1. Axel Grothey, MD Professor of Oncology Mayo Clinic Rochester, Minnesota Strategies to Improve Patient Outcomes in Gastric and Gastroesophageal Junction Cancer: Targeting HER2

2. Median OS Increased to > 1 Year With Trastuzumab-Based Treatment Median OS in patients with advanced gastric cancer (months) 1. Murad AM et al. Cancer. 1993;72:37-41. 2. Vanhoefer U et al. J Clin Oncol. 2000;18:2648-2657. 3. Ajani JA et al. J Clin Oncol. 2009; 27(S15):Abstract 4511. 4. Van Cutsem E et al. J Clin Oncol. 2006;24:4991-4997. 5. Dank M et al. J Clin Oncol. 2005;23[Suppl 16S]:4003. 6. Cunningham et al. N Engl J Med. 2008;358:36-46. 7. Kang YK et al. Ann Oncol. 2009;20:666−673. 8. Van Cutsem E et al. J Clin Oncol. 2009;27[Suppl15S]:Abstract 4509.

3. ToGA Trial Design Primary endpoint:OS Secondary endpoints:PFS, TTP, ORR, clinical benefit rate, duration of response, safety, quality of life, pain intensity, analgesic consumption *594 patients recruited (10 patients did not receive study drug and were excluded from analyses) 5-FU = 5-fluorouracil; GC = gastric cancer; HER2 = human epidermal growth factor receptor 2; ORR = overall response rate; OS = overall survival; R = randomised; TTP = time to progression; XP/FP = capecitabine/5-FU + cisplatin HER2-positive locally advanced or recurrent and/or metastatic GC (n = 584)* Capecitabine or 5-FU + cisplatin (XP/FP) (n = 290) Capecitabine or 5-FU + cisplatin (XP/FP) + trastuzumab (n = 294) 3807 patients screened; 810 HER2-positive R Van Cutsem E et al. J Clin Oncol. 2009; 27(Suppl 15S): Abstract 4509.

4. 294 290 277 266 246 223 209 185 173 143 147 117 113 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6565 4040 1010 0000 EventsMedian OSHR95% CIP value Trastuzumab + XP/FP 16713.8 mo0.740.60, 0.91.0046 XP/FP18211.1 mo Time (mo) 11.113.8 024681012141618202224262830323436 No. at risk 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Probability Trastuzumab + XP/FP Improves OS vs XP/FP Alone CI = confidence interval; HR = hazard ratio Van Cutsem E et al. J Clin Oncol. 2009; 27(Suppl 15S): Abstract 4509.

5. ToGA: OS in IHC 2+/FISH+ and IHC 3+ Subgroup (Exploratory Analysis) No. at risk EventsMedian OSHR95% CI Trastuzumab + XP/FP 12016.0 mo0.650.51, 0.83 XP/FP13611.8 mo 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 Time (mo) 11.816.0 246810121416182022242628303234360 0000 1010 11 3 218 198 4040 5353 12 4 20 11 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 39 20 28 13 Probability 228 218 FISH = fluorescence in situ hybridization; IHC = immunohistochemistry Van Cutsem E et al. J Clin Oncol. 2009; 27(Suppl 15S):Abstract 4509.

6. Trastuzumab Does Not Impact Overall or Cardiac Safety Adverse event, % Trastuzumab + XP/FP n = 294 XP/FP n = 290 All gradesGrade 3/4All gradesGrade 3/4 Nausea67 7 63 7 Anorexia466 6 Vomiting506 46 8 Fatigue35 4 28 2 Diarrhoea379 28 4 Asthenia195 18 3 Haematological AEs Neutropenia5327 57 30 Anaemia2812 21 10 Thrombocytopenia165 11 3 Cardiac AEs, total61 6 3 Cardiac failure < 1 Cardiac AEs leading to death< 1 AEs = adverse events Van Cutsem E et al. J Clin Oncol. 2009; 27(Suppl15S):Abstract 4509.

7. Patient History and Presentation of Disease Personal history: –64-year-old male accountant from Virginia –Healthy, good performance status Disease presentation: December 2009 –Developed dysphagia –Esophagogastroduodenoscopy revealed mass at the gastroesophageal junction –Biopsies confirmed adenocarcinoma –CT scan showed multiple intrahepatic metastases Patient consulted Mayo Clinic in January 2010; plans to move to Minnesota to be closer to his children in the Twin Cities

8. CT Scans Before Treatment (January 19, 2010) Imaging studies property of Axel Grothey, MD.

9. Treatment Identified goals of therapy: extend life and maintain quality of life as long as possible Started EOX as palliative therapy Initiated HER2 testing of outside (liver) biopsy –Tumor found to be HER2 IHC 3+ according to Hofmann criteria 1 From Cycle 2 on, trastuzumab utilized instead of epirubicin (“HOX” regimen) –Excellent tolerability of therapy –CT scans every 3 cycles (9 weeks), no treatment delays EOX = epirubicin, oxaliplatin and capecitabine 1. Hofmann M et al. Histopathology. 2008;52:797–805.

10. CT Scans Before and After Treatment Jan 19, 2010 Mar 23, 2010 Jun 25, 2010 Imaging studies property of Axel Grothey, MD.

11. CT Scans Before and After Treatment Jan 19, 2010 Mar 23, 2010Jun 25, 2010 Imaging studies property of Axel Grothey, MD.

12. Clinical Course Most recent appointment on June 28, 2010 Patient doing very well –No dysphagia –Feels energetic –Only relevant side effect at this point is grade 2 sensory neurotoxicity from oxaliplatin (780 mg/m 2 cumulative dose) Plan to continue trastuzumab + capecitabine, but omit oxaliplatin from therapy Continue assessment every 9 weeks

13. Gastric Cancer vs Gastroesophageal Junction Cancer Incidence of gastric cancer declining; incidence of gastroesophageal junction cancer increasing HER2 overexpression: –18  20% in adenocarcinoma of stomach –~30% in gastroesophageal junction cancer Given increasing incidence of gastroesophageal junction cancer and higher percentage of patients with HER2 overexpression, trastuzumab becomes even more important

14. Conclusions Trastuzumab is the first targeted therapy to show survival benefit in gastric and gastroesophageal junction cancers –Survival benefit greatest in patients with high levels of HER2 expression (median OS: 16 months) All patients with gastric and gastroesophageal junction cancers should be tested for HER2 Trastuzumab plus chemotherapy is well tolerated Trastuzumab plus chemotherapy is setting a new standard of care in patients with HER2-positive metastatic gastric cancer