XELOX NO16967 Investigators Meeting

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XELOX NO16967Investigators Meeting

• Chicago, June 1, 2007

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Efficacy and safety results ofthe NO16967
(XELOX-2) trial

• Allen Cohn, MD
• Rocky Mountain Cancer Centers, Denver, COUS
  Oncology Research

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Phase III NO16967 trial XELOX vs FOLFOX in
second-line therapy
RANDO MIS ATION
XELOX capecitabine 1 000mg/m2 bid d115
oxaliplatin 130mg/m2 d1q3w
n313
5-FU/irinotecan-pretreated mCRC Prior oxaliplatin
not allowed
FOLFOX45-FU 400mg/m2 bolus 600mg/m2 ci d1,
2 LV 200mg/m2 d1, 2 oxaliplatin 85mg/m2 d1q2w
n314
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Phase III NO16967 treatment regimens
XELOX 21-day cycle
OX 130mg/m2 iv 2h
Rest
oral capecitabine 1 000mg/m2 bid
d1
d2
d15
d21
FOLFOX4 14-day cycle
OX 85mg/m2 iv 2h
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
LV leucovorin OX oxaliplatin
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Study objectives

• Main endpoint PFS
• Primary objective
• XELOX is non-inferior to FOLFOX
• non-inferiority concluded if upper limit of 95
  CI 1.30
• Secondary endpoints
• OS, response rates, safety

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Study populations

• Intent-to-treat (ITT) all randomised patients
• Per protocol population (PPP) randomised
  patients who did not discontinue treatment before
  two cycles of XELOX or three cycles of FOLFOX,
  unless because of adverse events
• requested for primary endpoint analysis by
  regulatory authorities
• Safety population (SP) all randomised patients
  who received at least one dose of capecitabine,
  5-FU or oxaliplatin

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Study populations
Randomised populationITT (n627)
XELOX (n313)
FOLFOX (n314)
2 patients excluded(did not receive at least one
dose of capecitabine or oxaliplatin)
6 patients excluded(did not receive at least one
dose of 5-FU or oxaliplatin)
Safety populationSP (n619)
XELOX (n311)
FOLFOX (n308)
62 patients excluded(42 discontinued treatment
before receiving two cycles of XELOX)
62 patients excluded(51 discontinued treatment
before receiving three cycles of FOLFOX)
Per-protocol populationPPP (n503)
XELOX (n251)
FOLFOX (n252)
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Patient follow-up status
August 2006
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Study demographics
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Baseline characteristics
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History of colorectal cancer
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Efficacy results
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Primary endpoint metnon-inferior PFS with XELOX
(ITT)
Estimated probability
XELOX (n313)FOLFOX (n314)
1.0 0.8 0.6 0.4 0.2 0.0
HR0.97 (95 CI 0.831.14)Upper limit lt1.30
(non-inferiority margin)
4.8
4.7
0 5 10 15 20 25
Months
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Primary endpoint metnon-inferior PFS with XELOX
(PPP)
Estimated probability
XELOX (n251)FOLFOX (n252)
1.0 0.8 0.6 0.4 0.2 0.0
HR1.03 (95 CI 0.871.24)Upper limit lt1.30
(non-inferiority margin)
5.5
5.1
0 5 10 15 20 25
Months
15
Similar OS with XELOX vs FOLFOX (ITT)
Estimated probability
XELOX (n313)FOLFOX (n314)
1.0 0.8 0.6 0.4 0.2 0.0
HR1.03 (95 CI 0.871.23)
12.6
11.9
0 5 10 15 20 25 30 35 40
Months
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Similar OS with XELOX vs FOLFOX (PPP)
Estimated probability
XELOX (n251)FOLFOX (n252)
1.0 0.8 0.6 0.4 0.2 0.0
HR1.07 (95 CI 0.881.31)
13.2
12.7
0 5 10 15 20 25 30 35 40
Months
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PFS subgroup analysis
Lower Upper confidence confidence
n limit Estimate limit 627 0.83 0.97 1.14 295 0.8
1 1.02 1.29 332 0.74 0.92 1.15 207 0.66 0.87 1.16
420 0.84 1.02 1.24 293 0.77 0.98 1.23 333 0.77 0.9
6 1.20 242 0.74 0.96 1.24 385 0.81 0.99 1.21 398 0
.72 0.88 1.08 229 0.88 1.14 1.49
87 0.72 1.12 1.75 16 0.18 0.56 1.75 519 0.81 0.9
7 1.15
Subgroup
Category
All
0 1 or 2
ECOG PS at baseline
1 gt1
No. of metastatic sites at baseline
Abnormal Normal
Alkaline phosphatase
Female Male
Gender
lt65 years 65 years
Age subgroup
Asian or Pacific Islander Black White
Ethnicity
0.2 0.4 0.6 1 2 3 4 5 6
Risk ratio
Intent-to-treat
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PFS subgroup analysis by region
Subgroup All Eastern Asia South
Africa Canada USA Israel Northern Europe Southern
Europe British Isles Italy France Eastern Europe
Lower Upper confidence confidence
n limit Estimate limit 627 0.83 0.97 1.14 78 0.70
1.12 1.79 24 0.67 1.63 3.92 191 0.90 1.20 1.60 57
0.48 0.81 1.39 47 0.29 0.54 1.01 41 0.48 0.90 1.6
9 49 0.44 0.78 1.40 40 0.41 0.79 1.51 23 0.41 1.02
2.55 21 0.38 0.92 2.22 55 0.73 1.27 2.22
0.2 0.4 0.6 1 2 3 4 56 10 20
Risk ratio
Intent-to-treat
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OS subgroup analysis
Lower Upper confidence confidence
n limit Estimate limit 627 0.87 1.03 1.23 295 0.8
9 1.17 1.53 332 0.76 0.96 1.21 207 0.61 0.84 1.16
420 0.91 1.12 1.38 293 0.70 0.89 1.14 333 0.89 1.1
4 1.47 242 0.72 0.96 1.27 385 0.87 1.09 1.36 398 0
.73 0.91 1.13 229 1.00 1.34 1.80
87 0.58 0.95 1.54 16 0.32 1.01
3.18 519 0.86 1.04 1.27
Subgroup
Category
All
0 1 or 2
ECOG PS at baseline
1 gt1
No. of metastatic sites at baseline
Abnormal Normal
Alkaline phosphatase
Female Male
Gender
lt65 years 65 years
Age subgroup
Asian or Pacific Islander Black White
Ethnicity
0.2 0.4 0.6 1 2 3 4 5 6
Risk ratio
Intent-to-treat
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OS subgroup analysis by region
Lower confidencelimit
Upperconfidencelimit
Subgroup
n
Estimate
All
627
0.87
1.03
1.23
78 24 191 57 47 41 49 40 23 21 55
0.52 0.52 0.76 0.53 0.34 0.42 0.48 0.35 1.10 0.65
0.86
0.87 1.30 1.04 0.98 0.64 0.86 0.93 0.71 2.98 2.04
1.70
1.46 3.23 1.42 1.82 1.23 1.74 1.78 1.47 8.04 6.38
3.35
Eastern Asia South Africa Canada USA Israel Northe
rn Europe Southern Europe British
Isles Italy France Eastern Europe
0.2 0.4 0.6 1 2 3 4 5 6 10 20
Risk ratio
Intent-to-treat
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XELOX vs FOLFOXsimilar response rates
Intent-to-treat
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Concordance between investigator assessment and
IRC (ITT)
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Safety results and dose reductions
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Safety profile Grade 1 4 adverse events
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Safety withdrawals andon-treatment mortality
Safety population
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Treatment withdrawals duringprimary treatment
phase
Laboratory abnormalities included in AEs
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Patient deaths during entire study period
Safety population
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Deaths within 60 days of treatment start
Safety population
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Dose reductions for capecitabine or 5-FU
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Dose reductions for oxaliplatin
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Relative dose intensityby 6-week intervals
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Capecitabine dose modifications PFS
Estimated probability
1.0 0.8 0.6 0.4 0.2 0.0
No modification (n134)
Dose interruption (n53) Dose reduction (n77) Cyc
le delay (n170)
0 5 10 15 20 25
Months
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NO16967 study XELOX can replace FOLFOX in
second-line treatment of mCRC

• Primary endpoint met
• XELOX is non-inferior to FOLFOX in second-line
  treatment of mCRC
• Secondary endpoints (OS, response rates) support
  results of primary endpoint
• Similar safety profile with XELOX and FOLFOX
• XELOX can replace FOLFOX in second-line mCRC

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Thank you to

• The patients participating in this trial
  andtheir families
• The investigators
• The study nurses and site coordinators
• The study management team at Roche