Capecitabine versus Bolus Capecitabine versus Bolus 5-FU/Leucovorin as Adjuvant Therapy for 5-FU/Leucovorin as Adjuvant Therapy for

Colon Cancer: X-ACT Trial ResultsColon Cancer: X-ACT Trial Results

James Cassidy, MDColorectal Cancer Update Think Tank Meeting

June 24, 2005

1° endpoint: Disease-free survival (DFS)

2° endpoints Relapse-free survival (RFS) Overall survival Tolerability (NCIC CTC) Pharmacoeconomics QoL

Capecitabine1,250 mg/m2 twice daily,

d1–14, q21d n = 1,004

Bolus 5-FU/LV5-FU 425 mg/m2 plus

LV 20 mg/m2, d1–5, q28dn = 983

Recruitment1998–2001

X-ACT Trial in Adjuvant Treatment of X-ACT Trial in Adjuvant Treatment of Dukes’ C Colon CancerDukes’ C Colon Cancer

Chemo-naïve Dukes’ C,

resection ≤8 weeks

Source: Cassidy J. Presentation. ASCO 2005.

X-ACT Powered to Establish at Least X-ACT Powered to Establish at Least Equivalence of Equivalence of Capecitabine Capecitabine

Sample size to achieve

80% power for at least equivalence in DFS

Noninferiority margin 1.25 for hazard ratio of capecitabine vs 5-FU/LV

Analysis in per-protocol and ITT populations

Secondary analyses

Test for superiority in DFS, RFS, OS

Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

Standard Eligibility CriteriaStandard Eligibility Criteria

Eligible patients Aged 18–75 years Histologically confirmed

Dukes’ C colon cancer Fully recovered after

surgery ECOG PS: ≤1 Life expectancy

≥ 5 years

Excluded patients Metastatic disease Prior cytotoxic

chemotherapy or organ allografts

Clinically significant cardiac disease

Severe renal impairment

Central nervous system disorders

Pregnant or lactating women

Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

Protocol-Defined Populations and EndpointsProtocol-Defined Populations and Endpoints

Populations Intent to treat, all randomized patients Per-protocol population excludes major protocol

violations and patients with <12 weeks treatment Time-related endpoints

Disease-free survival• Relapses or new occurrences of colon cancer and

all deaths Relapse-free survival• Relapses/new occurrences of colon cancer and

deaths related to treatment or colon cancer Overall survival

Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

Bolus 5-FU/LVIV leucovorin

20 mg/m2 +IV 5-FU

425 mg/m2

CapecitabineCapecitabine

1,250 mg/m2 twice daily

Day

Treatment (days 1–14) Rest (days 15–21)

1 2 3 4 5 8 15 21

Repeat cycle x 8(24 weeks)

28

OR

Repeat cycle x 6(24 weeks)

X-ACT Treatment SchedulesX-ACT Treatment Schedules

Source: Twelves C et al. N Engl J Med 2005;352(26):2696-704.

X-ACT Treatment Arms Were Well BalancedX-ACT Treatment Arms Were Well Balanced

Capecitabinen = 1,004 (%)

Bolus 5-FU/LVn = 983 (%)

Age, median (range) 62 (25–80) 63 (22–82)

ECOG 0/1 85/15 85/15

Male/Female 54 / 46 54 / 46

Normal CEA 83 84

T1-2 10 10

T3 76 76

T4 14 14

N 1/2 70/30 71/29

Well differentiated 9 10

Moderately differentiated 65 63

Poorly differentiated/anaplastic 17 20

Source: Cassidy J. Presentation. ASCO 2005.

Other Prognostic Factors Were BalancedOther Prognostic Factors Were Balanced

Capecitabinen = 1,004 (%)

Bolus 5-FU/LVn = 983 (%)

Lymph nodes N1 70 71

N2 30 29

T-stage T1-2 10 10

T3 76 76

T4 14 14

Differentiation well 9 10

moderately 65 63

poorly 16 19

anaplastic 1 1

Source: Twelves C. Presentation. ASCO 2005.

Median follow-up 51 months

Strong Trend to Superior DFS (ITT)Strong Trend to Superior DFS (ITT)

1.0

0.8

0.6

0.40 1 2 3 4 5 6

Years

Est

imat

ed p

rob

abil

ity

Capecitabine (n = 1,004) 64.6%5-FU/LV (n = 983) 61%

HR = 0.87 (95% CI: 0.75–1.00)p < 0.0001

Source: Twelves C. Presentation. ASCO 2005.

Capecitabine versus Bolus 5-FU/LV: Capecitabine versus Bolus 5-FU/LV: Superior Relapse-Free Survival (ITT)Superior Relapse-Free Survival (ITT)

Est

imat

ed p

rob

abil

ity

Capecitabine (n = 1,004)5-FU/LV (n = 983)

0 1 2 3 4 5 6

Years

HR = 0.86 (95% CI: 0.74–0.99)p = 0.0407

1.0

0.8

0.6

0.4

Source: Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.

Capecitabine Showed Trend to Improved Capecitabine Showed Trend to Improved Overall Survival (ITT)Overall Survival (ITT)

Est

imat

ed p

rob

abil

ity

Capecitabine (n = 1, 004) 81.7%5-FU/LV (n = 983) 78.3%

0 1 2 3 4 5 6

Years

HR = 0.89 (95% CI: 0.74–1.07)p < 0.001

1.0

0.8

0.6

0.4

Source: Cassidy J. Presentation. ASCO 2005.

Fewer Relapses in Liver and Lymph Nodes Fewer Relapses in Liver and Lymph Nodes with with Capecitabine Capecitabine

Number of relapses

Capecitabinen = 1,004

Bolus 5-FU/LVn = 983

TotalAs only

site TotalAs only

site

Total number of relapses 323 357

Colon, rectum 58 41 60 43

Lymph nodes 44 20 57 35

Liver 126 93 145 110

Lung 58 35 58 39

Other 101 68 99 65

* Data points from KM curves

Sources: 1 Haller DG et al. J Clin Oncol 2004; In Press2 André T et al. J Clin Oncol 2003;15:2896–9033 IMPACT. Lancet 1995;345(8955):939–44

X-ACT Mayo Comparable to Mayo in Other Trials X-ACT Mayo Comparable to Mayo in Other Trials (Dukes’ C, Colon Only)(Dukes’ C, Colon Only)

INT0089*n = 7691

Andre*n = 2562

IMPACTn = 3133

X-ACTn = 983

Mayo3-year DFS

63 61 62 61

Mayo3-year OS

73 81 78 78

Treatment ExposureTreatment Exposure

Median dose intensity

Capecitabine 93% (quartiles 77-100%)

Bolus 5-FU/LV 92% (quartiles 78-100%)

Patients completing >12 weeks treatment at full dose

Capecitabine 75%

Bolus 5-FU/LV 67%

Majority of patients completed the full course of treatment

Capecitabine 84% completed all 8 cycles

Bolus 5-FU/LV 89% completed all 6 cycles

Fewer Key Grade III/IV Toxicities and Fewer Key Grade III/IV Toxicities and Later Onset with CapecitabineLater Onset with Capecitabine

1.0

0.8

0.6

0.4

0.2

0

p < 0.001

0 1 2 3 4 5 6 7 8Months

5-FU/LVCapecitabine

Overall safety profile: Grade III to IV diarrhea, stomatitis, nausea, vomiting, alopecia, HFS, neutropenia

Source: Cassidy J. Presentation. ASCO 2005.

Est

imat

ed p

rob

abil

ity

of

Gra

de

III/

IV a

dve

rse

even

t

* p < 0.001† Laboratory value

Treatment-related AEs

*

*

*

*

Diarrhea Stomatitis Hand-foot Neutropenia† Nausea/ Alopecia syndrome vomiting

100

80

60

40

20

0

Capecitabine (n = 993)

Bolus 5-FU/LV (n = 974)

*

*

Pat

ien

ts (

%)ToxicityToxicity

Nu

mb

er o

f cy

cles

Before After Before After Before After

Hand-foot syndrome Diarrhea Stomatitis

Grade II

Grade III

Grade IV

20

15

10

5

0

Capecitabine Dose Modification Reduces the Capecitabine Dose Modification Reduces the Recurrence of Adverse EventsRecurrence of Adverse Events

Improved Tolerability Profile of Capecitabine Improved Tolerability Profile of Capecitabine Maintained in ElderlyMaintained in Elderly

All grades

Capecitabine (%) Bolus 5-FU/LV (%)

≥70 years(n = 186)

≥70 years(n = 205)

Diarrhea 52 68

Stomatitis 23 67

Hand-foot syndrome 63 8

Nausea 33 47

Fatigue 17 19

Neutropenia 4 31

1.0

0.8

0.6

0.4

0.2

0

Est

imat

ed p

rob

abili

ty

0 12 24 36 48 60 72Months

Full dose capecitabineInter dose capecitabineLow dose capecitabine

Capecitabine Efficacy Maintained with Appropriate Capecitabine Efficacy Maintained with Appropriate Dose ReductionDose Reduction: DFS: DFS

532 510 459 403 332 280 194 113 61 12 4 0 0343 323 293 265 218 174 122 81 37 13 5 0 0120 90 77 70 60 50 34 20 10 3 1 0 0

No. at riskFull doseInter doseLow dose

X-ACT: Quality of Life Maintained Over Time X-ACT: Quality of Life Maintained Over Time (QLQ C-30)(QLQ C-30)

5-FU / LVCapecitabine

100

80

60

40

20

0Baseline 7 9 16 17 25

Weeks (of trial treatment)

889 817 894 912841 746 838 865

n = n =

Glo

bal

hea

lth

sta

tus

sco

re

Source: Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.

*Also balanced first- versus second-line chemotherapy

Poststudy Chemotherapy after RelapsePoststudy Chemotherapy after RelapseSimilar in Both ArmsSimilar in Both Arms

Percent patients with chemotherapy*

Capecitabinen = 372

5-FU/LVn = 404

Regimens based on:

5-FU 17 16

Irinotecan 39 35

Oxaliplatin 32 29

Capecitabine 4 10

Others 9 6

-1864

1450

-3004

-57 -259

7

Net costs per patient versus 5-FU/LV (£)

4 000

2 000

0

–2 000

–4 000

Total Drugs Administration Hospital Medications Consultations use

Sources: Updated from Douillard J-Y et al. Ann Oncol 2004;15(Suppl 3):iii73; Cassidy J. Presentation. Colorectal Cancer Update Think Tank Meeting 2005.

Replacement of 5-FU/LV with Xeloda is Net Cost Replacement of 5-FU/LV with Xeloda is Net Cost Saving: Direct Payer CostsSaving: Direct Payer Costs

X-ACT Trial ConclusionsX-ACT Trial Conclusions

Disease-free survival for capecitabine at least equivalent to 5-FU/leucovorin

Capecitabine improved relapse-free survival

Capecitabine associated with significantly fewer adverse events

Capecitabine is an effective alternative to IV 5-FU/leucovorin as adjuvant therapy in patients with Stage III disease