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

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 2013 (ASCO abstr 3630))

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

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 400+2400 mg/m², FA 400 mg/m² FOLFIRI: irinotecan 180 mg/m², 5-FU 400+2400 mg/m², FA 400 mg/m²

Methods II Technically non-resectable Cetuximab+FOLFOX 6 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

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%

Overall and progression free survival ▬ Overall survival All randomized patients 95% CI interval OS median 35.7 mo. [95% CI: 27.2-44.2] 3 year 48.3 % [95% CI: 38.9-57.7] 5 year 27.5 % [95% CI: 18.7-36.3] PFS median 10.8 mo. [95% CI: 9.3-12.2] 3 year 5.7% [95% CI: 1.4-10.0] Probability of survival

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: 28.1-43.6] Arm B 29.0 mo. [95% CI: 16.0-41.9] HR 1.03 [0.66-1.61], p=0.9 PFS Arm A 11.2 mo. [95% CI: 7.2-15.3] Arm B 10.5 mo. [95% CI: 8.9-12.2] HR 1.18 [0.79-1.74], p=0.4 Probability of survival

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: 25.3-47.8] k-ras mut 27.4 mo. [95% CI: 15.7-39.1] HR 1.41 [0.84-2.34], n.s. PFS k-ras wt 11.9 mo. [95% CI: 8.2-15.6] k-ras mut 9.9 mo. [95% CI: 4.5-15.2] HR 1.29 [0.82-2.04], n.s. Probability of survival

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: 21.1-51.1] Arm B 41.6 mo. [95% CI: 22.6-60.6] HR 0.86 [0.48-1.53], n.s. PFS Arm A 12.1 mo. [95% CI: 5.2-19.1] Arm B 11.5 mo. [95% CI: 8.8-14.1] HR 1.13 [0.69-1.85], n.s. Probability of survival

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: 35.9-71.9] not resected 21.9 mo. [95% CI: 17.1-26.7] HR 0.29 [0.17-0.50], p <‍ ‍0.001 PFS R0 resected 15.4 mo. [95% CI: 11.4-19.5] not resected 6.9 mo. [95% CI: 5.9-8.0] HR 0.31 [0.19-0.50]p <‍ ‍0.001 5 year survival in R0 resected patients: 46.2% [95% CI: 29.5-62.9%] Probability of survival

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: 5.8-14.0] months Comparison between groups: p < 0.001 Probability of survival

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: 0.21-0.86], p=0.021 Probability of survival

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.

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

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