Xeloda in colorectal cancer: moving into the adjuvant setting

1
Xeloda in colorectal cancer moving into the
adjuvant setting

• Axel Grothey
• Mayo ClinicRochester, Minnesota, USA

2
Oral Xeloda replacing 5-FU/LV as the backbone of
colorectal cancer (CRC) therapy

• Approved worldwide in first-line metastatic CRC
• highly effective, tolerable and more convenient
  combination partner than 5-FU/LV
• Provides improved adjuvant treatment vs 5-FU/LV
• consistent benefit in DFS, RFS and OS1
• favourable safety2
• no need for pumps and their associated risk3
• Xeloda should replace 5-FU now

1Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst
3509) 2Scheithauer W et al. Ann Oncol
200314173543 3Verso M et al. J Clin Oncol
200321366575
3
TP-activated oral Xeloda targets residual tumour
cells
Intestine
Liver
Xeloda
Tumour gtgt healthy tissue
Xeloda
CE
5'-DFCR
5'-DFCR
CyD
CyD
5'-DFUR
5'-DFUR
Thymidine phosphorylase (TP)
5-FU
5'-DFCR 5'-deoxy-5-fluorocytidine 5'-DFUR
5'-deoxy-5-fluorouridine CyD cytidine
deaminase CE carboxylesterase
4
Adjuvant chemotherapy improves outcomes in stage
III colon cancer

• Adjuvant therapy reduces risk of recurrence and
  death
• 5-FU-based chemotherapy superior to observation
• Best arm always contained leucovorin
• No advantage with 12 vs 6 months therapy
• 6 months bolus 5-FU/LV became standard of care

5
Adjuvant FOLFOX reduces the risk of relapse
compared with infused LV5FU2

• FOLFOX provides benefit in stage II / III colon
  cancer1
• 23 reduction in risk of recurrence with FOLFOX
  is a significant and meaningful benefit1
• DFS predicts for overall survival2 therefore
  improved survival would be expected with FOLFOX

1André T et al. N Engl J Med 2004350234351 2Sar
geant DJ et al. Proc Am Soc Clin Oncol
200423246 (Abst 3502)
6
X-ACT trialXeloda, a first choice in adjuvant
colon cancer
7
X-ACT trial in adjuvant treatment of Dukes C
colon cancer
Xeloda 1 250mg/m2 twice daily, d114, q21d n
1 004
Recruitment 19982001

• 1 endpoint disease-free survival (DFS)
• 2 endpoints
• relapse-free survival (RFS)
• overall survival
• tolerability (NCIC CTG)
• pharmacoeconomics
• QoL

Chemo-naïve Dukes C, resection lt8 weeks
24 weeks
Bolus 5-FU/LV 5-FU 425mg/m2 plus LV 20mg/m2,
d15, q28d n 983
8
X-ACT powered to establish at least equivalence
of Xeloda to 5-FU/LV

• Primary endpoint DFS (event driven)
• 80 power for at least equivalence
• if upper limit of 95 CI for HR lt1.25, then
  primary endpoint met
• Definitions
• RFS relapses / new colon cancer all deaths due
  to colon cancer or treatment
• DFS RFS all deaths from other causes
• All analyses shown were prospectively planned

9
X-ACT treatment armswere well balanced
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
10
X-ACT efficacy resultsMedian follow-up 3.8 years
11
Xeloda vs bolus 5-FU/LV strong trend to
superior DFS (ITT)
Estimated probability
3-year Xeloda (n1 004) 64.2 5-FU/LV
(n983) 60.6
1.0 0.8 0.6 0.4
HR 0.87 (95 CI 0.751.00)p0.0528
0 1 2 3 4 5 6
Years
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
12
Xeloda versus bolus 5-FU/LV superior RFS (ITT)
Estimated probability
3-year Xeloda (n1 004) 65.5 5-FU/LV
(n983) 61.9
1.0 0.8 0.6 0.4
HR 0.86 (95 CI 0.740.99)p0.0407
0 1 2 3 4 5 6
Years
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
13
Xeloda reduces risk of relapse versus bolus
5-FU/LV
Hazard ratio (HR)
Increased risk
2
No difference in risk
1
14 absolute risk reduction
Decreased risk
HR0.86 (95 CI 0.740.99) p0.0407
0
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
14
Xeloda showed trend to improved OS (ITT)
Estimated probability
3-year Xeloda (n1 004) 81.3 5-FU/LV
(n983) 77.6
1.0 0.8 0.6 0.4
HR 0.84 (95 CI 0.691.01)p0.0706
0 1 2 3 4 5 6
Years
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
15
Xeloda reduces risk of death versus bolus 5-FU/LV
Hazard ratio (HR)
Increased risk
2
No difference in risk
1
16 absolute risk reduction
Decreased risk
HR0.84 (95 CI 0.691.01) p0.0706
0
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
16
Treatment with Xeloda predicted for improved
DFS, RFS and OS

• Factors considered age, gender, lymph nodes,
  time from surgery to randomisation, baseline CEA,
  country

Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
17
DFS subgroup analysis for prognostic factors
Xeloda better
Bolus 5-FU/LV better
n
ITT population Male Female lt40 4069
years old 70 N1 (13 nodes) N2 (4
nodes) Baseline CEA ltULN Baseline CEA gtULN
1 987 1 074 912 76 1 543 396 1 389 593 1
672 155
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst
3509)
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
Hazard ratio and 95 CI
18
Xeloda consistent benefit in DFS, RFS and OS

• DFS
• 13 risk reduction (p0.0528)
• 3.6 absolute difference at 3 years
• RFS
• significant 14 risk reduction (p0.0407)
• 3.6 absolute difference at 3 years
• OS
• 16 risk reduction (p0.0706)
• 3.7 absolute difference at 3 years
• Efficacy results confirmed by multivariate and
  subgroup analysis

Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
19
Xeloda demonstrates improved efficacy versus
bolus 5-FU/LV . . .but what about safety?
20
Adjuvant Xeloda improves 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 200314173543
21
Difference in time to onset and incidence of key
grade 3/4 toxicities
Estimated probability of a grade 3/4 AE
1.0 0.8 0.6 0.4 0.2 0
5-FU/LV Xeloda
plt0.001
0 1 2 3 4 5 6 7 8
Months

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

22
Improved safety profile of Xeloda maintained in
elderly
Grade 3/4 lab abnormalities (NCI CTCAE v3.0)
Díaz-Rubio E et al. Proc Am Soc Clin Oncol
200423304 (Abst 3737)
23
Adjuvant chemotherapy needs active management
Cassidy J et al. Proc Am Soc Clin Oncol
Late-breaking Abstract Book 20042314 (Abst 3509)
24
Xeloda dose modification reduces the recurrence
of adverse events
cycles
20
Grade 2 Grade 3 Grade 4
15
10
5
0
Before After Before After Before After
Hand-foot syndrome Diarrhoea Stomatitis
25
Xeloda efficacy maintained with appropriate dose
reduction DFS
Estimated probability
1.0 0.8 0.6 0.4 0.2 0
Xeloda dose intensity gt90 (n532) 6090
(n343)
0 12 24 36 48 60 72
Months
26
Xeloda should be a first choice for the adjuvant
treatment of colon cancer

• Consistent benefit in DFS, RFS and OS
• Improved safety profile
• Xeloda should replace 5-FU/LV in adjuvant
  treatment of colon cancer

27
XELOX and XELIRI highly effective alternatives
to 5-FU-based combinations
28
Response rates with Xeloda backbonecompare
favourably with 5-FU combinations
Response ()
XELOX (n96)1
FOLFOX4 (n267)2
XELIRI (n52)3
IFL (n264)2
FOLFIRI (n145)4
1Cassidy J et al. J Clin Oncol 200422208491
2Goldberg R et al. J Clin Oncol 2004222330
3Patt YZ et al. Proc Am Soc Clin Oncol
200423271 (Abst 3602) 4Douillard JY et al.
Lancet 200035510417
29
Survival and TTP with Xeloda backbonecompare
favourably with 5-FU combinations
XELOX (n96)1
FOLFOX4 (n267)2
XELIRI (n52)3
TTP OS
IFL (n264)2
FOLFIRI (n145)4
Months
1Cassidy J et al. J Clin Oncol 200422208491
2Goldberg R et al. J Clin Oncol 2004222330
3Patt YZ et al. Proc Am Soc Clin Oncol
200423271 (Abst 3602)4Douillard JY et al.
Lancet 200035510417
30
Favourable safety of Xeloda in combination with
oxaliplatin randomised phase III trial
Patients ()
Grade 3/4 clinical adverse events
CAPOX (n164) FUFOX (n145)
Pain
Nausea
Vomiting
Infection
Hand-foot syndrome
Stomatitis
Diarrhoea
Neuropathy
Arkenau H-T et al. Proc Am Soc Clin Oncol
200423257 (Abst 3546)
31
Safety of XELIRI compares favourably with 5-FU
plus irinotecan combinations
Patients ()
XELIRI (n52)1 IFL (n264)2 FOLFIRI (n145)3


Neutropenia Febrile Diarrhoea Nausea/ Hand-foot
neutropenia vomiting syndrome



Not reported
1Patt YZ et al. Proc ASCO GI cancer symposium
200454 (Abst 288) 2Goldberg RM et al. J Clin
Oncol 2004222330 3Douillard JY et al. Lancet
200035510417
32
Adjuvant evaluations of Xeloda combinations in
colon cancer
33
Xeloda replacing 5-FU/LV as the backbone of CRC
treatment

• Superior first-line antitumour activity in MCRC
• Consistent benefits as adjuvant therapy
• A first choice in adjuvant
• superior RFS
• trend to superiority in DFS and OS
• Improved safety in MCRC and adjuvant
• Effective and well tolerated in combination