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Taxane-pretreated metastatic breast cancer (MBC): investigational agents
Responserate (%)
TTP(months)
OS(months)
Standard-dosevinorelbine (n=14) 0 N/A N/A Fazeny et al., 1996
Weekly vinorelbine(n=40) 25 3.4 6.0 Zelek et al., 1999
High-dose vinorelbine+ G-CSF (n=40) 25 3.0 7.6 Livingston et al., 1997
3-weekly docetaxel(n=46) 17 2.3 10.5 Valero et al., 1998
96-hour paclitaxelinfusion (n=26) 27 N/A N/A Seidman et al., 1996
Continuous infusion5-FU (n=18) 17 N/A N/A Ragaz et al., 1997
LY231514 (n=31) 6 N/A N/A Spielmann et al., 1999
Gemcitabine (n=23) 0 1.9 7.8 Smorenburg et al., 2000
TTP = median time to disease progressionOS = median overall survival
Phase II trials of Xeloda® monotherapy in MBC
Xeloda in patients pretreated withpaclitaxel (n=163)
Xeloda in patients pretreated withpaclitaxel or docetaxel (n=75 and n=100)
Xeloda versus paclitaxel in patientspretreated with anthracyclines (n=42)
Xeloda versus CMF as first-line treatment in women 55 years (n=95)
Phase II trial in paclitaxel-pretreated MBC
Large, multicentre, phase II trial (n=163*)
All patients were heavily pretreated – 100% had received prior paclitaxel– 91% had received prior anthracyclines– 82% had received prior 5-FU– mean number of agents per patient = 4.7
Xeloda 1,250mg/m2 twice daily for 14 days, followed by a 7-day rest period
Blum JL et al. J Clin Oncol 1999;17:485–93
*One patient withdrew prior to receiving treatment
Efficacy: phase II trial inpaclitaxel-pretreated MBC
Blum JL et al. J Clin Oncol 1999;17:485–93
20% objective tumour response– 29% tumour response in 42 patients refractory
to both paclitaxel and anthracyclines
43% stable disease
Median duration of response = 7.9 months
Median time to disease progression* = 3.0 months
Median survival = 12.6 months
*or death
Clinical Benefit Response: mean pain for pain responders over time
40
35
30
25
20
15
10
5
00 2 4 6 8 10 12 14 16 18 20 22 24
Pai
n s
core
(m
m)
Time (weeks)
Blum JL et al. J Clin Oncol 1999;17:485–93
47% of the 51 patients with considerable
pain at baseline experienced a durable 50% reduction in pain intensity
Survival: phase II trial in paclitaxel-pretreated MBC
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16
Est
imat
ed p
rob
abil
ity
12.6
Time (months)
Blum JL et al. J Clin Oncol 1999;17:485–93
Survival: phase II trial in paclitaxel-pretreated MBC (cont’d)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.00 2 4 6 8 10 12 14 16
ResponderStable diseaseProgressive disease
Time (months)
Est
imat
ed p
rob
abil
ity
Blum JL et al. J Clin Oncol 1999;17:485–93
Safety: phase II trial in paclitaxel-pretreated MBC
Most frequent grade 3/4 treatment-related adverse events were diarrhoea and hand-foot syndrome
Only 4% experienced grade 4 adverse events
Myelosuppression and alopecia were rare
No treatment-related deaths
Blum JL et al. J Clin Oncol 1999;17:485–93
Impact of Xeloda® dose modification on efficacy
The Xeloda dose modification scheme (treatment interruption or dose reduction) was implemented in the event of grade 2–4 side effects
A Cox regression analysis confirmed that the risk of disease progression* was not significantly increased in patients requiring Xeloda dose reduction for side effects compared with patients who received the standard dose– hazard ratio = 1.07 (Wald test p=0.73)
*or death
Summary of phase II trial in paclitaxel-pretreated MBC
Xeloda is an effective agent for paclitaxel- pretreated MBC
20% of patients had an objective response;an additional 43% had stable disease
Median survival was 12.6 months
Toxicities were manageable with dose interruption or, where necessary, dose adjustment without compromising efficacy
Blum JL et al. J Clin Oncol 1999;17:485–93
Phase II trial of Xeloda® intaxane-pretreated MBC
Multicentre, phase II, confirmatory, US trial
75* MBC patients
Xeloda 1,250mg/m2 twice daily for 14 days
followed by a 7-day rest period
All patients had received two to threeprior chemotherapy regimens and were pretreated with paclitaxel or docetaxel
*One patient withdrew prior to receiving treatment
Blum JL et al. (submitted)
Ongoing phase II trial of Xeloda® in taxane-pretreated MBC
Ongoing multicentre, phase II, German trial
131 taxane-pretreated MBC patients to be enrolled
Xeloda 1,250mg/m2 twice daily for 14 days followed by a 7-day rest period
Preliminary efficacy (100 patients) and safety (105 patients) data have been reported
Reichardt P et al. Breast Cancer Res Treat 2000;64:83 (Abst 331)
Efficacy of Xeloda® in taxane-pretreated MBC: summary
1Blum JL et al. J Clin Oncol 1999;17:485–932Blum JL et al. (submitted)
3Reichardt P et al. Breast Cancer Res Treat 2000;64:83 (Abst 331)
Pretreated with
Tumourresponse
(%)
Responseduration(months)
TTP(months)
Mediansurvival(months)
Paclitaxel1 (n=162) 20 7.9 3.0 12.6
Taxanes2 (n=74) 26 8.3 3.2 12.2
Paclitaxel 27
Docetaxel 20
Taxanes3 (n=100) 18 9.0 3.5 9.9
TTP = time to disease progression
Xeloda® versus paclitaxel in anthracycline-pretreated patients: randomised, phase II trial
42* patients with anthracycline-pretreated MBCwere randomised to either
– Xeloda (1,250mg/m2 twice daily intermittent
schedule, 14 days on treatment, 7 days off)
– paclitaxel (175mg/m2 on day 1 every 21 days)
O’Reilly SM et al. (submitted)
*One patient in the paclitaxel group withdrew prior to receiving treatment
Efficacy of Xeloda® versus paclitaxel: randomised, phase II trial
Xeloda(n=22)
Paclitaxel(n=19)
Response rate (%) 36 26
95% CI (%) 17–59 9–51
Complete response (%) 14 0
Median response duration(months) 9.4 9.4
Median time to diseaseprogression (months) 3.0 3.1
95% CI (%) 1.4–6.6 2.5–6.5
O’Reilly SM et al. (submitted)
Safety of Xeloda® versus paclitaxel: randomised, phase II trial
Alopecia, paraesthesias and neutropenia
were more common with paclitaxel
Nausea, vomiting, diarrhoea and hand-foot syndrome were more common with Xeloda
O’Reilly SM et al. (submitted)
Xeloda® versus CMF:randomised, phase II trial
Xeloda versus CMF as first-line treatment forMBC (patients who had received prior hormonal treatment for MBC were eligible)
95* women 55 years of age received either
– Xeloda 1,250mg/m2 twice daily intermittent schedule
– CMF (cyclophosphamide 600mg/m2, methotrexate 40mg/m2, 5-FU 600mg/m2) every 21 days
Median age of 69 and 70 years, respectively
O’Shaughnessy J et al. Ann Oncol (in press)
*One patient in each group withdrew prior to receiving treatment
Efficacy of Xeloda® versus CMF:randomised, phase II trial
Xeloda(n=61)
CMF(n=32)
Response rate (%) 30 16
95% CI (%) 19–43 5–33
Complete response (%) 5 0
Median TTP (months) 4.1 3.0
95% CI (months) 3.2–6.5 2.4–4.8
Median survival (months) 19.6 17.2
95% CI (months) 17.1–* 10.5–*
O’Shaughnessy J et al. Ann Oncol (in press)
*Upper limit not yet reached
Xeloda® versus CMF: time to disease progression
Xeloda (n=61)CMF (n=32)
1.0
0.8
0.6
0.4
0.2
0.00 2 4 6 8 10 12 14 16
Est
imat
ed p
rob
abil
ity
Time (months)
4.13.0
O’Shaughnessy J et al. Ann Oncol (in press)
Xeloda® versus CMF: survival
Xeloda (n=61)CMF (n=32)
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
00 2 4 6 8 10 12 14 16 18 20 22 24
Est
imat
ed p
rob
abil
ity
Time (months)
17.2 19.6
O’Shaughnessy J et al. Ann Oncol (in press)
Safety of Xeloda® versus CMF:randomised, phase II trial
Nausea, vomiting, stomatitis and fatiguehad similar incidences with CMF and Xeloda
Diarrhoea and hand-foot syndrome weremore common with Xeloda
Alopecia and neutropenia were morecommon with CMF
O’Shaughnessy J et al. Ann Oncol (in press)
Most frequent (>20%) treatment-related adverse events: safety population (n=319)
60
50
40
30
20
10
0
Grade 1/2
Grade 3
Grade 4
Diarrhoea Hand-foot Nausea Vomitingsyndrome*
Pat
ien
ts (
%)
*Grade 4 not applicable
Grade 3/4 haematological events: safety population (n=319)
Grade 3
Grade 4
10
8
6
4
2
0
Pat
ien
ts (
%)
Leucopenia Anaemia Neutropenia Thrombocytopenia
Patient education
Patient education is essential for the management of Xeloda side effects
Patients should be educated to – recognise the symptoms and severity of side
effects– interrupt treatment upon the development of
moderate or more severe side effects– contact their oncology team (physician, nurse
or pharmacist) for further advice
Conclusions: phase II Xeloda® monotherapy trials in MBC
Xeloda is a highly active treatment for MBC
Clinically meaningful response rates (18–26%) in heavily pretreated patients
Response rates of 30–36% as first- and second-line treatment in two randomised, phase II studies
Acceptable side-effect profile with adverse events manageable by dose titration in patients who develop toxicity while maintaining efficacy
Phase III first-line trial
Xeloda 1,000mg/m2 b.i.d.days 1–14 q21d
Continuous
Xeloda 666mg/m2 b.i.d.
ClassicalBonadonnaCMF q28d
RANDOMISATION
RANDOMISATION
Preferred
Xeloda regimen
CMF
ANZBCTG
Stage 1 Stage 2
1° endpoint: QoL-adjusted survival
RANDOMISATION
Xeloda 1,250mg/m2 b.i.d. intermittent3-weekly cycle x 8
Epirubicin 60mg + paclitaxel 175mg
3-weekly cycle x 8
Epirubicin 90mg 3-weekly cycle x 4
followed bypaclitaxel 90mg
weekly x 12
Xeloda monotherapy
Epirubicin or paclitaxel
monotherapy
Second-line therapy
Xelodamonotherapy
German AGO phase III trial
First-line therapy
1° endpoint: covariate TTP and overall survival
Xeloda® as adjuvant treatment for high-risk, node-negative breast cancer: CALGB trial
Randomised trial of adjuvant chemotherapy in women >65 years of age with early-stage breast cancer
Comparison of Xeloda versus CMF or AC
5-year relapse-free survival as 1° endpoint
2° endpoints: overall survival, QoL, physical function
Assessment of treatment adherence, tolerance to treatment, biological markers of response