Post on 26-Dec-2015
Xeloda and Xeloda-based combinations in the treatment of MBC
Steffan Kahlert
Insert affiliation
IntestineLiver
Xeloda
5'-DFCR
5'-DFUR
CyD
5'-DFCR
5'-DFUR
5-FU
Tumour >> healthy tissueXeloda
CyD
CE
5'-DFCR = 5'-deoxy-5-fluorocytidine; 5'-DFUR = 5'-deoxy-5-fluorouridine;CyD = cytidine deaminase; CE = carboxylesterase
Tumour/TP-activated oral Xeloda
Thymidinephosphorylase (TP)
Patient and disease characteristics influence treatment decisions
Sequenceversus
combination
Sequenceversus
combination
Prior adjuvantchemotherapyPrior adjuvantchemotherapy
Cumulative doseof anthracyclinesCumulative doseof anthracyclines
Cardiacimpairment
Cardiacimpairment
Increasing useof taxanes
Increasing useof taxanes
Long-termside effectsLong-term
side effectsDisease-free
interval Disease-free
interval
Diseasecharacteristics
Diseasecharacteristics
Sites ofmetastases
Sites ofmetastases
Tumor biologyTumor biology
TumorburdenTumorburden
Patientcharacteristics
Patientcharacteristics
AgeAge
Performance status
Performance status
PreferencePreference
Comorbiditiese.g. diabetes, impaired
cardiac function
Comorbiditiese.g. diabetes, impaired
cardiac function
Trial vs clinicpatients
Trial vs clinicpatients
Taxane naïve Xeloda vs paclitaxel
(n=41)1
Anthracycline/ taxane naïve
Xeloda vs CMF (n=93)2
Response rate (%) 36 26 30 16
Median TTP (months) 3.0 3.1 4.1 3.0
Median overall survival (months) 7.6 9.4 19.6 17.2
Xeloda monotherapy: highly active first-line therapy for MBC
1Talbot D et al. Br J Cancer 2002;86:1367–722O’Shaughnessy J et al. Ann Oncol 2001;12:1247–54
CMF = cyclophosphamide, methotrexate, 5-fluorouracilTTP = time to progression
Xeloda monotherapy in patients ≥65 years: highly effective in first-line MBC
Xeloda
1 250mg/m2 (n=30)
Xeloda 1 000mg/m2
(n=43)
Response rate (%) 37 35
Disease control (%) 70 81
Median TTP (months) 3.9 4.1
Median OS (months) 10.0 16.0
Bajetta E et al. J Clin Oncol 2005;23:2155–61
First-line Xeloda: similar high activityto anthracyclines and taxanes in MBC
Response rate (%)
First-line Xeloda1,2 30–58
First-/second-line Xeloda1 36
First-line anthracyclines1,3 36–41
Docetaxel (q3w) in anthracycline-pretreated MBC1,4,5
23–42
Paclitaxel in anthracycline-pretreated MBC1,6–8
13.8–29
1Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–82Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)
3Paridaens R et al. J Clin Oncol 2000;18:724–33; 4Alexandre J et al. J Clin Oncol 2000;18:562–735Sjöström J et al. Eur J Cancer 1999;35:1194–201 ; 6Dieras V et al. Semin Oncol 1995;22(Suppl. 8):33–9
7Nabholtz J et al. J Clin Oncol 1996;14:1858–67; 8Miller KD et al. Breast Cancer Res Treat 2005;94:S6 (Abst 3)
Large body of evidence with Xeloda in taxane-pretreated MBC
Five trials in 730 patients evaluated Xeloda monotherapy1
– pivotal USA (n=163)– confirmatory US/French (n=75)– German (n=136)– French (n=126)– US Xeloda ± Avastin (n=462)
Xeloda dose in all trials was 1 250mg/m2 twice daily for 14 days, followed by a 7-day rest period
Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8
Response rate (%)
Tumor control
(%)
Median TTP
(months)
Median OS
(months)
Blum (n=162) 20 63 3.0 11.6
Blum (n=74) 26 57 3.2 12.2
Reichardt (n=136) 15 62 3.3 10.4
Fumoleau (n=126) 28 63 4.9 15.2
Miller (n=230) 19 NR 4.2 14.5
Xeloda: consistently high activity in taxane-pretreated MBC
Xeloda is more effective than other monotherapies, p=0.0052
1Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–82Miles D et al. Clin Breast Cancer 2004;5:273–8
Favorable safety of single-agent Xeloda in all patient groups
Xeloda monotherapy in MBC: low incidence of grade 3 / 4 adverse events (n=713)
Minimal alopecia and myelosuppression No cumulative toxicity No treatment-related deaths
Hand-foot Diarrhoea Fatigue Stomatitis Nausea Dehydrationsyndrome
Patients (%)40
30
20
10
0
Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8
Xeloda monotherapy: minimal myelosuppression (n=498)
Patients (%)
Leukopenia Neutropenia Anemia Thrombo-cytopenia
40
20
0
Grade 3
Grade 4
Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8
Xeloda 1 000mg/m2 twice daily in patients ≥65 years
Grade 3/4 diarrhea: 13% with 1 250mg/m2, 2% with 1 000mg/m2
Efficacy of the two starting doses was similar (n=73)
Bajetta E et al. J Clin Oncol 2005;23:2155–61
Fatigue HFS Nausea Diarrhea Stomatitis Neutropenia
80
60
40
20
0
Grade 3/4Grade 1/2
Patients (%; n=43)
Xeloda treatment improves QoL in women with MBC (n=1 125)
Overall QoL stable or improved in >70% of patients
Segalla J et al. Eur J Cancer Suppl 2005;3:115 (Abst 410)
Patients (%)
0
20
40
60
80
Physical RoleFunction: Emotional Social Cognitive
MaintainedImproved (p<0.01)
MOSG: first-line Xeloda sequence or combination?
X1250 (n=62) PD
T100 (n=21)
P175 (n=4)
X825T75 (n=71)RANDOMIZATION
X825P175 (n=73)
PD = disease progressionMOSG = Mexican Oncology Study Group
n=345
Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)
XT
(n=71) XP
(n=73) X taxane
(n=62) p value
Overall RR (%)
CR
76
21
73
19
58
18 0.06
Median PFS (months) 10.1 9.2 8.6
NS
12-month OS (%) 82 76 71 NS
Median OS (months) 34 29 31 0.77
First-line Xeloda sequence compares favourably with combinations
Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)
Sequential Xeloda and taxanes is cost-saving
Xeloda followed by a taxane is cost-saving with similar efficacy to the combinations
Treatment regimen
Cost of treatment and follow-up (US$)
QALY
Mean cost (US$)/QALY
X→taxane 4 781 1.79 2 671
XP 6 177 1.66 3 721
XT 11 070 1.95 5 677
Reynoso N et al. Breast Cancer Res Treat 2005;94(Suppl. 1):S219 (Abst 5039)
Tailoring treatment to patients with single-agent Xeloda
First-line Xeloda is a highly active, well-tolerated, cost-effective option for patients
– with slowly progressing disease / low risk
– where QoL issues are paramount
– who are older or less fit
– after adjuvant anthracyclines and taxanes
First-line MBC: expanding treatment options with rationally designed Xeloda combinations
XTXT
XPXP ± Herceptin± Herceptin XNXN
XelodaXeloda
A standard of care treatment option for extending survival: fit patients with rapidly progressing disease and/or visceral metastases
A standard of care treatment option for extending survival: fit patients with rapidly progressing disease and/or visceral metastases
XT = Xeloda + Taxotere; XP = Xeloda + paclitaxel; XN = Xeloda + vinorelbine
Control
XT: preclinical synergy
MX-1 breast cancer xenografts6.0
5.0
4.0
3.0
2.0
1.0
0.0
–1.014 18 22 26 30 34 38 42
Tumour volume change (cm3)
Daysp<0.05 for each arm versus XT Sawada N et al. Clin Cancer Res 1998;4:1013–9
Taxotere
Xeloda
XT
2Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8
Overall population1
Taxotere
XTRelapse ≤2 years2
Survival benefit maintained in aggressive disease
1O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16 18 20 22 24 26
Months
Estimated probabilityXT
Taxotere
11.5 14.5
Log-rank p = 0.013
Hazard ratio = 0.77
XT (n=255)
Taxotere (n=255)
Addition of Xeloda to Taxotere extends survival
XT: superior response rate and TTP
4.2 6.1
Log-rank p=0.0001
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
1.0
0.8
0.6
0.4
0.2
0.0
Months
XT (n=255) 42%
Taxotere (n=256) 30%
Response rate
p=0.006
O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23
Estimated probability
XT significantly more active than sequential T X in first-line MBC
XT (n=50)
T X (n=50)
p value
Response rate, % CR PR
68 14 54
40 6
34
0.004
TTP (hazard ratio) 95% CI
0.547 0.312–0.756
0.001
OS (hazard ratio) 95% CI
0.528 0.283–0.811
0.006
Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407)
Xeloda/Taxotere vs T X: survival advantage with 74% cross-over
Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407)
1.0
0.8
0.6
0.4
0.2
0.00 5 10 15 20 25 30 35 40
Months
Survival probability
19 22
p = 0.006
Hazard ratio = 0.53
XT (n=50)
T X (n=50)
Acceptable safety of XT versus Taxotere (grade 3/4)
Patients (%)40
30
20
10
0HFS
Stomatitis
Diarrhea
Neutropenia
Neutropenic
fever Fatigue
AlopeciaEdema
Beslija S et al. Eur J Cancer Suppl 2005;3:118 (Abst 407)
XT (n=50)
T X (n=50)
O’Shaughnessy trial: XT dose reduction does not compromise efficacy – OS
1.0
0.8
0.6
0.4
0.2
0.00 5 10 15 20 25 30 35 40 45 50
Survival probability
Months
15.014.6
F. Hoffmann-La Roche, data on file
Cycle 2 dose
Both full, X1250T75
Both reduced, X1000T60
Leonard R et al. Semin Oncol 2004;31(Suppl. 10):21–8
O’Shaughnessy trial: less grade 3/4 toxicity after XT doses reduced
The Xeloda label recommends a reduced starting dose for patients with moderate renal impairment or those aged ≥60 years at baseline
Cycles (%)
20
16
12
8
4
0Diarrhea Stomatitis Hand-foot Neutropenic
syndrome fever
Both full dose, X1250T75
(670 cycles)Both reduced dose, X1000T60 (405 cycles)
Quality of life not compromised with XT
80
70
60
50
40
0
Global health status
0 6 12 18 24 30 36 42 48Weeks
XT
Taxotere
O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23
Xeloda/paclitaxel: consistent activity in MBC
Paclitaxel regimen Pretreated
Patients (n)
Response rate (%)
Median OS (months)
EU1
USA2
USA3
EU4
EU5
Q3W
Q3W
Q1W
Q1W
Q1W
Anthracycline
94% 1st-line
Anthracycline
Anthracycline
Anthracycline
72
47
55
11
15
52
51
50
73
40
16.5
29.9
NR
NR
NR
1Batista N et al. Br J Cancer 2004;90:1740–6; 2Gradishar W et al. J Clin Oncol 2004;22:2321–7
3Blum J et al. Breast Cancer Res Treat 2004;88(Suppl. 1):S202 (Abst 5053)4Susnjar S et al. J Clin Oncol 2005;23:90s (Abst 851); 5Uhlmann C et al. Oncology 2004;67:117–22
Favorable safety profile of q3w XP: low incidence of grade 3/4 adverse events
Gradishar W et al. J Clin Oncol 2004;22:2321–7Batista N et al. Br J Cancer 2004;90:1740–6
Grade 3/4 adverse events Range (%)
Neutropenia 5–15
Alopecia 13–22
Hand-foot syndrome 11
Dyspnea 0–9
Fatigue 0–8
Paresthesiae 1–6
Peripheral neuropathy 3–6
Xeloda/vinorelbine: consistently high activity in MBC
1Ghosn M et al. J Clin Oncol 2005;23:46s (Abst 673)2Stuart N et al. Proc Am Soc Clin Oncol 2003;22:46 (Abst 183)
3Ahn J et al. Proc Am Soc Clin Oncol 2003;22:54 (Abst 216)4Welt A et al. Ann Oncol 2005;16:64–9
5Estevez L et al. Ann Oncol 2004;15(Suppl. 3):iii44 (Abst 166P)
Phase
Treatment line No. of
patients ORR (%)
Lebanon1 II 1st 30 68
UK2 II 1st/2nd 52 40
Korea3 II 1st/2nd 43 50
Germany4 I / II 1st/2nd 33 55
Spain5 II 2nd 24 56
Xeloda-based regimens: expandingoptions for the first-line treatment of MBC
Xeloda is a highly effective and well-tolerated combination partner, allowing tailoring of treatment
Xeloda should be considered a first-line agent of choice in single-agent setting
XTXT
XPXP ± Herceptin± Herceptin XNXN
XelodaXeloda