high activity in early BC: EORTC-IDBBC phase I study  Phase I study in patients with previously untreated locally advanced/inflammatory or large, inoperable BC  DLTs: mucositis, nausea, febrile neutropenia  Efficacy: ORR = 83% (all dose levels) Xeloda 900mg/m 2 twice daily Days 1–14Rest Treatment = 6 x 21-day cycles Cyclophosphamide 600mg/m 2 plus epirubicin 100mg/m 2 Biganzoli L et al. Eur J Cancer 2001;37(Suppl. 6):S146 (Abst 539) Recommended regimen

Xeloda ® plus vinorelbine: feasible and active in a 21-day regimen 1 Ghosn M et al. Proc Am Soc Clin Oncol 2002;21:42b (Abst 1978) 2 Welt A et al. Proc Am Soc Clin Oncol 2001;20:58b (Abst 1979) 3 Ahn J-H et al. Proc Am Soc Clin Oncol 2002;21:55b (Abst 2030)  German regimen: randomised, phase III trial (vs XT) is under discussion  Predictable safety profile: neutropenia and gastrointestinal side effects are dose limiting

Xeloda ® plus Avastin TM : ongoing phase III trial  Avastin (bevacizumab) is a recombinant, humanised monoclonal antibody to vascular endothelial growth factor (VEGF)  Active in patients with previously treated MBC 1  Recruitment (~400 patients) for a randomised, phase III trial in taxane-pretreated MBC is ongoing –Xeloda monotherapy versus Xeloda plus Avastin 2 1 Cobleigh MA et al. Breast Cancer Res Treat 2001;69:301 (Abst 520) 2 Details provided on US National Cancer Institute Clinical Trials Database (URL

Xeloda ® plus Herceptin ® : at least additive activity in a BC xenograft model Fujimoto-Ouchi KF et al. Cancer Chemother Pharmacol 2002;49:211–16 1, * * * Tumour volume (mm 3 ) Control Xeloda Herceptin Xeloda + Herceptin Days after inoculation *p<0.05 BT474 xenograft

Xeloda ® plus Herceptin ® is a feasible combination: the German experience  18 patients with anthracycline- and taxane-pretreated HER2+ MBC received 21-day cycles of –standard-dose Herceptin, weekly –Xeloda 1,125mg/m 2 twice daily, days 1–14  62% ORR in 13 patients  Minimal side effects  Additional phase II investigation is ongoing Bangemann N et al. Ann Oncol 2000;11(Suppl. 4):143 (Abst 653P)

Xeloda ® /Herceptin ® plus Taxotere ® : at least additive activity against HER2+ BC xenograft model 1, Tumour volume (mm 3 ) Days after inoculation Xeloda 90mg/kg/day Adapted from Sawada N et al. Proc Am Assoc Cancer Res 2002;43:1088 (Abst 5388) Taxotere 10mg/kg Herceptin loading dose 15mg/kg Herceptin maintenance dose 7.5mg/kg KPL-4 xenograft ControlHerceptinHerceptin + Taxotere Xeloda + TaxotereXeloda + Herceptin + Taxotere

Ongoing trials: Xeloda ® /Herceptin ® plus a taxane as first-line therapy for HER2+ MBC  US phase II trial: 21-day regimen –Xeloda 825mg/m 2 twice daily, days 1–14 –standard-dose Herceptin, weekly –paclitaxel 175mg/m 2, every 3 weeks  Large, international, randomised, phase II trial (n=220): 21-day regimen –Herceptin 6mg/kg, day 1 (loading dose 8mg/kg) –Taxotere 75mg/m 2, day 1 –± Xeloda 950mg/m 2 twice daily, days 1–14

Ongoing phase I/II trials investigating Xeloda ® in all-oral combinations  Xeloda continuously + oral cyclophosphamide (New Zealand and Australia) 1 –MTD: Xeloda 666mg/m 2 twice daily, d1–28 + cyclophosphamide 125mg/m 2 d1–14, q28d –additional patients are being treated with Xeloda 666mg/m 2 + cyclophosphamide 100mg/m 2  Xeloda + oral idarubicin (Edinburgh, UK)  Xeloda + oral idarubicin/cyclophosphamide (China) 2  Xeloda + oral vinorelbine (Milan, Italy) 1 Findlay MP et al. Proc Am Soc Clin Oncol 2002;21:85b (Abst 2151) 2 Chan S-C et al. Proc Am Soc Clin Oncol 2002;21:53b (Abst 2023)

Moving Xeloda ® forward in combination Cyclophosphamide/epirubicin/ Xeloda (CEX) Taxane/anthracycline/Xeloda (TAX/TEX) Xeloda plus Herceptin Xeloda plus Avastin Xeloda plus vinorelbine Taxane- pretreated MBC Anthracycline- pretreated MBC Untreated MBC Early BC (neo-)adjuvant setting Xeloda plus Taxotere (XT) Xeloda plus paclitaxel Taxotere plus Herceptin ± Xeloda

Moving Xeloda ® forward: conclusions  With high activity and a favourable safety profile, oral Xeloda is showing potential –as (neo)adjuvant therapy –as first-line therapy for MBC –in patients with pretreated MBC  Ongoing trials will further define the role of this highy active, oral agent allowing Xeloda to become an integral component of breast cancer therapy