1. long term follow up of the CELIM trial
Cetuximab and chemotherapy in the treatment of patients with initially “non-resectable” colorectal (CRC) liver metastases –
long term follow up of the CELIM trial
Gunnar Folprecht,1 Thomas Gruenberger,2 Wolf Bechstein,3 Hans-Rudolf Raab,4 Jürgen Weitz,1 Florian Lordick,5 Joerg Thomas Hartmann,6 Hauke Lang,7 Tanja Trarbach,8 Jan Stoehlmacher-Williams,1 Torsten Liersch,9 Detlev Ockert,10 Dirk Jaeger,11 Ulrich Steger,12 Thomas Suedhoff,13 Claus-Henning Köhne4
1University Hospital Carl Gustav Carus, Dresden, Germany, 2University Vienna, Vienna, Austria, 3University Hospital Frankfurt, Germany, 4Klinikum Oldenburg, Germany, 5University Cancer Center Leipzig, Germany, 6University Kiel, Germany, 7University Hospital Mainz, Germany, 8 West German Cancer Center, Essen, Germany,
9University Hospital Göttingen, Germany, 10Krankenhaus der Barmherzigen Brüder, Trier, Germany, 11National Center of Tumor Diseases, Heidelberg, Germany, 12University Hospital Würzburg, Germany, 13Klinikum Passau, Germany

2. Background
Resection of liver metastases provides favorable long-term survival (Adam Ann Surg 2004)
Resectability of colorectal liver metastases depends on technical resectability and prognostic factors
Number of liver metastases is an important prognostic factor and pts with > 4 metastases were excluded from a neoadjuvant trial for resectable liver metastases (Nordlinger, Lancet 2007)
In primarily non-resectable liver metastases, resection rate correlates with response to chemotherapy
Cetuximab increases response rates and deepness of response when added to FOLFIRI or FOLFOX (Van Cutsem JCO 2011, Bokemeyer Ann Oncol 2011, Mansmann (ASCO abstr 3630))

3. Main inclusion criteria
Patients with non-resectable colorectal liver metastases
Definition of non-resectability:
≥ 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)
Expected resectability after response to chemotherapy was not an inclusion criterion
No extrahepatic disease

4. Methods I Endpoints Treatment
The primary endpoint (response rates), the resection rates and the results of the surgical review were published in Folprecht et al, Lancet Oncology 2010
The current analysis describes the secondary endpoints progression free survival, disease free survival and overall survival
Treatment
Cetuximab: 400 mg/m², then 250 mg/m² weekly
FOLFOX6: oxaliplatin 100 mg/m², 5-FU mg/m², FA 400 mg/m²
FOLFIRI: irinotecan 180 mg/m², 5-FU mg/m², FA 400 mg/m²

5. Methods II Technically non-resectable
Cetuximab+FOLFOX Cetuximab+FOLFIRI
Stratification: technically non-resectable / ≥ 5 liver metastases, Staging with PET, EGFR IHC
Patients with non-resectable CRC liver mets. (technically non-resectable / ≥ 5 liver mets.) without extra-hepatic metastases
Randomization
Biopsy: EGFR screening
Therapy: 8 cycles (~ 4 months)
Technically resectable
Resection
Therapy continuation for 6 cycles (~ 3 months)
Evaluation of resectability
4 additional chemotherapy cycles
FOLFOX6
Early closed arm
EGFR IHC 0

6. Response and resection
FOLFOX
FOLFIRI
All
cetuximab
patients
n=53
n=106
CR/PR
68%
57%
62%
95% CI
54-80%
42-70%
52-72%
R0 resections
38%
30%
34%
R0 / R1 resect. / RFA
49%
43%
46%
KRAS wild-type
KRAS mutant
n=67
n=27
CR/PR
70%
41%
95% CI
58-81%
22-61%

7. Overall and progression free survival
▬ Overall survival
All randomized patients
95% CI interval
OS median 35.7 mo. [95% CI: ]
3 year % [95% CI: ]
5 year % [95% CI: ]
PFS median 10.8 mo. [95% CI: ]
3 year 5.7% [95% CI: ]
Probability of survival

8. Survival according to treatment arm
··· Progression free survival
▬ Overall survival
Arm A (FOLFOX/Cetuximab)
Arm B (FOLFIRI/Cetuximab)
OS Arm A 35.8 mo. [95% CI: ]
Arm B 29.0 mo. [95% CI: ]
HR 1.03 [ ], p=0.9
PFS Arm A mo. [95% CI: ]
Arm B mo. [95% CI: ]
HR 1.18 [ ], p=0.4
Probability of survival

9. Survival according to k-ras status
··· Progression free survival
▬ Overall survival
k-ras wild type
k-ras mutant
OS k-ras wt 36.6 mo. [95% CI: ]
k-ras mut 27.4 mo. [95% CI: ]
HR 1.41 [ ], n.s.
PFS k-ras wt mo. [95% CI: ]
k-ras mut mo. [95% CI: ]
HR 1.29 [ ], n.s.
Probability of survival

10. Survival in k-ras wt patients, according to treatment arm
··· Progression free survival
▬ Overall survival
Arm A, k-ras wild type
Arm B, k-ras wild type
OS Arm A 36.1 mo. [95% CI: ]
Arm B 41.6 mo. [95% CI: ]
HR 0.86 [ ], n.s.
PFS Arm A mo. [95% CI: ]
Arm B mo. [95% CI: ]
HR 1.13 [ ], n.s.
Probability of survival

11. Survival according to metastasectomy
··· Progression free survival
▬ Overall survival
R0 resected patients
R1 resection / ablation
Not resected patients
OS R0 resected 53.9 mo. [95% CI: ]
not resected 21.9 mo. [95% CI: ]
HR 0.29 [ ], p <‍ ‍0.001
PFS R0 resected mo. [95% CI: ]
not resected 6.9 mo. [95% CI: ]
HR 0.31 [ ]p <‍ ‍0.001
5 year survival in R0 resected patients:
46.2% [95% CI: %]
Probability of survival

12. Probability of survival
DFS after R0 resection
··· Disease free survival after resection
All patients
< 5 metastases
5-10 metastases
> 10 metastases
DFS 9.9 [95% CI: ] months
Comparison between groups:
p < 0.001
Probability of survival

13. Survival according to metastasectomy in patients with PR/CR
▬ Overall survival in patients with PR/CR and
R0 resection
R1 resection / ablation
Without resection
R0 resection vs. no resection:
HR 0.42 [95% CI: ], p=0.021
Probability of survival

14. Summary / conclusions
Patients in this multidisciplinary study were treated
with an effective systemic therapy and
in a consequent multidisciplinary approach.
In the ITT population, the median OS was 35.7 months, the 5 year survival rate 27.5%.
The 5 year survival rate of R0 resected patients after cetuximab based “conversional” therapy was 46.2%.
Resection had a significant influence on overall survival in all patients and in patients responding to treatment.
The influence of number of metastatic lesions on the prognosis was confirmed.
A difference between the treatment arms was not detected in a direct comparison. Due to small sample size, differences cannot be excluded
The known predictive value of k-ras mutations on OS/PFS could not be confirmed with the current patient number in contrast to other trials, which have shown a higher efficacy of cetuximab in k-ras wild type patients.

15. We thank…. … all patients and all investigators at the study sites:
University Hospital Dresden,
Klinikum Oldenburg,
University Hospital Vienna,
University Hospital Tübingen,
University Hospital Göttingen,
University Hospital München rechts der Isar,
Krankenhaus der Barmherzigen Brüder Trier,
University Hospital / NCT Heidelberg,
The study was supported by Merck KGaA, Sanofi-Aventis and Pfizer
University Hospital Würzburg,
Klinikum Passau,
University Hospital Frankfurt,
Klinikum Celle,
University Hospital Essen,
Klinikum Magdeburg,
Klinikum Aschersleben,
University Hospital Mannheim,
Klinikum Essen-Mitte

16. Supplemental: CELIM: Blinded Review
Baseline Follow-up
32%
60%, p<0.01
Folprecht et al, Lancet Oncology 2010