Xeloda and Xeloda-based combinations in the treatment of MBC Steffan Kahlert Insert affiliation.

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


Xeloda monotherapy: minimal myelosuppression (n=498)

Patients (%)

Leukopenia Neutropenia Anemia Thrombo-cytopenia

40

20

0

Grade 3

Grade 4


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


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


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


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


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


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

Xeloda and Xeloda-based combinations in the treatment of MBC Steffan Kahlert Insert affiliation.

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