1. A Discussion on Biologic Agents in Gastric Cancer Treatment Yoon-Koo Kang, MD Professor of Medicine Asan Medical Center University of Ulsan College of Medicine Seoul, Korea

2. Phase 3 trial results with 2 biologic agents recently reported With ToGA trial, trastuzumab plus chemotherapy became new standard of care –Highly important to select patients mostly likely to benefit from trastuzumab Opening the Door to Targeted Therapy in Gastric Cancer

3. In ToGA, 22% of patients were HER2+ 1 –Real-life HER2+ rate estimated to be 10% to 15% ToGA subgroup analysis suggested patients with HER2 IHC 2+/FISH+ or IHC 3+ benefit most from trastuzumab treatment 2 HER2 testing algorithm recommended Selecting Patients for Trastuzumab Therapy in Gastric Cancer FISH = fluorescence in situ hybridization; HER2 = human epidermal growth factor receptor 2; IHC = immunohistochemistry 1. Chung H et al. Eur J Cancer Suppl.2009; 7:364. 2. Van Cutsem E et al. J Clin Oncol. 2009; 27[Suppl15S]:Abstract 4509.

4. 0 FISH +– Eligible for trastuzumab 1+2+3+ IHC Patient tumor sample Recommended HER2 Testing Algorithm in Metastatic Gastric and Gastroesophageal Junction Cancer Trastuzumab EU SmPC: http://www.ema.europa.eu/humandocs/PDFs/EPAR/ Herceptin/emea-combined-h278en.pdf. Important to test secondary and resected tumors, as they may differ in HER2 expression

5. AVAGAST: A Randomized, Double-Blind, Placebo-Controlled, Phase-3 Study *5-FU also allowed if capecitabine contraindicated Capecitabine 1000 mg/m 2 oral bid, d1–14, 1-week rest Cisplatin 80 mg/m 2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Capecitabine and bevacizumab/placebo until disease progression Stratification Factors: 1.Geographic region 2.Fluoropyrimidine backbone 3.Disease status Capecitabine*/cisplatin (XP) + placebo q3w Capecitabine*/cisplatin (XP) + bevacizumab q3w Locally advanced or metastatic gastric cancer R Kang Y-K et al. J Clin Oncol. 2010;28[18S]:Abstr LBA4007.

6. AVAGAST Primary Endpoint: Overall Survival 387 343 355 271 291 204 232 146 178 98 104 15 19 XP + Placebo XP + Bev Number at risk 54 50 0000 XP + placebo XP + bevacizumab HR = 0.87 95% CI 0.73–1.03 P =.1002 Survival rate 39 1518 2124 0 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 6 12 Study month 10.1 12.1 CI = confidence interval; HR = hazard ratio Kang, et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.

7. AVAGAST Secondary Endpoints: PFS and ORR HR = 0.80 95% CI 0.68–0.93 P = 0.0037 1.0 0.8 0.6 0.4 0.2 0 5.3 6.7 XP + bevacizumab (n = 387) XP + placebo (n = 387) ORR143 (46%)111 (37%) P =.0315 03691215182124 Survival rate Study month XP + placebo XP + bevacizumab PFS = progression-free survival; ORR = overall response rate Kang et al. J Clin Oncol. 2010;28[18S]:Abstract LBA4007.

8. Although bevacizumab did not meet primary endpoint of OS, secondary endpoints of PFS and ORR were significantly improved –Further study warranted for bevacizumab in gastric cancer Efficacy of bevacizumab varied by geographic region –OS was longest in Asia, but benefit was the smallest –OS was shortest in Pan-America, but benefit was the largest AVAGAST: Areas for Further Study

9. Grb2 Trastuzumab Raf MEK MAPK Ras SOS STAT Receptor MoAb internalisation HER2 Gene transcription /cell cycle Proliferation Apoptosis Invasion/metastasis Angiogenesis Signal transduction cascade blocked Cetuximab Panitumumab EGFR Bevacizumab Multiple Targets and Agents in Gastric Cancer Ramucirumab VEGF Lapatinib mTOR2 Everolimus Akt Gefitinib Erlotinib PI-3 kinase mTOR1

10. Conclusions Numerous targeted agents are being investigated in gastric cancer To date, trastuzumab is the only targeted agent shown to improve OS in patients with advanced gastric cancer Important to test HER2 status in all patients with advanced gastric cancer