Phase III studies of Xeloda ® in colorectal cancer (CRC) Two phase III trials with identical...

Phase III studies of Xeloda® in colorectal cancer (CRC)

Two phase III trials with identical protocols (one in the Americas, one in Europe, Israel and Australasia)

Patients were randomised to first-line

– Xeloda: 1,250mg/m2 twice daily for 14 days followed by a 7-day rest period

– Mayo Clinic regimen: leucovorin (LV) 20mg/m2 + 5-FU 425mg/m2 days 1–5 every 28 days, i.v. bolus

Baseline characteristics

Xeloda(n=603)

5-FU/LV(n=604)

Male/female (%) 59/41 61/39

Age (years): median, range 64 (23–86) 63 (24–87)

KPS (%): median, range 90 (70–100) 90 (70–100)

KPS 90% (%) 68 68

Colon/rectal cancer (%) 70/30 71/29

Predominant metastatic siteLiver/lung (%) 72/12 73/14

Prior adjuvant treatment (%) 24 26

Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)KPS = Karnofsky Performance Score

Overall tumour response rate

Xeloda(n=603)

5-FU/LV(n=604)

PR + CR (%) 25.7 16.7 p<0.0002

Stable disease (%) 47.8 52.2

PR = partial response; CR = complete response

Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

Response rates by subpopulation

Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)*p<0.05†Predominant site of metastases

Res

po

nse

ra

te (

%)

Prior No prior Liver† Lung† Single Multipleadjuvant adjuvant metastatic metastatic

site sites

*

**

*

*

*

40

35

30

25

20

15

10

5

0

Xeloda (n=603)

5-FU/LV (n=604)

Time to first response

0

2

4

6

8

10

12

14

0–63 64–105 106–147 >147

Xeloda (n=603)

5-FU/LV (n=604)

Study day

Pat

ien

ts (

%)


Time to disease progression*

1.0

0.8

0.6

0.4

0.2

0

Hoff PM. Ann Oncol 2000;11 (Suppl. 4):60 (Abst 263)*or death

Median (CI) Xeloda: 4.6 (4.3–5.3)5-FU/LV: 4.7 (4.3–5.4)

Hazard ratio = 0.997(0.885–1.123)

Log-rankp=0.9535

0 5 10 15 20 25

Time (months)

Xeloda (n=603) 5-FU/LV (n=604)

4.6 4.7

Est

imat

ed p

rob

abili

ty

Overall survival

Median (CI) Xeloda: 12.9 (12.0–14.0)5-FU/LV: 12.8 (11.8–14.0)

Hazard ratio = 0.96(0.85–1.08)

Log-rankp=0.48


0 5 10 15 20 25 30 35 40 45

Est

imat

ed p

rob

abili

ty

Time (months)

Xeloda (n=603) 5-FU/LV (n=604)

12.8 12.9

1.0

0.8

0.6

0.4

0.2

0

Summary of efficacy

Oral Xeloda achieves at least equivalent efficacy compared with 5-FU/LV

Superior (p<0.0002) response rates

Equivalent time to disease progression

Equivalent overall survival


Most common treatment-related clinical adverse events

0

10

20

30

40

50

60

70

Diarrhoea Stomatitis Hand-foot Nausea Vomiting Alopecia Fatiguesyndrome

Pat

ien

ts (

%)

Xeloda (n=596)

5-FU/LV (n=593)

*

*

*

*

*

*p<0.001 Hoff PM. Ann Oncol 2000;11(Suppl. 4):60 (Abst 263)

Grade 3/4 treatment-relatedadverse events

0

2

4

6

8

10

12

14

16

18Xeloda (n=596)5-FU/LV (n=593)

Pat

ien

ts (

%)

Diarrhoea Stomatitis Hand-foot Nausea Vomiting Neutropenicsyndrome† fever + sepsis

*p<0.0001†Grade 4 not applicable

**

*


Most common grade 3/4 laboratory abnormalities

Xeloda (%)(n=596)

5-FU/LV (%)(n=593)

HaematologyHaemoglobin (<80g/L)White blood cells (<2.0x109/L)Neutrophils (<1.0x109/L)Platelets (<50x109/L)

2.01.32.21.0

1.711.621.1

0.3

ChemistryASAT (SGOT) (>5.0 x ULN)Alkaline phosphatase (>5.0 x ULN)Total bilirubin (>1.5–3 x ULN)Total bilirubin (>3 x ULN)

0.73.4

18.34.5

1.24.13.42.5

NCIC common toxicity criteria; ULN = upper limit of normal


Hospitalisations for treatment-related adverse events

0

20

40

60

80

100

120Xeloda (n=596)5-FU/LV (n=593)

Diarrh

oea

Vomiti

ng

Stom

atiti

s

Neutro

penic

feve

r + s

epsi

sOve

rall

No

. o

f h

osp

ital

isat

ion

s

Hand-fo

ot

syndro

me

Infe

ctio

ns

*p<0.005

**

*


Incidence and timing of dose modification

Xeloda(n=596)

5-FU/LV(n=593)

Any dose reduction (%) 33.9* 42.2

First-level reduction† (%) 29.2 41.3Median time to reduction (months) 2.5 1.2

Second-level reduction‡ (%) 12.2 0.5Median time to reduction (months) 3.6 3.2

*P=0.0037†Reduction to 75% of baseline Xeloda dose or 70–80% of baseline 5-FU dose‡Reduction to 50% of baseline Xeloda dose or 49–64% of baseline 5-FU dose

Cassidy J. Ann Oncol 2000;11(Suppl. 4):62 (Abst 271)

Xeloda® dose modification: impact on efficacy

The risk of disease progression or death was not increased in patients requiring Xeloda dose modification– for patients with any dose reduction, hazard

ratio = 0.97 – for patients with dose reductions to 50%

of baseline dose, hazard ratio = 1.06

The Xeloda dose modification scheme was effective in preventing the recurrence of toxicities


Xeloda® dose modification:impact on adverse events

*Grade 4 not applicable

No

. o

f p

atie

nts

100

80

60

40

20

0Before After Before After Before After

Hand-foot syndrome* Diarrhoea Stomatitis


Grade 2

Grade 3

Grade 4

Patient education

Patient education is essential for the management of Xeloda toxicities

Patients should be educated to– recognise the symptoms and severity of

side effects– interrupt treatment upon the development

of moderate or more severe toxicities– contact their oncology team (physician,

nurse or pharmacist) for further advice

Summary of safety

Compared with 5-FU/LV, oral Xeloda provides clinicallymeaningful improvements

Significantly lower incidence of diarrhoea, stomatitis,nausea and alopecia

Significantly less grade 3/4 stomatitis and neutropenia leading to less neutropenic fever/sepsis

More hand-foot syndrome, but rarely led to hospitalisation or withdrawal

Fewer and later dose reductions

Significantly lower treatment-related hospitalisation rate


Xeloda® monotherapy in CRC: conclusions

Xeloda is a convenient oral agent for first-line treatment of metastatic CRC

High efficacy (superior response rate, equivalent overall survival and time to disease progression) compared with i.v. 5-FU/LV (Mayo Clinic regimen)

Better tolerated than i.v. 5-FU/LV

This opens perspectives for adjuvant treatment and for combination treatment in advanced CRC

Xeloda® as adjuvant treatment for colon cancer: X-ACT study

Open-label, randomised, multicentre, phase III trial

Recruitment of 1,956 Dukes’ C colon cancer patients is on target for completion in 2001

Xeloda 1,250mg/m2 twice daily, days 1–14 every21 days x 8 versus 4-weekly Mayo Clinic regimen x 6

Disease-free survival as 1° endpoint

2° endpoints: overall survival, safety, quality of life, health economics, measurement of biochemical markers in selected centres

Phase III trials in CRC: study regimen versus Mayo Clinic regimen‡§

Study regimen/Mayo Clinic regimen; *p0.01†Response rate reported for measurable patients only (79% of ITT population)‡Comparator arm: i.v. bolus 5-FU 500mg/m2, days 1–5 every 28 days, without LV§Comparator arm: LV 200mg/m2 plus 5-FU 400mg/m2, days 1–5 every 28 days

RegimenResponse rate

(%)TTP

(months)Median survival

(months)

AIO 20.5/11.5 6.4/4.1* 13.2/12.0 Schmoll et al. 2000

De Gramont† 32.6/14.4* 6.3/5.0* 14.2/13.0 De Gramont et al. 1997

Roswell Park‡ 30.3/12.1* N/A 12.6/10.6 Petrelli et al. 1989

Raltitrexed 19.3/16.7 4.7/3.6 10.3/10.3 Cunningham et al. 1996

Raltitrexed§ 18.6/18.1 3.9*/5.1 10.9/12.3 Cocconi et al. 1998

UFT/LV 11.7/14.5 3.5*/3.8 12.4/13.4 Pazdur et al. 1999

Xeloda 25.7/16.7* 4.6/4.7 12.9/12.8 Hoff 2000

Phase III studies of Xeloda ® in colorectal cancer (CRC) Two phase III trials with identical...

Documents

Transcript of Phase III studies of Xeloda ® in colorectal cancer (CRC) Two phase III trials with identical...