Dirk Arnold

1
New treatment options for colorectal
cancer with XELIRI

• Dirk Arnold
• Martin Luther UniversityHalle Wittenberg, Germany

2
Evolving role of irinotecancombinations in mCRC

• MOSAIC trial1,2 and NSABP C-073 will lead to
  increased use of adjuvant oxaliplatin
• Resulting in an increase in first-line irinotecan
  use
• cumulative oxaliplatin neurotoxicity
• oxaliplatin resistance
• Emergence of irinotecan combinations in
  first-line
• Addition of Avastin prolongs PFS and overall
  survival
• with combinations such as FOLFIRI4 or IFL5

1. André et al. N Engl J Med 2004 2. de Gramont
et al. ASCO 2007 3. Wolmark et al. ASCO 2008 4.
Fuchs et al. J Clin Oncol 2007, 2008 5. Hurwitz
et al. N Engl J Med 2004
3
Proven benefits of Avastin with irinotecan-based
therapy
8.5
FOLFIRI alone1
(n109)
Avastin FOLFIRI (BICC-C)2
(n209)
11.2
11.7
Avastin FOLFIRI (PACCE)3
(n115)
Phase IIIV clinical trials
11.1
Avastin FOLFIRI (AVIRI)4
(n209)
(n43)
12.5
Avastin FOLFIRI (MD Anderson)5
Avastin XELIRI (AIO 0604)6
(n120)
12.1
(n280)
Avastin FOLFIRI (BRiTE)7
10.9
Daily practice
Avastin FOLFIRI (First-BEAT)8
(n503)
11.6
0 2 4 6 8 10 12 14
Median PFS (months)
Large prospective, observational trials
1. Tournigand et al. JCO 2004 2. Fuchs et al.
JCO 2007 3. Hecht et al. ASCO GI 2008 4.
Ackland et al. ASCO GI 2008 5. Kopetz et al.
ASCO 20076. Reinacher-Schick et al. ASCO 2008
7. Kozloff et al. ASCO GI 2007 8. Berry et al.
ASCO 2008
4
XELIRI high efficacy in Phase II

• First-line mCRC14
• ORR 3550
• PFS/TTP 7.89.2 months
• overall survival 16.824.7 months
• Ongoing debate on optimal regimen
• Xeloda and irinotecan doses
• q2w vs q3w schedule

1. Bajetta et al. Cancer 20042. Borner et al.
Ann Oncol 20053. Rea et al. Ann Oncol 2005 4.
Patt et al. Am J Clin Oncol 2007
5
CAIRO-1 XELIRI in Phase III
R A N D O M I S A T I O N
Combination
Sequential
Xeloda 1250mg/m2 bid d114 q3w
XELIRIXeloda 1000mg/m2 bid d114irinotecan
250mg/m2 d1 q3w
Irinotecan350mg/m2 d1 q3w
XELOXXeloda 1000mg/m2 bid d114oxaliplatin
130mg/m2 d1 q3w
XELOXXeloda 1000mg/m2 bid d114oxaliplatin
130mg/m2 d1 q3w

• Primary endpoint overall survival

Koopman et al. Lancet 2007
6
CAIRO-1 XELIRI efficacy
XELIRI1(n402)
PFS (months) 7.8
ORR () 41
Overall survival (months) 17.4
1. Koopman et al. Lancet 2007
7
CAIRO-1 XELIRI efficacy similar to FOLFIRI in
cross-trial comparison
XELIRI1(n402) FOLFIRI2(n199) FOLFIRI3(n109)
PFS (months) 7.8 6.7 8.5
ORR () 41 41 56
Overall survival (months) 17.4 17.4 21.5
1. Koopman et al. Lancet 20072. Douillard et al.
Lancet 2000 3. Tournigand et al. J Clin Oncol
2004
8
CAIRO-1 XELIRI safety
Grade 3/4 AEs () XELIRI1(n398)
Hand-foot syndrome 6
Diarrhoea 26
Nausea 9
Vomiting 9
Mucositis/stomatitis 2
Febrile neutropenia 7
Neutropenia 7
1. Koopman et al. Lancet 2007
9
CAIRO-1 XELIRI safety similar to FOLFIRI in
cross-trial comparison
Grade 3/4 AEs () XELIRI1(n398) FOLFIRI2(n145) FOLFIRI3(n110)
Hand-foot syndrome 6 0
Diarrhoea 26 44 14
Nausea 9 7 13
Vomiting 9 11 10
Mucositis/stomatitis 2 0 10
Febrile neutropenia 7 9 7
Neutropenia 7 29 24
1. Koopman et al. Lancet 20072. Douillard et al.
Lancet 2000 3. Tournigand et al. J Clin Oncol
2004
10
Why was the tolerability profile of XELIRI less
favourable in previous studies?

• XELIRI had a manageable safety profile in
  CAIRO-11
• Possible reasons for different safety outcomes in
  BICC-C and EORTC studies2,3
• inadequate toxicity management
• possible interaction between Xeloda and celecoxib

1. Koopman et al. Lancet 2007 2. Fuchs et al. J
Clin Oncol 2007 3. Köhne et al. J Clin Oncol 2007
11
Why was the tolerability profile of XELIRI less
favourable in previous studies?

• XELIRI had a manageable safety profile in
  CAIRO-11
• Possible reasons for different safety outcomes in
  BICC-C and EORTC studies2,3
• inadequate toxicity management
• possible interaction between Xeloda and celecoxib
• regional differences in fluoropyrimidine
  tolerability4

Adjusted relative risk US vs RoW (95 CI) Adjusted relative risk US vs RoW (95 CI) Adjusted relative risk US vs RoW (95 CI)
mCRC Adjuvant CC
Grade 3/4 AEs 1.77 (1.352.31)plt0.001 1.47 (1.091.97)p0.012
1. Koopman et al. Lancet 2007 2. Fuchs et al. J
Clin Oncol 2007 3. Köhne et al. J Clin Oncol
2007 4. Haller et al. J Clin Oncol 2008
12
EORTC 40015 celecoxib may have a negative impact
on XELIRI efficacy
EORTC 400151
XELIRI placebo(n21) XELIRI celecoxib(n23) FOLFIRI placebo(n22) FOLFIRI celecoxib(n19)
ORR () 48 22 45 32

• High rate of early discontinuations could have
  compromised efficacy small sample size
• Results celecoxib were not reported by
  treatment arm for BICC-C2

1. Köhne, Irinotecan combined with infusional
5-fluorouracil/folinic acid or capecitabine plus
celecoxib or placebo in the first-line treatment
of patients with metastatic colorectal cancer.
EORTC study 40015, Annals of Oncology, 2008, 19,
920926, by permission of Oxford University Press
or the sponsoring society if the journal is a
society journal. 2. Fuchs et al. J Clin Oncol
2007
13
AIO trial Avastin XELOX vsAvastin XELIRI
a novel XELIRI schedule
Avastin XELOX Avastin 7.5mg/kg iv d1 Xeloda
1000mg/m2 bid d114 Oxaliplatin 130mg/m2 iv d1
q3w
RANDO MIS ATION
Untreated mCRCn255
Avastin XELIRI Avastin 7.5mg/kg iv d1Xeloda
800mg/m2 bid d114 Irinotecan 200mg/m2 iv d1 q3w

• Primary endpoint PFS at 6 months

Reinacher-Schick et al. ASCO 2008
14
Avastin XELOX vs Avastin XELIRI similar PFS
PFS Avastin XELOX (n127) Avastin XELIRI (n120)
At 6 months () 76 84
Median (months) 10.4 12.1
Estimated probability
1.0
0.8
0.6
0.4
Log-rank test p0.27
0.2
0.0
0
6
12
18
24
30
36
Months
Reinacher-Schick et al. ASCO 2008
15
AIO trial treatment cycles administered
Avastin XELOX (n127) Avastin XELIRI(n120) Total(n247)
Total cycles(evaluable patients) 1158 1269 2427
Cycles per patient
Mean SD 9.1 6.7 10.6 7.1 9.9 6.9
Median 8 9 9
Reinacher-Schick et al. ASCO 2008
16
Avastin XELOX vs Avastin XELIRI similar
overall survival
Overall survival Avastin XELOX (n127) Avastin XELIRI (n120)
Median (months) 26.7 NR
Estimated probability
1.0
0.8
0.6
0.4
Log-rank test p0.55
0.2
0.0
0
6
12
18
24
30
36
Months
NR not reached
Reinacher-Schick et al. ASCO 2008
17
Avastin XELOX vs Avastin XELIRI similar
response rate
Patients () Avastin XELOX (n127) Avastin XELIRI(n120)
ORR 53 55
CR 5 6
PR 48 49
SD 29 28
PD 5 6
RECIST criteria ITT population investigators assessments RECIST criteria ITT population investigators assessments
Reinacher-Schick et al. ASCO 2008
18
AIO trial Avastin XELIRI is well tolerated
Grade 3/4 AEs () Avastin XELOX (n127) Avastin XELOX (n127) Avastin XELIRI (n120) Avastin XELIRI (n120)
Grade 3 Grade 4 Grade 3 Grade 4
Diarrhoea 21 0 16 0
Sensory neuropathy 24 1 0 0
Hand-foot syndrome 11 0 8 0
Thrombocytopenia 6 0 0 0
Neutropenia 2 0 8 2
Thrombosis/embolism 3 2 4 1
Hypertension 4 0 3 0
Haemorrhage/bleeding 1 0 0 0
Reinacher-Schick et al. ASCO 2008
19
AIO trial Avastin XELIRI is well tolerated
Grade 3/4 AEs () Avastin XELOX (n127) Avastin XELOX (n127) Avastin XELIRI (n120) Avastin XELIRI (n120)
Grade 3 Grade 4 Grade 3 Grade 4
Diarrhoea 21 0 16 0
Sensory neuropathy 24 1 0 0
Hand-foot syndrome 11 0 8 0
Thrombocytopenia 6 0 0 0
Neutropenia 2 0 8 2
Thrombosis/embolism 3 2 4 1
Hypertension 4 0 3 0
Haemorrhage/bleeding 1 0 0 0
Reinacher-Schick et al. ASCO 2008
20
Ongoing MEXICO trial Avastin XELIRI vs
Avastin FOLFIRI
XELIRI Avastin7.5mg/kg iv d1 q3w x 8 cycles
RANDO MIS ATION
Untreated mCRCn138
FOLFIRIAvastin5mg/kg iv d1 q2w x 12 cycles

• Primary endpoint PFS
• Recruitment completed

21
EU label extension March 2008
Xeloda is indicated for the treatment of mCRC
including combinations with irinotecan and Avastin

• Xeloda treatment dose 8001000mg/m2 bid d114
  q3w
• For first-line treatment of patients with mCRC
• CAIRO-1 Xeloda 1000mg/m2 bid d114 q3w with
  irinotecan
• AIO Xeloda 800mg/m2 bid d114 q3w with
  irinotecan and Avastin

Xeloda SPC
22
Expanding options Xeloda in combination with
irinotecan

• CAIRO-1 feasibility of XELIRI combination
• AIO study Avastin Xeloda 800mg/m2 bid
  irinotecan 200mg/m2 q3w is a new treatment option
• at least as effective as Avastin XELOX
• reduced dose may be associated with
• favourable safety profile
• prolonged PFS