Xeloda monotherapy: origin of a species

1
Xeloda monotherapy origin of a species
2
A changing environment
1970
2000
1980
1990
Perez DJ et al. J Clin Oncol. 19919214852 Joens
uu H et al. J Clin Oncol. 199816372030
3
A changing environment

• Mid-1980s efficacy improved by
  incorporationinto combination regimens

1970
2000
1980
1990
Perez DJ et al. J Clin Oncol. 19919214852 Joens
uu H et al. J Clin Oncol. 199816372030
4
Impact of anthracyclines on survival in MBC
Positive
Negative
PolyCT vs monotherapy PolyCTAnthracycline vs
PolyCTwithout Anthracycline PolyCT vs
CMF PolyCTEpirubicin vs PolyCTDoxorubicin High vs
low-dose CT CT hormone therapy vs CT
0 0.5 1.0 1.5 2.0
Hazard Ratio
CT chemotherapy
Fossati R et al. J Clin Oncol 199816343960
5
Anthracyclines an initial step forward in
breast cancer
Anthracyclines
Cyclophosphamide
5-FU
1970
2000
1980
1990
6
A changing environment
1970
2000
1980
1990
7
1990s a changing environment in first line

• Vinorelbine is active with response rates of 411

1970
2000
1980
1990
1Fumoleau P et al. Ann Oncol 1996716571
2Fumoleau P et al. J Clin Oncol 19931112445 52
3Feher O et al. EBCC 2002 (Abst 110)
8
1990s a changing environment in first line

• Vinorelbine is active with response rates of 411
• Docetaxel response rates gt60 in phase II trials2

1970
2000
1980
1990
1Fumoleau P et al. Ann Oncol 1996716571
2Fumoleau P et al. J Clin Oncol 19931112445 52
3Feher O et al. EBCC 2002 (Abst 110)
9
1990s a changing environment in first line

• Vinorelbine is active with response rates of 411
• Docetaxel response rates gt60 in phase II
  trials2
• Gemcitabine response rate of 163

1970
2000
1980
1990
1Fumoleau P et al. Ann Oncol 1996716571
2Fumoleau P et al. J Clin Oncol 19931112445 52
3Feher O et al. EBCC 2002 (Abst 110)
10
Regimens combining anthracyclines with taxanes
do not improve survival
1Jassem J et al. J Clin Oncol 200119170715
2Biganzoli L et al. J Clin Oncol 200214311421
3Lück HJ et al. ASCO 20001973a (Abst 280)
4Carmichael J et al. ASCO 20012022a (Abst 84)
5Nabholtz JM et al. ASCO 199918127a (Abst
485) 6Mackey JR et al. ASCO 20022135a (Abst
137) 7Bonneterre J et al. ASCO 20012042a (Abst
163)
11
An evolutionary leaprationally designed Xeloda
Xeloda
12
Tumour-activated Xeloda
Intestine
Liver
Tumour gtgt healthy tissue
Xeloda
Xeloda
CE
5'-DFCR
5'-DFCR
CyD
CyD
5'-DFUR
5'-DFUR
Thymidine phosphorylase (TP)
5-FU
5'-DFCR 5'-deoxy-5-fluorocytidine 5'-DFUR
5'-deoxy-5-fluorouridine CyD cytidine
deaminase CE carboxylesterase
13
TP is significantly more active in human tumour
tissue
No. patients
115 115
Colorectal Gastric Breast Liver (metastasis)

291 351

309 309

Healthy tissue Tumour tissue
16 20

0 100 200 300 400 500
TP activity (µg 5-FU/mg protein/hour)
Adapted from Miwa M et al. Eur J Cancer
199834127481
plt0.05
14
Rationally designed more 5-FU in the tumour
with Xeloda
x 3.2
x 21.4
Normal tissue
Plasma
Tumour tissue
Ratio of median values
Schüller J et al. Cancer Chemother Pharmacol
2000452917
15
Patients prefer oral therapy
Patients ()
100 80 60 40 20 0
Liu et al. (n103)1 Borner et al. (n31)2
1Liu G et al. J Clin Oncol 19971542532 2Borner
M et al. Eur J Cancer 20023834958
16
Conquering a challenging environmentXeloda in
taxane-pretreated MBC
Blum JL et al. Eur J Cancer 200137(Suppl.
6)S190 (Abst 693)Blum JL et al. Cancer
200192175968 Reichardt et al. Ann Oncol
200314(8)122733 Fumoleau P et al. Eur J Cancer
2003 In press Maung K. Clin Breast Cancer
200333757
17
A gentle approach in a challenging environment
low incidence of grade 3/4 events (n728)
60 40 20 0

• No complete hair loss
• No treatment-related deaths

Patients ()
Hand-foot Diarrhoea Fatigue Stomatitis Nausea Deh
ydration syndrome
18
Xeloda monotherapy myelosuppression is rare
(n498)
60 40 20 0
Patients ()
Leucopenia Neutropenia Anemia
Thrombo- cytopenia
19
Xeloda monotherapy highly active front-line
therapy for MBC
NR not reported
1Talbot D et al. Br J Cancer 200286136772
2OShaughnessy J et al. Ann Oncol 200112124754
20
Support for Xeloda as a front-line treatment
option

• Only marginal benefit from
• combinations versus monotherapy
• anthracycline-containing combinations
• anthracycline/taxane combinations
• Xeloda monotherapy compares favourably with
• paclitaxel1
• CMF2
• Xeloda is well tolerated with minimal
  myelosuppression, alopecia
• Patients prefer oral chemotherapy3

1Talbot D et al. Br J Cancer 200286136772 2OSh
aughnessy J et al. Ann Oncol 200112124754 3Liu
G et al. J Clin Oncol 19971542532
21
Oral Xeloda a giant leap for MBC therapy

• Oral Xeloda is an essential component of
  treatment
• Taxane-pretreated only Xeloda achieves
  consistently good efficacy with overall survival
  of ?1 year
• Front-line Xeloda is an active and
  well-tolerated alternative to standard i.v.
  treatments