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

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

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

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

Overall survival by treatment arms 100% 80% 60% 40% 20% 0% N Median — FOLFOX/Cet 54 35.7 (29.9-41.6) — FOLFIRI/Cet 55 29.0 (18.1-39.8) HR 1.09 (0.69-1.72) 0 12 24 36 48 60 Overall survival in months all patients (%) 100 90 62 47 28 Pts at risk 109 98 67 45 14 Median overall survival in all patients: 33.1 months (95% CI: 25.8-40.4).

Progression free survival 100% 80% 60% 40% 20% 0% N Median — FOLFOX/Cet 53 11.2 (7.2-15.3) — FOLFIRI/Cet 53 10.5 (8.9-12.2) HR 1.15 (0.77-1.70) 0 12 24 36 48 60 Progression free survival in months all patients (%) 100 43 15 6% Pts at risk 106 45 16 5 Median progresison free survival in all patients: 10.8 months (95% CI: 9.3-12.2).

Survival by k-ras status Progression free survival Overall survival N Median — K-ras wild type 67 11.9 (8.25-15.6) — K-ras mutant 27 9.9 (4.5-15.2) HR 1.31 (0.83-2.07) N Median — K-ras wild type 69 36.1 (24.4-47.8) — K-ras mutant 28 27.4 (15.7-39.1) HR 1.48 (0.88-2.48) 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% 0 12 24 36 48 60 months 0 12 24 36 48 60 months

Survivial in the k-ras wild type subset Progression free survival Overall survival N Median — FOLFOX/Cet 33 12.1 (5.2-19.1) — FOLFIRI/Cet 34 11.5 (8.8-14.1) HR 1.09 (0.66-1.79) N Median — FOLFOX/Cet 34 35.8 (30.2-41.4) — FOLFIRI/Cet 35 41.6 (24.8-58.5) HR 1.01 (0.55-1.86) 100% 80% 60% 40% 20% 0% 100% 80% 60% 40% 20% 0% 0 12 24 36 48 60 months 0 12 24 36 48 60 months

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 (1.35-3.16) p=0.001 HR 2.34 (1.37-4.01) p=0.002 Median PFS: 15.4 95%CI: 11.4-19.5 Median PFS: 8.9 95%CI: 6.7-11.0 Median OS: 46.7 95%CI: 30.7-62.7 Median OS: 27.3 95%CI: 21.2-33.3 0 12 24 36 48 60 0 12 24 36 48 60 100 89 78 64 49% 100 91 54 37 16% 100 91 82 59 46% 100 89 62 47 22% 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)

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 36 9.9 mo. (5.8-14.0) N Median < 5 met. 11 16.8 5-10 met. 22 8.2 >10 met. 3 2.5 p<0.001 0 12 24 36 48 60 months 0 12 24 36 48 60 months DFS 100 47 19 8% k-ras wt 100 50 18 5% subset median DFS in k-ras wt pts: 11.5 mo. DFS was measured from resection to recurrence or death

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

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 (0.44-1.50) p=0.5 HR 0.47 (0.27-0.83) p=0.007 0 12 24 36 48 60 0 12 24 36 48 60 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).

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 [1.37-4.01] 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)

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