1. 149
Survival with cetuximab / FOLFOX or cetuximab / FOLFIRI of patients with nonresectable colorectal liver metastases in the CELIM study
Gunnar Folprecht,1 Thomas Gruenberger,2 Wolf Bechstein,3 Florian Lordick,4* Hauke Lang,5 Juergen Weitz,6 Thomas Suedhoff,7 Joerg T Hartmann,8* Torsten Liersch,9 Claus-Henning Koehne10
1University Hospital Carl Gustav Carus, Dresden, Germany, 2University Hospital Vienna, Austria
3University Hospital Frankfurt, Germany, 4Klinikum Braunschweig, Germany,
5University Hospital Mainz, Germany, 6University Hospital Heidelberg, Germany, 7Klinikum Passau, Germany, 8University Hospital Kiel, Germany, 9University Hospital Goettingen, Germany, 10 Klinikum Oldenburg, Germany *current institution of the author

2. Background
CELIM study enrolled patients with non-resectable liver metastases
≥ 5 liver metastases and/or
liver metastases that are technically non-resectable defined by local surgeon in cooperation with local radiologist (amount of functional liver tissue remaining, infiltration of non-resectable structures)
R0 resection in 34% of all patients
Response rates of 70% in k-ras wild type patients
An independent surgical review confirmed that resectability based on CT/MRI images (without clinical data) improved
Current presentation shows survival follow up of June, 2011

3. Randomization EGFR IHC non-detected
Patients with non-resectable colorectal liver metastases (technically non-resectable / ≥ 5 liver metastases) without extrahepatic disease
Biopsy: EGFR screening
closed early, patients were randomized to cetuximab arms
Randomization
EGFR IHC non-detected
FOLFOX6 + cetuximab FOLFIRI + cetuximab
FOLFOX6
Therapy: 8 cycles (~ 4 months)
Evaluation of resectability
Technically non-resectable
4 additional therapy cycles
Technically resectable
Resection
Therapy continuation for 6 cycles (~ 3 months)
Primary endpoint: Response
Folprecht et al, Lancet Oncology 2010

4. Response and resection rates
All
FOLFOX6 +
FOLFIRI +
K-ras
pts
cetuximab
wild-type
mutant
n=106
n=53
n=67
n=27
CR/PR
62%
68%
57%
70%
41%
95% CI
52-72%
54-80%
42-70%
58-81%
22-61%
R0 resections
34%
38%
30%
33%
25-44%
25-52%
18-44%
22-45%
14-50%
Folprecht et al, Lancet Oncology 2010

5. Overall survival by treatment arms
100%
80%
60%
40%
20% 0%
N Median
— FOLFOX/Cet
( )
— FOLFIRI/Cet
( )
HR 1.09 ( )
Overall survival in months
all patients (%)
Pts at risk
Median overall survival in all patients: 33.1 months (95% CI: ).

6. Progression free survival
100%
80%
60%
40%
20% 0%
N Median
— FOLFOX/Cet
( )
— FOLFIRI/Cet
( )
HR 1.15 ( )
Progression free survival in months
all patients (%) %
Pts at risk
Median progresison free survival in all patients: 10.8 months (95% CI: ).

7. Survival by k-ras status
Progression free survival
Overall survival
N Median
— K-ras wild type ( )
— K-ras mutant ( )
HR 1.31 ( )
N Median
— K-ras wild type
( )
— K-ras mutant
( )
HR 1.48 ( )
100%
80%
60%
40%
20% 0%
100%
80%
60%
40%
20% 0%
months
months

8. Survivial in the k-ras wild type subset
Progression free survival
Overall survival
N Median
— FOLFOX/Cet
( )
— FOLFIRI/Cet
( )
HR 1.09 ( )
N Median
— FOLFOX/Cet
( )
— FOLFIRI/Cet
( )
HR 1.01 ( )
100%
80%
60%
40%
20% 0%
100%
80%
60%
40%
20% 0%
months
months

9. Survival and R0 resection
Progression free survival
Overall survival
100%
80%
60%
40%
20% 0%
100%
80%
60%
40%
20% 0%
— R0 resected
— Not R0 resected
— R0 resected
— Not R0 resected
HR 2.07 ( )
p=0.001
HR 2.34 ( )
p=0.002
Median PFS: 15.4
95%CI:
Median PFS: 8.9
95%CI:
Median OS: 46.7
95%CI:
Median OS: 27.3
95%CI: % % % %
R0 resected, N=36
not R0 resected, N=70
R0 resected (k-ras wt subset, N=22)
not R0 resected (k-ras wt subset, N=45)

10. Disease free survival after R0 resection
All R0 resected pts.
By number of metastases
at randomization
100%
80%
60%
40%
20% 0%
100%
80%
60%
40%
20% 0%
N Median
DFS mo.
( )
N Median
< 5 met
5-10 met
>10 met
p<0.001
months
months
DFS %
k-ras wt %
subset
median DFS in k-ras wt pts: 11.5 mo.
DFS was measured from resection to recurrence or death

11. CELIM: Blinded surgical review
Baseline Follow-up
32%
60%, p<0.01
As defined in the inclusion criteria, all patients were initially technically non-resectable and/or had ≥ 5 metastases.
CT/MRI images of patients were retrospectively reviewed by a group of surgeons who were blinded to all clinical data and to the imaging time (before / after treatment). Surgeons voted for non-resectable (red), borderline resectable with chemotherapy preferred first (yellow) and resectable/exploratory laparotomy with aim of resection (green/light green).
Folprecht et al, Lancet Oncology 2010

12. Survival by surgical review
After chemotherapy
and cetuximab
Imaging at baseline
100%
80%
60%
40%
20% 0%
„non-resectable“ (N=53)
„resectable“ (N=22)
100%
80%
60%
40%
20% 0%
„non-resectable“ (N=34)
„resectable“ (N=41)
HR 0.81
( )
p=0.5
HR 0.47
( )
p=0.007
months
As inclusion criteria, all patients were technically non-resectable and/or had ≥ 5 metastases.
Surgical review based on CT/MRI images only (without any clinical information).

13. Summary and Conclusions
Multidisciplinary treatment including cetuximab plus FOLFOX6 or FOLFIRI resulted in a median overall survival of 33.1 months and a 4-year OS-rate of 28%
Patient with R0 resection lived significantly longer than patients with medical treatment alone (HR 2.34 [ ] p=0.002).
In R0 resected patients, 3-year- and 4-year- OS-rates are 64% and 49%.
Cetuximab/FOLFOX and cetuximab/FOLFIRI showed similar progression- free and overall survival
With cetuximab plus FOLFOX or FOLFIRI, k-ras wild type had by numbers a longer OS and PFS compared to k-ras mutant patients
Despite favorable long term survival, median DFS after R0-resection of ~ 10 months demonstrates the need for multidisciplinary cooperation and patient selection, especially in patients with high number of metastases
Resectability after treatment with cetuximab and FOLFOX or FOLFIRI but not at baseline was associated with longer survival (based on independent surgical review of CT/MRI images without clinical data)

14. We thank... All patients and their relatives
All investigators at the study sites University Hospital Dresden Klinikum Oldenburg University Hospital Vienna University Hospital Tübingen University Hospital Göttingen University Hospital Munich Rechts der Isar Klinikum Passau Krankenhaus der Barmherzigen Brüder Trier University Hospital / NCT Heidelberg University Hospital Würzburg University Hospital Frankfurt Klinikum Celle University Hospital Essen Klinikum Magdeburg University Hospital Mannheim Klinikum Aschersleben Klinikum Essen-Mitte
The companies which supported this study Merck KGaA, Sanofi-Aventis, and Pfizer