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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
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A discussion of sequential versus combination therapy David Cunningham Head of Gastrointestinal Unit The Royal Marsden Hospital London and Surrey, UK
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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 2001 2 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
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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?
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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
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Improved safety profile with Xeloda ® Xeloda (n=596) 5-FU/LV (n=593) Patients (%) Hand-footStomatitisDiarrhoeaVomitingNeutro-Neutropenic syndromepeniafever + sepsis * * * *p<0.05 25 20 15 10 5 0 * Grade 3/4 treatment-related adverse events Cassidy J et al. Ann Oncol 2002;13:566–75
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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
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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
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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?
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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
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FOLFIRI has similar efficacy to FOLFOX Achille E et al. Eur J Cancer 2001;37(Suppl. 6):289 (Abst 1067) *First-line therapy
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TTP is similar with FOLFIRI and FOLFOX regimens 1.0 0.8 0.6 0.4 0.2 0.0 048121620242832 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)
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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
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FOLFOX is better than the IFL-Saltz regimen Goldberg R et al. Proc Am Soc Clin Oncol 2002;21:128a (Abst 511)
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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)
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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?
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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
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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
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Xeloda ® plus oxaliplatin (XELOX): highly active, first-line combination therapy for metastatic CRC
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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;13:558–65 181521 Oxaliplatin 130mg/m 2 (2-hour infusion) Oral Xeloda 1,000mg/m 2 twice daily Days 1–14Rest Repeat cycle at day 22 Day
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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
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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)
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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 1.0 0.8 0.6 0.4 0.2 0.0 0246810121416182022 Estimated probability Time (months)
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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 1.0 0.8 0.6 0.4 0.2 0.0 0246810121416182022 Time (months) Tabernero J et al. Proc Am Soc Clin Oncol 2002;21:133a (Abst 531)
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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)
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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)
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Xeloda ® plus irinotecan: under intensive investigation in metastatic CRC
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Xeloda ® plus 3-weekly irinotecan: an active and convenient regimen Day 181521 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)
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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)
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Xeloda ® plus 3-weekly irinotecan: promising antitumour activity Kerr DJ et al. Proc Am Soc Clin Oncol 2002;21:161a (Abst 643)
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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
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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 +
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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)
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Xeloda ® : simplifying chemoradiation for rectal cancer
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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 1815222935
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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
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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 1815222935
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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 1815222935
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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
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Xeloda ® in oesophagogastric cancer David Cunningham Head of Gastrointestinal Unit The Royal Marsden Hospital London and Surrey, UK
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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)
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Xeloda ® /cisplatin: a promising new combination for advanced gastric cancer Kim TW et al. Ann Oncol. Submitted Day 181521 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%)
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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)
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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)
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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
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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
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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
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Xeloda ® /Taxotere ® (XT) improves survival in anthracycline-pretreated MBC
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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
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Xeloda ® /Taxotere ® (XT) : significantly superior TTP and response rate 1.0 0.8 0.6 0.4 0.2 0.0 4.26.1 0246810121416182022242628 Time (months) Estimated probability of TTP XT Taxotere Response rates: XT = 42% Taxotere = 30% p=0.006 Hazard ratio = 0.652 Log-rank p=0.0001
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Xeloda ® /Taxotere ® (XT) : significantly superior overall survival (OS) Time (months) XT Taxotere Hazard ratio = 0.775 Log-rank p=0.0126 0246810121416182022242628 O’Shaughnessy J et al. J Clin Oncol 2002;20(12). In press Estimated probability of OS 11.514.5 1.0 0.8 0.6 0.4 0.2 0.0
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Survival update* for Xeloda ® Investigator Meeting, ASCO 2002 04812162024283236404448 Time (months) (1 year)(2 years)(3 years)(4 years) *Minimum follow up = 27 months 1.0 0.8 0.6 0.4 0.2 0.0 11.514.5 XT Taxotere Hazard ratio = 0.780 Log-rank p<0.01 Estimated probability of OS
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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 80 70 60 50 40 30 20 10 0 Stomatitis Patients (%)
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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
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US Oncology: what are our next steps with Xeloda ® /Taxotere ® (XT) combination therapy? Evaluation in the adjuvant setting
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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)
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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?
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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
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Starting the 2nd cycle with a lower Xeloda ® dose has no impact on TTP 1.0 0.8 0.6 0.4 0.2 0.0 02468101214161820222426 Time (months) 4.26.26.5 2nd cycle, full dose of Xeloda 2nd cycle, reduced dose of Xeloda Taxotere 100mg/m 2 Estimated probability of TTP
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Received versus planned * dose: Xeloda ® and Taxotere ® in the XT arm Received vs planned dose 1.0 0.8 0.6 0.4 0.2 0.0 1–34–67–910–1213–1516–1819–2122–2425–2728–30Overall Time interval (weeks) Xeloda Taxotere *First dose x 28 per expected 3-week cycle, excluding dose reductions, interruptions or delays
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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
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Xeloda ® monotherapy: the reference therapy for taxane-pretreated MBC
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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 2002 4 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)
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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)
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Xeloda ® in taxane-pretreated MBC: TTP 1.0 0.8 0.6 0.4 0.2 0.0 024681012141618 Time (months) Pivotal US trial (n=162) US/French trial (n=74) German trial (n=136) French trial (n=126) 3.0 3.3 3.2 4.6 Estimated probability of TTP
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Xeloda ® in taxane-pretreated MBC: favorable OS 04812162024283236 Time (months) 1.0 0.8 0.6 0.4 0.2 0.0 Estimated probability of OS 10.4 11.6 12.215.2 Pivotal US trial (n=162) US/French trial (n=74) German trial (n=136) French trial (n=126)
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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
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Xeloda ® monotherapy: myelosuppression* is rare (n=498) Leukopenia Neutropenia Anemia Thrombo- cytopenia Grade 3 Grade 4 *Recorded as grade 3/4 laboratory adverse events
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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
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Xeloda ® : powerful, oral chemotherapy for MBC (summary)
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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
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Future of Xeloda ® in metastatic breast cancer and in adjuvant trials David Cameron Senior Lecturer in Medical Oncology Western General Hospital Edinburgh, UK
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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
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Xeloda as monotherapy…
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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
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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
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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
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Xeloda in combination...
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Rationale for Xeloda ® in combination: TP upregulation Paclitaxel100 Docetaxel15 Vinblastine3 Vindesine5 Mitomycin C5 Doxorubicin7.5 Cisplatin10 Cyclophosphamide200 Gemcitabine90 Vinorelbine12 012345678910 * * * * * * * † *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)
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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
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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
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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) 181521 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
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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 1 81521
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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
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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 http://www.cancer.gov/clinical_trials/)
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Xeloda ® plus Herceptin ® : at least additive activity in a BC xenograft model Fujimoto-Ouchi KF et al. Cancer Chemother Pharmacol 2002;49:211–16 1,000 800 600 400 200 100 2025303540455055 * * * Tumour volume (mm 3 ) Control Xeloda Herceptin Xeloda + Herceptin Days after inoculation *p<0.05 BT474 xenograft
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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)
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Xeloda ® /Herceptin ® plus Taxotere ® : at least additive activity against HER2+ BC xenograft model 1,000 100 10 Tumour volume (mm 3 ) Days after inoculation Xeloda 90mg/kg/day 20304050 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
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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
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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)
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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
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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
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