1. Integration of EGFR targeting into first line therapy: is it time?
Prof Eric Van Cutsem, MD, PhD
Leuven, Belgium

2. The Epidermal Growth Factor Receptor pathway
Scaltriti M & Baselga J. Clin Cancer Research 2006

3. Anti-EGFR antibodies in mCRC
3rd line
BOND: cetuximab ± irinotecan
NCIC C0.17: cetuximab vs BSC
Panitumumab vs BSC (K-ras wild type)
Benefit demonstrated
2nd line
EPIC: irinotecan ± cetuximab
Benefit
1st line
(randomized) Phase II studies
CRYSTAL: FOLFIRI ± cetuximab
PACCE: chemo/bevacizumab ± panitumumab
Other phase III studies in progress

4. Cetuximab +/- irinotecan in irinotecan refractory EGFR+ mCRC: Response rate (primary endpoint)
56 [49-62] ** 60 50 *
32 [24-42] 40
Percentage
23 [18-29] 30 20
11 [6-18] 10
Response Rate
Disease Control (CR+PR+SD)
cetuximab + irinotecan
(n=218)
cetuximab
(n=111)
* p=0.0074; ** p<0.001; [] = 95% CI
Cunningham D … Van Cutsem E. N Engl J Med 2004

5. Cetuximab and panitumumab in chemorefractory EGFR expressing CRC
Panitumumab vs BSC¹
n = 463
Cetuximab vs BSC²
n = 572
Cross over allowed
No cross over
Primary endpoint:
met
PFS
HR=0.54 (95% CI: )
Stratified log-rank test: p <
Survival
HR=0.77 (95% CI: ) Stratified log rank test: p =
Secondary
endpoints
Survival: HR 1.00; p= NS
RR: 10% vs 0%
PFS: HR 0.68 ( ); p <
RR: 7% vs 0%
KRAS analysis
Activity confined to wild type KRAS³: HR for PFS: 0.45
RR: 17 % in wild type
0 % in KRAS mutated
Pending
¹Van Cutsem E et al, J Clin Onc 2007; ²Jonker D et al, N Engl J Med 2007; ³ Amado R, Van Cutsem E et al; Eur J Cancer (Proc ECCO), 2007

6. EPIC trial: Cetuximab in second line treament of mCRC
Irinotecan + cetuximab Irinotecan
n = n = 650
cross over allowed
Survival (median)
10.71 mo mo
HR = (95% CI = – 1.114)
p =
PFS (median)
4.0 mo mo
HR = (95 % CI 0.617–0.776)
p < RR
DCR (CR+PR+SD)
16.4 % %
61.4 % %
Sobrero A et al. AACR 2007

7. Anti-EGFR antibodies in first line treatment of mCRC
Phase II studies: high response rates and high disease control rates
Fluoropyrimidine/irinotecan + cetuximab
Fluoropyrimidine/oxaliplatin + cetuximab
Randomized phase II studies
CALGB
Opus
SAKK
BOS - EORTC
Randomized phase III studies
COIN: 3 arm question on duration and on ± cetuximab
CAIRO-2: XELOX/bevacizumab ± cetuximab
US intergroup: 3 arm: bevacizumab vs cetuximab vs combination
Nordic: FOLFOX ± cetuximab
FOLFOX ± panitumumab
…….

8. Advanced Colorectal Cancer: CALGB 80203
+ cetuximab
RANDOMI
ZAT
ION 
n =
238/2200
FOLFIRI 
- cetuximab
Stratify
Prior adj
Prior XRT
+ cetuximab 
FOLFOX 
- cetuximab
Venook A et al ASCO 2006

9. CALGB 80203: Response Cetuximab - / +
CR + PR
46 (38%)
61 (52%)
Other
75 (62%)
56 (48%)
p = 0.029; chi-sq
p = 0.029; chi-sq
Venook A et al ASCO 2006

10. SAKK Phase II Study: Preliminary Results
Capox
(n=37)
Capox + cetuximab
Partial response
21%
43%
Helbling D, et al. ESMO 2006 A328
AIO CRC Study Group Phase II First-Line study
Capox+ cetuximab (n=29)
CapIri+ cetuximab (n=33)
P-value
Response rate (CR + PR)
65.5%
42%
0.081
Disease control rate (CR + PR + SD)
93%
91%
1.0
Heinemann V, et al. ASCO GI, 2007

11. OPUS trial in first line mCRC: large randomized phase II study
FOLFOX
n = 168
FOLFOX/cetuximab
n = 169
Response Rate (%) 36 46
p =0.06
Response duration (mo)
(95 % CI)
5.7 [5.4–7.7]
9.0 [5.9–11.1]
Disease control (%)
81.5
[74.8–87.1]
85.2
[78.3–89.7]
PFS (mo)
7.2
[6.0–7.8]
[5.6–7.7]
HR = (0.705–1.230)
Bokemeyer C, et al. ECCO 2007 (Abstract No. 3004)

12. OPUS: safety Incidence, n (%) Adverse event (AE) FOLFOX-4 (n=168)
Cetuximab + FOLFOX-4
(n=170)
Any grade 3/4 AE occurring in 3 subjects
Neutropenia
53 (31.5)
47 (27.6)
Diarrhea
10 (6.0)
12 (7.1)
Neurotoxicitya
6 (3.5)
Leukopenia
9 (5.4)
Fatigue
5 (3.0)
Other grade 3/4 toxicity
Skin reactions
24 (14.1)b
Infusion-related reactions
3 (1.8)
7 (4.1)
Treatment-related deaths
Cetuximab
Chemotherapy
1 (0.6)
aIncludes peripheral sensory neuropathy and neuropathy
bThere were no grade 4 skin reactions or acne-like rash
Magnesium measurements were available only from a subset of patients
Bokemeyer C, et al. ECCO 2007 (Abstract No. 3004)

13. COIN trial: Phase III study
Previously untreated patients with mCRC
Cetuximab + oxaliplatin/5-FU or capecitabine R
Oxaliplatin + 5-FU or capecitabine
Intermittent oxaliplatin + 5-FU or capecitabinea
UK National Cancer Research Institute study, 84 participating centers
Current accrual: 1800 (n=2421 planned)
Preliminary safety analysis on 804 patients randomized up to June 20061
Explanation of third bullet:
The outcome of the safety analysis was that the treatment arm with ERBITUX + oxaliplatin + capecitabine (as the 5-FU drug), capecitabine will be reduced to 850 mg/m2 bid (instead of having 1000 mg/m2 bid), due to an increase in diarrhea.
a12 weeks, monitor and repeat on PD
1Maughan T, et al. ASCO 2007 (Abstract No. 4070)

14. COIN trial: Any Grade 3 /4 toxicity (%) in the first 12 weeks† †
† = p<0.001 compared to same regimen minus cetuximab
1Maughan T, et al. ASCO 2007 (Abstract No. 4070)

15. COIN study: Chemo-type toxicities (%) in the first 12 weeks
No cetuximab
(Arms A + C)
Cetuximab (C)
(Arm B)
Significance
* p<0.05
† p<0.001
Regimen
Ox + Cap
OxMdG
Ox + Cap
OxMdG
+/- cap
+/- cet n
333
203
166
102
Neutropenia 2 18 1 26 †
N & vomiting 7 3 14 7 * *
Diarrhoea 15 7 25 13 † *
All cause 60 day mortality
5.65
5.0
7.2
4.9
Treatment related deaths
0.6
0.5
1.8
1.0
1Maughan T, et al. ASCO 2007 (Abstract No. 4070)

16. CRYSTAL trial in first line mCRC
Cetuximab + FOLFIRI
Cetuximab IV 400 mg/m2 on day 1,
then 250 mg/m2 weekly + irinotecan (180mg/m2)
+ 5-FU (400 mg/m2 bolus +
2400 mg/m2 as 46-hr
continuous infusion)
+ FA every 2 weeks
EGFR-expressing
metastatic CRC R
FOLFIRI
irinotecan (180 mg/m2)
+ 5-FU 400 mg/m2 bolus +
2400 mg/m2 as 46-hr
continuous infusion)
+ FA every 2 weeks
Stratification factors:
Regions
ECOG PS
Populations
Randomized patients n=1217
Safety population n=1202
ITT population: n=1198
Van Cutsem E, et al. Proc ASCO, 2007

17. CRYSTAL trial: Primary endpoint PFS ITT population independent review
1.0
FOLFIRI, n=599
Cetuximab + FOLFIRI, n=599
0.8
0.9
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
HR = 0.851; 95% CI = [ ]
Stratified log-rank p-value =
8.9 mo
PFS estimate
1-year PFS rate
23% vs 34%
8.0 mo 2 4 6 8 10 12 14 16 18 20
Subjects at risk
FOLFIRI alone
599
492
402
293
178 83 35 16 7 4 1
Cetuximab +
FOLFIRI
499
392
298
196
103 58 29 12 5
Progression-free survival time (months)
Van Cutsem E, et al. Proc ASCO, 2007

18. CRYSTAL trial: Response Rate and Surgery with curative intent
FOLFIRI alone Cetuximab + FOLFIRI
Liver metastases only population (exploratory)
ITT population (pre-planned)
p=0.0034*
odds ratio 3.0
[95% CI: ]
4.5
9.8 1 2 3 4 5 6 7 8 9 10
Percentage (%)
n=134/n=122
No residual tumor in patients
with liver metastases
*CMH test
Van Cutsem E, et al. Proc ASCO, 2007

19. CRYSTAL trial: Safety: Grade 3/4 AE
FOLFIRI
n=602, %
Cetuximab + FOLFIRI
n=600, %
Any
59.5
78.0
Neutropenia
23.3
26.7
Febrile neutropenia
2.2
2.7
Diarrhea
10.5
15.2
Vomiting
5.0
4.5
Fatigue
Skin reactionsa
0.2
18.7
Infusion-related reactions
2.3
aThere were no grade 4 skin reactions
Magnesium levels were measured in only 20% of the patients (0.2% vs. 1.8%)
Van Cutsem E, et al. Proc ASCO, 2007

20. PACCE: Panitumumab Advanced Colorectal Cancer Evaluation
Randomized, Open-Label, Controlled Phase 3b Trial
Panitumumab 6 mg/kg Q2W
Ox-CT
Bevacizumab
Ox-based CT
(eg, FOLFOX)
N = 800
Inv choice S C R E N I G R A N D O M I Z E
1:1
Ox-CT
Bevacizumab
Panitumumab 6 mg/kg Q2W
Iri-CT
Bevacizumab
Iri-basedCT
(eg, FOLFIRI)
N = 200
Inv choice
1:1
Iri-CT
Bevacizumab
Stratification Factors: ECOG score, prior adjuvant tx, disease site, Ox doses/Iri regimen, number of metastatic organs
Hecht R et al, Ann Oncol, WCGIC Barcelona 2007

21. PACCE trial: Progression-free Survival: Ox-CT Cohort (Interim Analysis, May 2007 Data Cutoff)
Central Reviewa
Local Reviewb
# PFS events (%)
Median (95%CI), mos 59
9.6 ( ) 52
11.1 ( )
# PFS events (%)
Median (95% CI), mos 70
9.6 ( ) 64
11.0 ( )
pmab+bev/Ox-CT
bev/Ox-CT
HR = 1.27 (95% CI: 1.05–1.53)*
HR = 1.27 (95% CI: 1.07–1.50)*
*Descriptive only
*Descriptive only
aCensoring based on last available scan read centrally Q12W
bCensoring based on last day of patient contact or visit Q2W
Hecht R, Mitchel E et al, GI Cancers Symposium, Orlando, jan 2008

22. CALGB 80405 trial: Phase III study
FOLFOX or FOLFIRI, and bevacizumab
Previously untreated patients with mCRC
FOLFOX or FOLFIRI, and cetuximab R
FOLFOX or FOLFIRI, bevacizumab and cetuximab
Primary endpoint: overall survival
Secondary endpoints include response, PFS, toxicity and resection rate
Accrual = 1084/2289
No safety concerns (regular IDMC review)

23. CAIRO-II trial: Phase III study
Previously untreated patients with mCRC
Cetuximab + bevacizumab + XELOX R
Bevacizumab + XELOX
Accrual complete (n=755)
Interim safety analysis (n=381) reported acceptable AEs in both treatment groups
Except for cetuximab-associated skin reactions, there was no difference in the incidence of grade 3/4 AEs between treatment groups
Tol J, et al. ECCO 2007 (Abstract No. 3000)

24. CAIRO-2 study Overall toxicity
Arm A
n = 197
Arm B
n = 192
p-value
All grade 3-4
72%
81%
0.03
(skin excluded)
71%
0.87
60-day mortality 2% 3%
Tol J, et al. ECCO 2007 (Abstract No. 3000)

25. EORTC phase II BOS study
Previously untreated patients with resectable mCRC (liver)
FOLFOX + cetuximab
for 3 months (n=50)
Resect
ion
Adjuvant therapy for 3 months (same schedule as pre-operatively) R
FOLFOX + cetuximab
+ bevacizumab
for 3 months (n=50)
Neoadjuvant
therapy

26. EGFR inhibitors in mCRC: questions & challenges
Optimal cytotoxic partner?
Optimal setting: more advanced disease or first line treatment?
Predictive markers for response and activity?
Selection of patients?
Prediction of and decreasing toxicity?
Relevance of correlation skin toxicity and efficacy
What is the clinical significance of increased resection rate of metastases with cetuximab in first line ?
Can EGFR antibodies be combined with other biologics?
bevacizumab?
How can we explain negative results of chemo + bevacizumab and panitumumab in first line?
Economic burden

27. Patient Selection After EGFR Inhibitors
Skin rash
EGFR - IHC
Downstream markers?
Gene Mutations
KRAS
EGFR gene copy number, as assessed by FISH ?
Ligands: amphiregulin, epiregulin …

28. Cetuximab / panitumumab and K-RAS
Khambata-Ford S et al, J Clin Onc 2007

29. Amado R, Van Cutsem E et al, J Clin Oncol 2008, in press
Chemorefractory patients: Panitumumab + BSC vs BSC Maximum Percent Decrease in Target Lesions Final Analysis, KRAS Evaluable Group
160
140
120
100 80 60 40 20
% Change
-20
-40
-60
-80
PR (0%)
SD (12%)
PD (70%)
Mutant
Patient
Pmab
+ BSC
PR (17%)
SD (34%)
PD (36%)
Wild-Type
SD (8%)
PD (60%)
BSC
Alone
PD (75%)
Amado R, Van Cutsem E et al, J Clin Oncol 2008, in press

30. First line treatment with cetuximab
First line treatment: cetuximab (n = 33)
Response rate: 10 %; Stabile disease: 34%
Pessino A, Sobrero A et al, Ann Oncol epub 2007
First line treatment: cetuximab followed by FOLFIRI/cetuximab (n = 52)
Tabernero J et al, GI Cancers symp 2008

31. Anti-EGFR antibodies in first line treatment of mCRC
Specific issues/questions?
Do anti-EGFR antibodies increase the activity of chemotherapy in first line?
yes (cetuximab trial), but which subgroup?
no data in comparison with bevacizumab
Do anti-EGFR antibodies increase the toxicity?
yes
Is the toxicity in first line acceptable?
Is there an interaction between panitumumab and bevacizumab?
Is KRAS a predictive marker for activity in first line in combination with chemotherapy?
more data expected
Does cetuximab increase the resection rate in first line metastatic CRC?
probably yes

32. EGFR inhibitors in CRC
Are EGFR inhibitors an option in first line treatment of mCRC?
Probably yes
For who?
Biomarker or clinically driven selection?
Data:
Cetuximab
Panitumumab under evalution
Are EGFR inhibitors today a standard treatment in first line mCRC? No