XELOX NO16967 Investigators Meeting

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XELOX NO16967Investigators Meeting

• Chicago, June 1, 2007

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XELOX the new chemotherapystandard in the
treatment of metastatic colorectal cancer
Highlights from the NO16966 (XELOX-1) trial

• Prof. Jim Cassidy, MD, FRCP
• Cancer Research UK Department of
  OncologyUniversity of Glasgow, Glasgow, UK

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CRC treatment landscape not only 5-FU
Capecitabine
Bevacizumab
5-FU
Addition of LV to 5-FU
Oxaliplatin
Panitumumab
1950
2010
1960
1970
1980
1990
2000
Irinotecan
Cetuximab
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Novel options lead to novel questions in the
treatment of mCRC

• Can capecitabine replace 5-FU?
• Multiple effective agents and regimens what is
  the best strategic use of options?
• What is the optimal way of combiningantiangiogeni
  cs with cytotoxics?
• Do drug holidays improve chemotherapy tolerance
  or confer drug resistance?
• Is there a role for maintenance therapy?

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Capecitabine effectivelyreplacing 5-FU in mCRC

• In mCRC, capecitabine vs bolus 5-FU13
• superior response rate
• equivalent TTP and OS
• favourable safety profile
• cost-saving
• Capecitabine reduces risks associated with
  central venous catheters (e.g., deep-vein
  thrombosis)

1. Van Cutsem E et al. Br J Cancer
200490119072. Cassidy J et al. Ann Oncol
200213566753. Twelves C et al. Eur J Cancer
200137597604
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XELOX (capecitabine oxaliplatin)a
supra-additive combination
Tumour xenograft volume (cm3)
10 5 1 0.5 0.1
Control Capecitabine Oxaliplatin XELOXplt0.05 vs
both single agents
1 11 21 31 41 51
Days after drug treatment
Cassidy J et al. J Clin Oncol 200422208491
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XELOX Phase I studyrecommended regimen in mCRC
1
8
15
21
Day
oxaliplatin130mg/m2 (2-hour infusion) d1
capecitabine1 000mg/m2 d114 bid q3w
Rest
Day 1 (pm) Day 15 (am)
Repeat cycle at day 22

• Grade 3 / 4 AEs diarrhoea (26),
  thrombocytopenia (22),neutropenia (17),
  paraesthesia (13)
• ORR 26, response duration 4.9 months

Díaz-Rubio E et al. Ann Oncol 20021355865
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XELOX Phase II studyORR and TTP comparable with
FOLFOX
XELOX
TTP (months)
ORR ()
FOLFOX
60
10
50
8
40
6
30
4
20
2
10
0
0
n961
n2672
n2103
n961
n2672
n2103
1. Cassidy J et al. J Clin Oncol
2004222084912. Goldberg RM et al. J Clin
Oncol 2004222330 3. de Gramont A et al. J
Clin Oncol 200018293847
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NO16966 study XELOX bevacizumab vs FOLFOX
bevacizumab
RecruitmentJune 2003 May 2004
RecruitmentFebruary 2004 February 2005
XELOX placebo n350
XELOX bevacizumab n350
XELOX n317
FOLFOX4 placebo n351
FOLFOX4 bevacizumab n349
FOLFOX4 n317
Initial two-arm open-label study(n1 000)
Protocol amended to 2x2 placebo-controlled design
after bevacizumab Phase III data became available
(n1 400)
Cassidy J et al. Ann Oncol 200617(Suppl. 9)
(Abst LBA3) Cassidy J et al. Proc ASCO GI 2007
(Abst 270)
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NO16966 study treatment regimens
XELOX bevacizumab/placebo 21-day cycle
BV or PL 7.5mg/kg iv 3090 min
OX 130mg/m2 iv 2h
Rest
Oral capecitabine 1 000mg/m2 bid
d1
d2
d15
d21
FOLFOX4 bevacizumab/placebo 14-day cycle
OX 85mg/m2 iv 2 h
BV or PL 5mg/kg iv 3090 min
5-FU 600mg/m2 iv 22h
5-FU 600mg/m2 iv 22h
5-FU 400mg/m2 iv bolus
5-FU 400mg/m2 iv bolus
LV 200mg/m2 iv 2h
LV 200mg/m2 iv 2h
d1
d2
d3
BV bevacizumab LV leucovorin OX
oxaliplatin PL placebo
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NO16966 study objectives

• Main endpoint PFS
• Two primary objectives
• XELOX is non-inferior to FOLFOX
• non-inferiority concluded if upper limit of
  97.5 CI 1.23
• bevacizumab chemotherapy is superior
  toplacebo chemotherapy
• superiority concluded if p0.025

Cassidy J et al. Ann Oncol 200617(Suppl. 9)
(Abst LBA3) Cassidy J et al. Proc ASCO GI 2007
(Abst 270)
Chemotherapy FOLFOX and XELOX
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NO16966 study populations

• Intent-to-treat (ITT) all randomised
• used for the bevacizumab superiority analyses
• Eligible patient population (EPP) ITT minus
  major protocol violators and patients not
  receiving at least one dose of study drug
• used for the XELOX non-inferiority analyses due
  to health authority requirements
• Safety population (SP) all patients receiving at
  least one dose of the respective study drug

Cassidy J et al. Ann Oncol 200617(Suppl. 9)
(Abst LBA3) Cassidy J et al. Proc ASCO GI 2007
(Abst 270)
With informed consent
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NO16966 studybaseline characteristics well
balanced


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NO16966 study efficacy results
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XELOX primary objective met non-inferior PFS
ITT
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XELOX/XELOXplacebo/XELOXbevacizumab (n1
017)FOLFOX/FOLFOXplacebo/FOLFOXbevacizumab
(n1 017)
HR1.04 (97.5 CI 0.931.16)Upper limit
lt1.23(non-inferiority margin)
8.5
8.0
0 5 10 15 20 25 30
X/P
X/BV
X
Months
F/P
F/BV
F
Cassidy J et al. Proc ASCO GI 2007 (Abst 270)
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XELOX primary objective met non-inferior PFS
EPP
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XELOX/XELOXplacebo/XELOXbevacizumab (n967)FOLF
OX/FOLFOXplacebo/FOLFOXbevacizumab (n937)
HR1.05 (97.5 CI 0.941.18)Upper limit
lt1.23(non-inferiority margin)
8.5
7.9
0 5 10 15 20 25 30
X/P
X/BV
X
Months
F/P
F/BV
F
Cassidy J et al. Ann Oncol 200617(Suppl. 9)
(Abst LBA3)
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PFS non-inferiority subgroup analysis
Favours XELOX
Favours FOLFOX
All ECOG PS at baseline 0 1 No. of metastatic
sites at baseline 1

gt1 ALP Abnormal

Normal Liver as metastatic site at baseline
No Yes Gender Female

Male Age
lt65 years

?65 years Prior adjuvant chemotherapy No

Yes Ethnicity Asian or
Pacific Islander White
X/P
X/BV
X
0.2 0.4 0.6 1 2 3 4 5 6
F/P
F/BV
F
Risk ratio
XELOX/XELOX placebo/XELOX bevacizumabFOLFOX
/FOLFOX placebo/FOLFOX bevacizumab
Cassidy J et al. Ann Oncol 200617(Suppl. 9)
(Abst LBA3)
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XELOX vs FOLFOXsimilar PFS in initial two-arm
study
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XELOX (n317)FOLFOX (n317)
HR0.96 (97.5 CI 0.801.16)
7.7
7.3
0 5 10 15 20 25 30
X/P
X/BV
X
Months
F/P
F/BV
F
Intent-to-treat
Cassidy J et al. Proc ASCO GI 2007 (Abst 270)
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XELOX vs FOLFOXsimilar OS in initial two-arm
study
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XELOX (n317)FOLFOX (n317)
HR0.89 (97.5 CI 0.721.11)
18.6
17.3
0 5 10 15 20 25 30 35
X/P
X/BV
X
Months
F/P
F/BV
F
Intent-to-treat
Cassidy J et al. Proc ASCO GI 2007 (Abst 270)
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XELOX is similar to FOLFOXin combination with
bevacizumab PFS
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XELOX bevacizumab (n350)FOLFOX
bevacizumab (n349)
HR1.01 (97.5 CI 0.831.23)
9.4
9.3
0 5 10 15 20 25 30
X/P
X/BV
X
Months
F/P
F/BV
F
Intent-to-treat
Cassidy J et al. Proc ASCO GI 2007 (Abst 270)
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XELOX vs FOLFOXequivalent tumour response
X/P
X/BV
X
F/P
F/BV
F
XELOX/XELOX placebo/XELOX bevacizumabFOLFOX
/FOLFOX placebo/FOLFOX bevacizumab
Cassidy J et al. Proc ASCO GI 2007 (Abst 270)
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Bevacizumab superioritymain efficacy analysis
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Bevacizumab primary endpoint met superior PFS vs
placebo
Estimated probability
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
XELOX/FOLFOX bevacizumab (n699)XELOX/FOLFOX
placebo (n701)
HR0.83 (97.5 CI 0.720.95)p0.0023
9.4
8.0
0 5 10 15
20 25
X/P
X/BV
X
Months
F/P
F/BV
F
Intent-to-treat
Saltz LB et al. Proc ASCO GI 2007 (Abst 238)
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NO16966 study safety results
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XELOX vs FOLFOXbalanced safety profile
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Bevacizumab vs placebograde 3 / 4 adverse events
X/P
X/BV
X
F/P
F/BV
F
Saltz LB et al. Proc ASCO GI 2007 (Abst 238)
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NO16966 update at ASCO

• Poster session
• Saturday June 2, 14.00 18.00
• Room S403
• Posters 15, 17
• Abstracts 4028, 4030
• Poster discussion session
• Saturday June 2, 17.00 18.00
• Room S406 (Vista Room)
• Posters 15, 17
• Abstracts 4028, 4030
• The poster will also be available to view at
• www.xeloda.roche.com

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Optimising mCRC treatment with XELOX

• Effective
• XELOX PFS and OS compare favourably with FOLFOX
• similar response rates with XELOX and FOLFOX
• XELOX is effective in combination with
  bevacizumab
• Safe
• less neutropenia and febrile neutropenia
• more diarrhoea and hand-foot syndrome
• Convenient
• simplifies combinations with biologicals
• less administration time
• flexibility to tailor dose adjustments
• reduced risk of permanent venous access
  complications