1. Randomized multicenter study of cetuximab plus FOLFOX or cetuximab plus FOLFIRI in neoadjuvant treatment of non-resectable colorectal liver metastases (CELIM study) G. Folprecht 1, T. Gruenberger 2, J.T. Hartmann 3, F. Lordick 4, J. Stoehlmacher 1, W. Bechstein 5, D. Ockert 6, T. Herrmann 4, T. Liersch 7, C.-H. Köhne 8 1 University Hospital Carl Gustav Carus, Dresden, Germany, 2 University Hospital Vienna, Austria, 3 University Hospital Tübingen, Germany, 4 National Center for Tumor Diseases, Heidelberg, Germany, 5 University Hospital Frankfurt, Germany, 6 Krankenhaus der Barmherzigen Brüder, Trier, Germany, 7 University Hospital Goettingen, Germany, 8 Klinikum Oldenburg, Oldenburg, Germany

2. Abstract BACKGROUND Resectability of colorectal liver metastases (mets) can be induced by an effective chemotherapy regimen. Combinations of cetuximab with FOLFIRI or FOLFOX have been shown to increase response and resection rates. METHODS Patients (pts) with non-resectable liver mets were randomized to receive FOLFOX6 or FOLFIRI plus cetuximab in this multicenter, randomized phase II study. Pts were stratified according to the reason for non- resectability (technically non-resectable vs. ≥ 5 liver mets), the use of PET scans at initial staging, and EGFR status. Preoperative treatment was planned for 8 cycles. In case of persistent non-resectability, multidisciplinary evaluation was planned every 4 cycles. RESULTS From December 2004 to March 2008, 124 pts were screened for the study. 111 pts were randomized to receive FOLFOX plus cetuximab (56 pts) or FOLFIRI plus cetuximab (55 pts). Median age was 63 years. Out of the 111 pts, 60 pts (54%) were judged as technically non-resectable, 20 pts (18%) were staged with PET, and 81 pts (73%) were EGFR detectable. At the interim analysis in March 2008, response and resection data were available from 81 pts. Best response was 75.3% (61/81 pts, 95%CI 64.5-84.2%, combined analysis for both arms) and confirmed response was 59.3% (48/81 pts, 95% CI 47.7-70.0%). KRAS status was available for 86 pts; best response rate in KRAS wild-type pts was 85.4% (41/48 pts, 95%CI 72.2-93.9%), and 50% (7/14 pts) in KRAS mutant pts. Sixteen resections were performed in pts with ≥ 5 liver mets, 18 resections in technically non-resectable pts. In total, 34/81 pts were resected (42.0%, 95%CI 31.1-53.5%), 29 with microscopically free margins (R0). Interim data on toxicity of 98 pts demonstrated acne-like rash (32%), neutropenia (20%), diarrhea (15%), allergic reaction (6%), and neurologic toxicity (5%) to be the most common preoperative grade ≥3 toxicities in both arms. One patient had a fatal pulmonary embolism (2.9%). CONCLUSION In the interim analysis, the combination of cetuximab with standard chemotherapy has demonstrated high activity and an encouraging rate of liver resection. Mature resection and response data per treatment arm and KRAS status will be reported at the meeting.

3. Background Resection of liver metastases provides favorable long-term survival (Adam Ann Surg 2004) Resectability of colorectal liver metastases depends on: - technical resectability - prognostic factors Number of liver metastases is regarded as an important prognostic factor and is an exclusion criterion in neoadjuvant trials for resectable liver metastases (Nordlinger, Lancet 2007) Standard systemic chemotherapy regimens for colorectal cancer include FOLFOX and FOLFIRI For both regimens, high response rates were reported in phase II studies and – more recently – in randomized trials such as CRYSTAL (Van Cutsem ASCO 2008) and OPUS (Bokemeyer ASCO 2008) Multi-institutional randomized trials investigating patients with isolated liver metastases are lacking

4. Patient selection Patients with non-resectable, histologically confirmed colorectal liver metastases Definition of non-resectability: –≥ 5 liver metastases and/or –liver metastases that are technically non-resectable (local surgeon in cooperation with local radiologist defined non-resectability based on the amount of functional liver tissue remaining, infiltration of all liver veins, and infiltration of both hepatic arteries, both portal branches, or both bile ducts) Patients with simultaneous liver metastases were eligible if the primary tumor was resected ≥1 month prior to chemotherapy. (Expected resectability after response to chemotherapy was NOT an inclusion criterion) No extrahepatic disease Karnofsky PS ≥ 80% and adequate hepatic, renal, and bone marrow function No prior chemotherapy (except adjuvant chemotherapy ≥ 6 months ago); no concurrent immunotherapy, chemotherapy or hormone therapy; no previous malignancy other than colorectal cancer, basal cell carcinoma, or pre-invasive carcinoma of the cervix; no inflammatory bowel disease; no relevant coronary heart disease Informed consent

5. Methods Patients were randomized to: 1) FOLFOX6 (oxaliplatin 100 mg/m², 5-FU 400 mg/m² [bol], 5-FU 2400 mg/m², FA 400 mg/m²) plus cetuximab (400 mg/m², then 250 mg/m²) 2) FOLFIRI (irinotecan 180 mg/m², 5-FU 400 mg/m² [bol], 5-FU 2400 mg/m², FA 400 mg/m²) plus cetuximab (400 mg/m², then 250 mg/m²) 3) FOLFOX6 (patients with negative immunohistochemistry for EGFR) This arm was closed after the third patient and all subsequent patients were randomized to arm (1) or (2) Patients were evaluated for response every fourth cycle (every 8 weeks) Resection was planned in case of resectability after 8 cycles If patients were non-resectable, resectability was further evaluated with each CT scan Patients were regarded to have a confirmed response if confirmed according to RECIST or if the confirmation CT scan was not performed because the patient underwent resection Central surgical review is being performed (data not yet available)

6. Patients with non-resectable colorectal liver metastases (technically non-resectable / ≥ 5 liver metastases) without extrahepatic metastases Biopsy: EGFR screening Randomization FOLFOX6 + cetuximab FOLFIRI + cetuximab Therapy: 8 cycles (~ 4 months) Technically non-resectable Technically resectable 4 additional CTX cycles Resection Therapy continuation for 6 cycles (~ 3 months) Primary endpoint: Response Evaluation of resectability

7. Enrollment and analysis From December 2004 to March 2008, 114 patients were randomized into the study 17 centers participated actively in the trial –43% of patients were randomized at 3 study sites, 75% at 7 study sites 3 patients were randomized to FOLFOX6 (arm closed early) –These patients are not included in the current analysis 111 patients were randomized to FOLFOX6 plus cetuximab or FOLFIRI plus cetuximab 2 patients did not receive planned treatment: –1 patient withdrew consent –1 patient retrospectively revealed known extrahepatic disease 105 patients were evaluable for response Presented data are based on an interim analysis as of August 15, 2008

8. Patient characteristics FOLFOX6 +FOLFIRI +All cetuximab patients n=56n=55n=111 Median age65.1 y62.0 y63.3 y Sex male64% Stratified characteristics ≥5 metastases45%46%45% Technically non-resectable55% Staged using PET *16%20%18% EGFR-positive (IHC)71%75%73% * PET is not generally reimbursed in Germany

9. Patient characteristics FOLFOX6 +FOLFIRI +All cetuximab patients n=56n=55 n=111 KRAS (n=99) wild-type 70%71% Primary tumor site Rectal cancer36%52%44% Primary tumor stage T3/489%83%86% Adjuvant chemotherapy yes9%23%16% Adjuvant radiotherapy yes4%15%8%

10. Patient characteristics FOLFOX6 +FOLFIRI +All cetuximab patients n=56n=55 n=111 Primary UICC stage I-II17%10%13% III4%16%10% IV79%74%77% Prior liver resection yes17%9%13% Synchronous liver metastases yes72%70%71% UICC, International Union Against Cancer

11. Patient characteristics FOLFOX6 +FOLFIRI +All cetuximab patients n=56n=55 n=111 Number liver metastases <5 23%31%27% 5-10 55%49%52% >10 20%15%17% NA 2%5%4% Fong score (n=83)* 0-117%10%13% 2 17%31%24% 3 34%38%36% 4-5 32%21%27% * Fong score is evaluated for resectable liver metastases Fong score data not available for all pts.

12. Preoperative toxicity FOLFOX6 +FOLFIRI +All cetuximab patientsp-value n=54n=55n=109* All grade 3/4 72%73% n.s. Neutropenia24%22%23%n.s. Thrombopenia9%05%0.02 Allergic reaction11%4%7%n.s. Skin toxicity28%38%33%n.s. Diarrhea9%18%14%n.s. Nausea/Vomiting7%04%0.04 Infection09%5%0.02 Neuropathy*20%010%0.001 Other neurologic toxicity6%4%5%n.s. Alopecia*07%4%0.04 * grade >1 One patient died from pulmonary embolism *Two randomized pts did not receive therapy

13. Efficacy: Response FOLFOX6 +FOLFIRI +KRASAll cetuximab wild-typepatients n=52n=53n=67n=105* CR/PR 85%66%79%75% (44 pts)(35 pts)(53 pts)(79 pts) 95% CI71.9-93.1%51.7-78.5%67.4-88.1%65.9-83.1% SD11%23%13%17% (6 pts)(12 pts)(9 pts)(18 pts) PD4%11%8% (2 pts)(6 pts)(5 pts)(8 pts) Responses are not yet confirmed Data regarding response confirmation are still pending for 14 pts * 105 pts evaluable for efficacy

14. Resections FOLFOX6 +FOLFIRI +All cetuximab patients n=52n=53n=105* All resections40%43%42% (21 pts)(23 pts)(44 pts) R0 resections37%34%35% (19 pts)(18 pts)(37 pts) * 105 pts evaluable for efficacy

15. Time to intervention 44 patients were resected, 5 patients had exploratory laparotomy Median time to intervention (resection/laparotomy): 5.0 months Median number of cycles prior to intervention: 8

16. Resections according to tumor response Best responses PR/CRSDPD n=79n=18n=8 R0 resections35 pts2 pts0 Without R0 resection44 pts16 pts8 pts 35/37 of resected pts (95%) had a tumor response The 2 remaining pts had minor responses

17. Resections by patient subgroup Technically≥ 5 liverKRAS non-resectablemetastaseswild-type n=57n=48n=67 All resections40%44%43% (23 pts)(21 pts)(29 pts) R0 resections32%40%34% (18 pts)(19 pts)(23 pts) Comparison of R0 resections between strata technically non-resectable and ≥ 5 liver mets: p=0.4

18. Among patients with initially non-resectable liver metastases, 42% had a liver resection and 35% had an R0 resection FOLFOX6 plus cetuximab and FOLFIRI plus cetuximab are highly active regimens and induced high response rates –79% unconfirmed CR/PR in KRAS wild-type patients The current data do not allow us to draw conclusions regarding differences between FOLFOX6 and FOLFIRI in the preoperative setting as final data are still pending There were no major differences in resection rates between patients who entered the study with technically non-resectable disease and those who had ≥ 5 liver metastases Tumor response is a precondition for resection of liver metastases, as nearly all patients achieved a tumor response before resection Median time to intervention (resection/laparotomy) was 5.0 months Data for progression-free survival and surgical review of resectability are not yet mature and will be presented at a later meeting Conclusions

19. We thank... All patients 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, University Hospital Würzburg, Klinikum Passau, University Hospital Frankfurt, Klinikum Celle, University Hospital Essen, Klinikum Magdeburg, Klinikum Aschersleben, University Hospital Mannheim, Klinikum Essen-Mitte The study was supported by: Merck KGaA, Sanofi-Aventis, and Pfizer