1. Cetuximab plus weekly oxaliplatin/5FU/FA (FUFOX) in 1 st line metastatic gastric cancer. Final results from a multicenter phase II study of the AIO upper GI study group. F. Lordick 1, S. Lorenzen 1, S. Hegewisch-Becker 2, G. Folprecht 3, E. Wöll 4, T. Decker 5, E. Endlicher 6, N. Röthling 7, F. Fend 1, C. Peschel 1 1 Klinikum rechts der Isar, Technische Universität München, Munich, Germany 2 Onkologische Schwerpunktpraxis Eppendorf, Hamburg, Germany 3 Universitätsklinikum Carl Gustav Carus, Dresden, Germany 4 Krankenhaus St. Vinzenz, Zams, Austria 5 Onkologische Schwerpunktpraxis Ravensburg, Germany 6 Klinikum der Universität Regensburg, Germany 7 Center for Clinical Studies, Munich, Germany

2. Phase II according to Simon‘s two stage optimal design Null hypothesis: 30% response; alternative hypothesis: 50% Inclusion of 15 patients in stage 1. If > 6 responders in stage 1, continuation of accrual to a minimum of 46 patients (  = 0.05; 1-  =0.80). Endpoints: - Response rate (according to RECIST) Secondary: - Toxicity (according to NCI.AE reporting system, version 3.0) - Time to progression (time from inclusion to tumor progression) - Overall survival (time from inclusion to death of any cause) 7 active study sites Enrollment of 52 patients from 04/2005 - 03/2006 Study design

3.  Histologically proven adenocarcinoma of the stomach or esophago gastric junction  ECOG performance status 0-2  Metastatic disease  Measurable disease  No prior malignancy (except in situ carcinoma of the cervix, basal or squamous cell carcinoma of the skin)  No prior chemotherapy for metastatic disease. Perioperative CTx allowed, if stopped > 6 months prior to inclusion into this trial  No CNS metastases  No peripheral neuropathy > grade 2  No serious concomitant illness and organ dysfunction  Written informed consent  Age > 18 years Main eligibility criteria

4. Infusion days: 1, 8, 15, 22; qd 36 *Cetuximab 400 mg/m 2 at first infusion followed by 250 mg/m 2 Cetuximab was given also on day 29 of each cycle Treatment regimen LV 200 mg/m 2 LV Oxaliplatin 50 mg/m 2 Oxaliplatin 5-FU 2,000 mg/m 2 via 24-h Infusion Cetuximab 250 mg/m 2 * Cetuximab - 2 0 2 24 26 hours

5. Patients‘ characteristics (I) Agemedian 63 years (38-80) Genderfemale 13 pts. male39 pts. ECOG-PS*019 pts. 125 pts. 2 8 pts. * ECOG-PS indicates Performance Status according to the Eastern Cooperative Oncology Group

6. Primary tumor localization Esophago-gastric junction 25 pts. (48%) Stomach 27 pts. (52%) Stage Metastatic52 pts. (100%) Prior therapy Surgery26 pts. (50%) Chemotherapy (adjuvant/neoadjuvant)12 pts. (23%) Radiation (adjuvant) 3 pts. (6%) Patients‘ characteristics (II)

7. Sites of disease SiteN (%) Primary tumor26 (50%) Lymph nodes45 (86%) Liver23 (46%) Peritoneum16 (31%) Lung9 (17%) Bone4 (8%) Other sites5 (10%) Median number of sites/patient: 3 (range 1-5)

8. 60-day-mortality rate: 9.6% (5 pts.)* Tumor-related: 3 pts (5.8%) All three pts. died from rapid tumor progression: 2 in extracerebral sites and 1 in the CNS Treatment-related: 2 pts (3.8%)  1 pt. died from septic shock (febrile neutropenia and diarrhea)  1 pt. died 2 weeks after he had suffered an allergic shock and aspiration during the first cetuximab infusion followed by pneumonia. He had been premedicated with an anti-histamine and dexamethasone *The 60-day mortality rate in the previously published phase II study evaluating FUFOX without cetuximab in metastatic gastric cancer was 4.2% (Lordick et al., Brit J Cancer 2005; 93: 190-194). Safety

9. Patients completed median 2 cycles (cy) of chemotherapy (range 0-8) The median duration of study treatment was 10 weeks (range 0-42) Feasibility

10. Adverse events °1/2 (NCI.AE) ( > 5% of 51 evaluable pts.) Grade 1 (n)Grade 2 (n)Grade 1/2 (%) Anemia321042 (82%) Neutropenia17623 (45%) Thrombocytopenia13215 (29%) Diarrhea13 26 (51%) Nausea21728 (54%) Emesis10515 (29%) Sensory neuropathy171633 (65%) Fatigue/Asthenia141630 (59%) Alopecia729 (18%) Hand-foot syndrome8816 (31%) Skin rash151833 (65%)

11. Adverse events grade °3/4 (NCI.AE) Grade 3 (n)Grade 4 (n)Grade 3/4 (%) Anemia000 (0%) Neutropenia213 (6%) Febrile neutropenia011 (2%) Thrombocytopenia011 (2%) Diarrhea14317 (33%) Nausea303 (6%) Emesis000 (0%) Sensory neuropathy202 (4%) Fatigue/Asthenia505 (10%) Hand-foot syndrome303 (6%) Skin rash12012 (24%)

12. Discontinuation of study treatment Reasons for stopping study treatment Progression17 pts (33%) Good response (investigators recommendation)13 pts (25%) Toxicity / adverse event 8 pts (15%) Patient‘s decision 6 pts (11%) Early death 5 pts (10%) Resection (with no further postop. treatment) 2 pts (4%) Deterioration of general condition 1 pt (2%)  Only 33% received treatment until disease progression as indicated in the study protocol. Early treatment discontinuation was decided due to a variety of other reasons.

13. Best response (RECIST; centrally reviewed) (evaluable in 46 patients) Complete response (CR) 4 8.7 Partial reponse (PR) 26 56.5 Stable disease (SD) 8 17.4 Progressive disease (PD) 8 17.4 Overall response rate (ORR)30 65.2 n% Response 95% CI [49.8–78.6] Confirmed responses (RECIST) 18 39.1 Disease stabilization rate38 74.5 95% CI [60.5–85.7]

14. Time to tumor progression (TTP) TTP Median7.6 months 95% CI 5.0-10.1 months Mean8.5 months SD+/- 1.0 months

15. Overall survival (OS) OS Median9.5 months 95% CI 7.9-11.1 months Mean10.6 months SD+/- 1.0 months

16. EGFR Immunohistochemistry (ICH) Central testing for EGFR is available in 42 patients Definition for positivity: detection of EGFR in >1% of the tumor cells; with faint, moderate or intense staining intensity. Positive staining for EGFR 25 pts. 59.5% Outcome according to EGFR-IHCdetectablenon-detectable Overall response (ORR) 54.2% 76.5% Disease stabilization (SD+PR+CR) 79.2% 82.4% Time to progression (TTP) 7.0 mon 9.4 mon Overall survival (OS) 8.1 mon 9.9 mon

17. Secondary treatments Secondary tumor resections 3 pts (6%) (primary tumor with or without metastases) Second-line chemotherapy13 pts(25%) - Taxanes (single agent or combination 3 pts - Irinotecan (singe agent or comination) 7 pts - Alternative Platin-fluoropyrimidine combination 3 pts Secondary radiation 0 pts (0%)

18. These phase II results indicate that in metastatic gastric cancer Cetuximab plus FUFOX 1 st -line  Is a feasible regimen leading to expected toxicities  Has a promising activity: The ORR (65.2%) is higher than expected as expressed by the alternative study hypothesis which was set to 50%  Is associated with a very promising time to progression: The TTP of 7.6 months compares favorable to TTP‘s obtained with conventional chemotherapy regimens  Is active independent of the detectability of EGFR by IHC Discussion (I)

19. The overall survival of 9.5 months is not superior compared to what has been achieved with other regimens. It has to be taken into account that:  Patient selection was on the unfavourable side with - altered performance status in 63% - liver involvement in 46% and peritoneal disease in 31% - high tumor burden (median number of involved sites 3) - prior adjuvant or neoadjuvant chemotherapy in 23%  Only every fourth patient received 2 nd line chemotherapy Discussion (II)

20. Conclusion Cetuximab plus a platin-fluoropyrimidine combination deserves further investigation in phase III