Xeloda for the adjuvant treatment of stage III colon cancer

Chris Twelves University of Leeds and Bradford NHS Trust

UK

X-ACT trial in adjuvant treatment of stage III colon cancer

1° endpoint: disease-free survival (DFS)

2° endpoints: relapse-free survival (RFS); overall survival; tolerability (NCIC CTG); pharmacoeconomics; quality of life

Chemonaïve Stage III,

resection 8 weeks

Xeloda1 250mg/m2 twice daily,

days 1–14, q21d (n=1 004)

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

LV 20mg/m2, days 1–5, q28d(n=983)

Recruitment1998–2001

24 weeks

X-ACT powered to establish at least equivalence of Xeloda to 5-FU/LV

Primary endpoint DFS

– timing of analysis driven by number of events

– 80% power for at least equivalence

– if upper limit of 95% CI for HR <1.25, then primary endpoint met

Secondary analyses

– tests for superiority

– DFS, RFS, overall survival

– multivariate, subgroup

All analyses shown were prospectively planned

Twelves C et al. N Engl J Med 2005;352:2696–704

Primary endpoint clearly met: trend to superior DFS with Xeloda (ITT)

Estimated probability

0 1 2 3 4 5 6

1.0

0.8

0.6

0.4

Absolute differenceat 3 years: 3.6%

Test for superiorityp=0.0528

Xeloda (n=1 004)

5-FU/LV (n=983)

Years

HR=0.87 (95% CI: 0.75–1.00)Compared to HR upper limit 1.20, p<0.0001

Twelves C et al. N Engl J Med 2005;352:2696–704

3-year DFS

64.2%

60.6%

Xeloda reduces risk of relapse versus bolus 5-FU/LV (DFS)

Hazard ratio and 95% CI

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Decreased risk Increased risk

HR=0.87 (95% CI: 0.75–1.00)p=0.0528

13% absolute risk reduction

Twelves C et al. N Engl J Med 2005;352:2696–704

Xeloda consistently better than 5-FU/LV in subgroup analysis for DFS

Hazard ratio and 95% CI

Xeloda better Bolus 5-FU/LV better

0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8

ITT population

MaleFemale

<40 40–69 years old70

N1 (1–3 nodes)N2 (4 nodes)

Baseline CEA <ULNBaseline CEA >ULN

1 987

1 073 914

76 1 514 397

1 391 596

1 669 159

n

Twelves C et al. N Engl J Med 2005;352:2696–704

What’s the difference between RFS and DFS?

In patients with documented relapse

RFS RelapseNew colon

cancer

DFS RelapseNew colon

cancer

In patients without relapse, death due to

Colon cancer

Treatment

toxicity

Colon cancer

Treatment

toxicityOther

causes

Xeloda versus bolus 5-FU/LV: significantly superior RFS (ITT)

Estimated probability

Absolute difference at 3 years: 3.6%

1.0

0.8

0.6

0.40 1 2 3 4 5 6

Years

HR=0.86 (95% CI: 0.74–0.99)p=0.0407

3-year

Xeloda (n=1 004) 65.5%

5-FU/LV (n=983) 61.9%

Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

Xeloda reduces risk of relapse versus bolus 5-FU/LV (RFS)

Hazard ratio and 95% CI

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Decreased risk Increased risk

HR=0.86 (95% CI: 0.74–0.99)p=0.0407

14% absolute risk reduction

Twelves C et al. N Engl J Med 2005;352:2696–704

Xeloda showed trend to improved overall survival (ITT)

Estimated probability

0 1 2 3 4 5 6

Years

Absolute difference at 3 years: 3.7%

1.0

0.8

0.6

0.4

3-year

Xeloda (n=1 004) 81.3%

5-FU/LV (n=983) 77.6%

HR=0.84 (95% CI: 0.69–1.01)p=0.0706

Twelves C et al. N Engl J Med 2005;352:2696–704

Xeloda reduces risk of death versus bolus 5-FU/LV (overall survival)

Hazard ratio and 95% CI

0.4 0.6 0.8 1.0 1.2 1.4 1.6

Decreased risk Increased risk

HR=0.84 (95% CI: 0.69–1.01)p=0.0706

16% absolute risk reduction

Twelves C et al. N Engl J Med 2005;352:2696–704

Xeloda versus 5-FU/LV: consistent benefit in all efficacy parameters

Worsethan

5-FU/LV

Betterthan

5-FU/LV

0.6 0.8 1.0 1.2 1.4 1.6

Upper margin for equivalence in DFS

DFS

Overall survival

Upper margin forsuperiority

Same as

5-FU/LV

p=0.0528

p=0.0407

p=0.0706

Twelves C et al. N Engl J Med 2005;352:2696–704

RFS

Riskreduction

(%)

13

16

14

Treatment with Xeloda significantly improved DFS, RFS and OS

Consistent 20% reduction in risk with Xeloda

Multivariate analysis Hazard ratio 95% CI p value

DFS 0.826 0.709–0.962 0.0141

RFS 0.809 0.691–0.946 0.0080

OS 0.788 0.643–0.964 0.0208

Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

Xeloda has a favourable safety profile

Adjuvant Xeloda has improved safety versus bolus 5-FU/LV

Significantly less

– diarrhoea, nausea / vomiting, stomatitis, alopecia

– grade 3/4 neutropenia and neutropenic fever/sepsis

– early severe toxicity

Improved safety profile maintained in older patients

Hand-foot syndrome more common, but manageable

Scheithauer W et al. Ann Oncol 2003;14:1735–43

Grade 3 / 4 diarrhoea, stomatitis, nausea, vomiting, alopecia, hand-foot syndrome, neutropenia

1.0

0.8

0.6

0.4

0.2

0.0

Estimated probability of agrade 3 / 4 adverse event

0 1 2 3 4 5 6 7 8Months

5-FU/LVXeloda

p<0.001

Fewer and later onset of key grade 3 / 4 adverse events with Xeloda versus 5-FU/LV

Twelves C et al. N Engl J Med 2005;352:2696–704

*p<0.001†Laboratory value

Adjuvant Xeloda: improved safety profile versus bolus 5-FU/LV (all grades)

Treatment-related AEs

*

*

*

*

Diarrhoea Stomatitis Hand-foot Neutropenia† Nausea/ Alopeciasyndrome vomiting

100

80

60

40

20

0

Xeloda (n=993)

Bolus 5-FU/LV (n=974)

*

*

Patients (%)

Scheithauer W et al. Ann Oncol 2003;14:1735–43

Adjuvant Xeloda: improved safety profile versus bolus 5-FU / LV (grade 3 / 4)

* *

Diarrhoea Stomatitis Hand-foot Neutropenia† Nausea/ Neutropenicsyndrome vomiting fever/sepsis

Patients (%)

* *

80

70

60

50

40

30

20

10

0

*p<0.001†Laboratory value Scheithauer W et al. Ann Oncol 2003;14:1735–43

Xeloda (n=993)

Bolus 5-FU/LV (n=974)

Improved safety profile of Xeloda maintained in older patients (>70 years)

All grades

Xeloda (%) (n=186)

Bolus 5-FU/LV (%) (n=205)

Diarrhoea 52 68

Nausea 33 47

Stomatitis 23 67

Hand-foot syndrome 63 8

Fatigue 17 19

Neutropenia* 4 31

Díaz-Rubio E et al. J Clin Onco 2004;22:303s (Abst 3737)

*Grade 3/4 laboratory abnormalities (NCI CTCAE)

Oral Xeloda enables active management

Patients (%)

Xeloda (n=995)

Bolus 5-FU/LV(n=974)

Completed full course of treatment

84 88

Needed dose reduction 42 44

Needed interruption 15 5

Needed delay 46 29

Needed dose reduction, interruption or delay 57 52

F. Hoffmann-La Roche, data on file

Cycles (%)

Before After Before After BeforeAfterHand-foot syndrome Diarrhoea Stomatitis

Grade 2

Grade 3

Grade 4

Xeloda dose modification reduces the recurrence of AEs

20

15

10

5

0

Cassidy J et al. J Clin Oncol 2004;22:247s (Abst 3509)

Xeloda is more convenient and cost saving compared with 5-FU/LV

Xeloda has improved convenience: only nine ambulatory consultations vs 30 with 5-FU/LV

Mean visitsper patient

Xeloda (n=995)

5-FU/LV (n=974)

3 0

2 0

1 0

0AE treatment Drug administration Total

McKendrick JJ et al. J Clin Oncol 2004;23:264s (Abst 3578; poster update)

–1324

–142

–1182

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

Replacement of 5-FU/LV with Xeloda

is net cost saving: travel costs

Total Travel Travel time

4 000

2 000

0

–2 000

–4 000

Cassidy J et al. Submitted

Fewer outpatient visits for chemotherapy administration with Xeloda versus 5-FU/LV

Mean number per 100 patients

3 000

2 500

2 000

1 500

1 000

500

0Xeloda (n=995) 5-FU/LV (n=974)

2 800

735

Cassidy J et al. Submitted

Fewer hospitalisations for adverse events (AEs) with Xeloda versus 5-FU/LV

10.6

113

12.8

130

Mean number per 100 patients

Admissions Total days

150

125

100

75

50

25

0

Xeloda (n=995)

5-FU/LV (n=974)

Cassidy J et al. Submitted

Xeloda requires fewer costly medications for management of AEs

Days of use per 100 patients

Medication Xeloda (n=995) 5-FU/LV (n=974)

Antiemetics/antidiarrhoeals 1933 2534

Dermatologicals/emollients 951 229

Stomatologicals/triazoles 140 775

Benzodiazepines 152 245

Antibiotics/cephalosporins 128 133

Cytokines/growth factors 5 21

Total 3 317 3 945

Cassidy J et al. Submitted

1479

-4732

-61 -260

9

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

4 000

3 000

2 000

1 000

0

–1 000

–2 000

–3 000

–4 000

–5 000

€5 810 saved per patient

Xeloda is a uniquely ‘dominant’ treatmentin cancer chemotherapy: UK, Italy, USA

Drugs Administration Hospital Medications Consultations use

-3565

Total

Cassidy J et al. Br J Cancer. In press

Xeloda as a dominant treatment strategy confirmed in Italian study

Xeloda 5-FU/LV

Planned treatment received (%) 92 93

Clinic visits (n) 7.4 28.0

Acquisition cost (€) 2533 231

Administration cost (€) 152 4338

Increase in QALM vs 5-FU/LV 6.5

Cost-savings for Xeloda (€) 2234

Di Costanzo F et al. Eur J Cancer Suppl 2005;3:191 (Abst 675)

Xeloda versus Mayo Clinic regimenin adjuvant treatment

Benefits

At least equivalent efficacy

Trend to improved DFS and OS

Improved RFS

toxicity

Convenience

Cost savings

Risks

hand-foot syndrome (manageable)

Xeloda-based combinations in the adjuvant treatment of colon cancer

1de Gramont A et al. J Clin Oncol 2005;23:246s (Abst 3501); 2Wolmark N et al. J Clin Oncol 2005;23:246s (Abst LBA3500)

Combinations in adjuvant chemotherapy: recent evidence

Oxaliplatin combinations

DFS hazard ratio

(95% CI)

p value

OS hazard ratio

(95% CI)

p value

MOSAIC1 0.77 (0.65–0.90)

<0.001

0.91 (0.75–1.11)

NR

NSABP C-072 0.79 (0.67–0.93)

<0.004

NR

NR

NR = not reported

3CALGB89803 NR 0.84 NR NR

PETACC-34 0.89 (0.77–1.11)

0.091

NR

NR

3Saltz LB et al. J Clin Oncol 2004;22:245S (Abst 3500); 4Van Cutsem E et al. J Clin Oncol 2005;23:3s (Abst LBA8)

Irinotecan combinations

Xeloda: a replacement for 5-FU/LV in adjuvant treatment

Based on the X-ACT data, Xeloda is replacing 5-FU/LV for the adjuvant treatment of colon cancer

XELOX can optimise oxaliplatin-containing combinations

– similar high efficacy and favourable safety profile compared with FOLFOX in metastatic CRC

– improved convenience

– simplifies increasingly complex combinations with biologics in ongoing trials

XELOXA: adjuvant Xeloda + oxaliplatin (XELOX) versus 5-FU / LV

1º endpoint: DFS – XELOX >5-FU/LV

2º endpoints: survival; tolerability; convenience; pharmacoeconomics

Completed recruitment September 2004

XELOX 24 weeks

Bolus 5-FU/LV Mayo Clinic

or Roswell Park

24 or 32 weeks

Chemotherapy-naive stage III

colon cancer n=1 886

XELOX is an ideal combination in the adjuvant setting

1Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)

XELOXA1

Grade 3/4 toxicities XELOX 5-FU/LV

Diarrhoea 19 20

Stomatitis <1 8

Nausea 5 4

Vomiting 6 3

Neurosensory 11 0

HFS 5 <1

Neutropenia 8 15

Febrile neutropenia <1 4

XELOX is an ideal combination in the adjuvant setting

1Schmoll H-J et al. Eur J Cancer Suppl 2005;3:173 (Abst 617)2André T et al. N Engl J Med 2004;350:2343–51

3Smith R et al. Proc Am Soc Clin Oncol 2003;22:294 (Abst 1181; poster update)

XELOXA1 MOSAIC2 NSABP C-073 Grade 3/4 toxicities 5-FU/LV FOLFOX FLOX

Diarrhoea 20 12 36

Stomatitis 8 3 NR

Nausea 4 5 15

Vomiting 3 6 12

Neurosensory 0 12 8

HFS <1 2 NR

Neutropenia 15 41 5

Febrile neutropenia 4 2 NR

XELOX

19

<1

5

6

11

5

8

<1

Adjuvant evaluations of Xeloda combinations in colon cancer

Trial Patients (n) Endpoint Status

XELOXA

XELOX vs bolus 5-FU / LV

1 850 DFS Recruitment complete

Roche three-arm trial

FOLFOX vs XELOX + Avastin vs FOLFOX + Avastin

3 450 DFS Recruiting

QUASAR 2

Xeloda ± Avastin

3 510 DFS Recruiting

Xeloda: the evidence

At least as effective as 5-FU/LV for stage III colon cancer

– superior RFS, trend to superior DFS and OS

Fewer grade 3/4 toxicities than 5-FU/LV

Dosing flexibility improves side-effect management

Convenience of oral administration allows patients to lead a more normal lifestyle

Cost effective

Effective, safe and convenient combination partner, simplifying combination treatment

The fluoropyrimidine of choice in the adjuvant treatmentof colon cancer