taxane-pretreated metastatic breast cancer (mbc): investigational agents ttp = median time to...

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