1. Overview of Targeted Therapies for Esophageal and Gastric Cancers Johanna Bendell, MD Director, GI Oncology Research Associate Director, Drug Development Unit Sarah Cannon Research Institute Nashville, TN

2. Basic Numbers Esophageal cancer –17,460 new cases in the U. S. 2012 –15,070 deaths Gastric cancer –21,320 new cases in the U. S. 2012 –10,540 deaths 5 year survival rate <5% for patients with metastatic disease

3. Why targeted therapy? Going after what makes the cancer a cancer Our drug development is catching up with the lab Identification of certain pathways that are key in cancer development and survival We are still learning –One set of targets does not fit all –All of the pathways talk to each other –Side effect profiles are different, but can be just as toxic to the patient –Chronic cancer treatment?

4. Can Targeted Therapies Improve Outcomes? Pathways with targeted therapies where we have data or are currently under later stage study –HER2 –VEGF –EGF –mTOR –Met

5. ToGA trial – HER2 + gastric cancer HER2-positive advanced GC (n=584) 5-FU or capecitabine a + cisplatin (n=290) R a Chosen at investigator’s discretion GEJ, gastroesophageal junction 5-FU or capecitabine a + cisplatin + trastuzumab (n=294) Stratification factors −advanced vs metastatic −GC vs GEJ −measurable vs non-measurable −ECOG PS 0-1 vs 2 −capecitabine vs 5-FU Phase III, randomized, open-label, international, multicenter study 3807 patients screened 1 810 HER2-positive (22.1%) Bang, Y., et al. Lancet, 2010

6. Primary end point: OS Time (months) 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 No. at risk 11.113.8 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 024681012141618202224262830323436 Event FC + T FC Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 Median OS 13.8 11.1 T, trastuzumab Van Cutsem ASCO 2009

7. Secondary end point: PFS 0246810121416182022242628303234 Event 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9393 8282 6262 6161 6161 4040 2020 0000 5.56.7 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 Time (months) FC + T FC Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 Median PFS 6.7 5.5 Van Cutsem ASCO 2009

8. Bang, Y. Lancet, 2010 ToGA: Overall Survival (FISH+ or IHC3+)

9. ToGA Survival: IHC 2+/FISH+ or IHC 3+ (Post-hoc Exploratory Analysis) Bang, Y. Lancet, 2010

10. Secondary end point: tumor response rate 2.4% 5.4% 32.1% 41.8% 34.5% 47.3% Intent to treat ORR= CR + PR CR, complete response; PR, partial response p=0.0599 p=0.0145 F+C + trastuzumab F+C p=0.0017 Patients (%) CRPRORR Van Cutsem ASCO 2009

11. LOGiC Trial: Gastric Cancer Randomized Phase III Stratification ₋ Region of the world ₋ Prior neoadjuvant and/or adjuvant chemotherapy Adenocarcinoma of the stomach, GEJ, or esophagus HER2 positive (FISH+, IHC 3+) No previous treatment for advanced disease N = 545 CapOx (as above) + Placebo daily CapOx (Oxaliplatin 130 mg/m 2 IV Day 1 for up to 8 cycles + Capecitabine 850 mg/m 2 BID Days 1-14) + Lapatinib 1250 PO daily RANDOMIZERANDOMIZE

12. TYTAN Trial: Second Line Gastric Cancer Randomized Phase III Stratification ₋ Prior gastrectomy ₋ Prior anti HER2 therapy Adenocarcinoma of the stomach, GEJ, or esophagus HER2 positive Second Line China, Korea, Japan, Taiwan N = 261 Paclitaxel 80 mg/m 2 IV D1, 8, 15 of 28 day cycle N = 131 Paclitaxel 80 mg/m 2 IV D1, 8, 15 of 28 day cycle + Lapatinib 1500 PO daily N = 130 RANDOMIZERANDOMIZE Bang GI ASCO 2013

13. TYTAN ITT Population T + LT OS (mo)11.0 HR 0.84 [0.64,1.11] 8.9 PFS (mo)5.4 HR 0.85 [0.63,1.13] 4.4 HER2 IHC 3+ T + LT OS (mo)14.0 HR 0.59 [0.37,0.93] 7.6 PFS (mo)5.6 HR 0.54 [0.33,0.90] 4.2 Bang GI ASCO 2013

14. T-DM1 structure T-DM1 is a novel ADC Average drug: antibody ratio ≅ 3.5:1 Highly potent cytotoxic agent Monoclonal antibody: Trastuzumab Systemically stable Target expression : HER2 Cytotoxic agent: DM1 Linker: MCC T-DM1 Trastuzumab

15. * Dose selection based on PK/safety/efficacy ** Investigator’s choice between paclitaxel 80 mg/m 2 /wk and docetaxel 75 mg/m 2 q 3 wk Phase II: 3 arm; 2:2:1 randomization; endpoints: safety, PK, PFS, ORR; n=100 2L Her2 positive mGC PS: 0 -1 IHC 3+ or IHC 2+/ISH+ Prior Ctx + prior HER2 N=412 Chemotherapy ** T-DM1 2.4 mg/kg/wk T-DM1 3.6 mg/kg q3 wk Phase II n=100 2 2 1 Trastuzumab Emtansine: Phase II Study of 2L treatment for HER2+ Metastatic Gastric Cancer Stratified by: region, PS, prior gastrectomy, prior HER2-targeted tx

16. HER2 blockade for gastric cancers TOGA trial shows survival benefit using trastuzumab for patients with advanced gastric cancer – –We should be testing patients early – –What is the definition of HER2 positivity? IHC 3+ and/or FISH + But do FISH+ with IHC 0/1+ benefit? What are the next steps (follow breast cancer)? – –Lapatinib – –TDM-1 – –Trastuzumab plus lapatinib? – –Pertuzumab combinations? – –Neoadjuvant use?

17. AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III Study Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes Capecitabine*/Cisplatin (XP) + Placebo q3w Capecitabine*/Cisplatin (XP) + Bevacizumab q3w Locally advanced or metastatic gastric cancer R *5-FU also allowed if cape contraindicated Cape 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 Cape and bevacizumab/placebo until PD Stratification factors: 1. Geographic region 2. Fluoropirimidine backbone 3. Disease status Kang ASCO 2010

18. 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 + Bev HR = 0.87 95% CI 0.73–1.03 p = 0.1002 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 Kang ASCO 2010

19. Progression-Free Survival 387 279 306 145 201 86 123 55 71 32 38 3333 15 11 0000 XP + Placebo XP + Bev Number at risk XP + Placebo XP + Bev HR = 0.80 95% CI 0.68–0.93 p = 0.0037 Progression-free survival rate 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 39 1518 2124 0 6 12 5.3 6.7 Study month Kang ASCO 2010

20. Best Overall Response: Measurable Disease Population XP + Placebo N=387 XP + Bev N=387 Patients with measurable disease297311 Overall response111 (37%)143 (46%) 95% CI31.9–43.140.3–51.7 Difference9% 95% CI0.6–16.6 P value (  2 ) 0.0315 Complete response3 (1%)5 (2%) Partial response108 (36%)138 (44%) Stable disease90 (30%)93 (30%) Progressive disease63 (21%)44 (14%) Not assessable33 (11%)31 (10%) Kang ASCO 2010

21. Regional Differences in Efficacy Region XP + Placebo Median, mo XP + Bev Median, mo Delta, mo Hazard Ratio95% CI OSAsia12.113.91.80.970.75–1.25 Europe8.611.12.50.850.63–1.14 America6.811.54.70.630.43–0.94 PFSAsia5.66.71.10.920.74–1.14 Europe4.46.92.50.710.54–0.93 America4.45.91.50.650.46–0.93 Kang ASCO 2010

22. Patient Characteristics by Region % of patientsAsiaEuropePan-America Age<65726877 ≥65283223 ECOG PS0–1979196 23*94 Primary siteStomach947884 GEJ62216 Extent of diseaseMetastatic999592 Locally advanced158 Prior gastrectomyyes322327 no687773 Measurable lesionyes738877 no271223 Liver metastasisyes273742 no736358 *1 additional patient had an ECOG PS of 4 Kang ASCO 2010

23. Gastric cancer types Intestinal type –Well-differentiated –Related to gastritis, gastric atrophy, intestinal metaplasia –More common in in older men, East Asia, Eastern Europe, Central and South America –Decreasing incidence Diffuse type –Undifferentiated –Related to pangastritis –More common in younger patients, M = F –Increasing incidence –Worse prognosis

24. Gastric cancer by location Gastric cardia tumors –Rapidly increasing incidence in the West –Correlates with the increasing incidence of esophageal and GE junction adenocarcinoma –Poorer prognosis than distal stomach –Shares demographic and pathologic features of Barrett’s-associated esophageal cancer –Not associated with atrophic gastritis and intestinal metaplasia –Different genetic polymorphisms seen between cardia and non-cardia tumors, suggesting they have different biology El-Serag 2002, Powell 1992

25. AVAGAST Conclusions Overall the study was negative for survival benefit However, looking at the Americas patients there appears to be a benefit to using bevacizumab Highlights the difference in gastric cancers in different parts of the world – different epidemiology, different survivals, different responses to treatment

26. REGARD: Randomized Phase III Trial 2 nd Line Ramicirumab vs. Placebo 1:1 Second line metastatic gastric and GEJ adenocarcinoma R Ramucirumab IV q 2 weeks Placebo q 2 weeks 26 Primary EP: OS N = 355 Press release 10/12: met primary endpoint of OS and secondary endpoint of PFS Press release 1/23/13: OS 5.2 vs. 2.6 mo PFS 2.1 vs. 1.3 mo

27. RAINBOW: Randomized Phase III Trial 2 nd Line Paclitaxel +/- Ramicirumab 1:1 Second line metastatic gastric and GEJ adenocarcinoma R Paclitaxel 80 mg/m2 d1, 8, 15 + Ramucirumab IV q 2 weeks Paclitaxel 80 mg/m2 d1, 8, 15 + Placebo q 2 weeks 27 Primary EP: OS N = 665

28. Randomized Phase II Trial 1 st Line FOLFOX +/- Ramucirumab 1:1 First line metastatic esophagogastric adenocarcinoma R Ramucirumab IV + FOLFOX q 2 weeks Placebo + FOLFOX q 2 weeks 28 Primary EP: PFS

29. REAL-3 Waddell ASCO 2012

35. EXPAND: Randomized Phase III Trial 1 st Line Capecitabine/Cisplatin +/- Cetuximab 1:1 First line metastatic gastric and GEJ adenocarcinoma N = 904 R Cetuximab IV + Capecitabine/Cisplatin q 3 weeks N = 455 Capecitabine/Cisplatin q 3 weeks N = 449 35 Primary EP: PFS Lordick ESMO 2012

36. EXPAND Cape/Cis + Cetuximab (n = 455) Cape/Cis (n = 449) PFS (months)4.4 5.6 HR 1.091 [0.92,1.29] P = 0.316 OS (months)9.410.7 RR29%30%

37. Gefitinib in advanced esophageal cancer progressing after chemotherapy Patients progressing following chemotherapy Planned: 18 months to recruit 450 patients Primary endpoint: Overall survival - powered to detect an increase in 1 year survival from 10 to 18%, 82.5% power, 5% significance level. Secondary endpoints: PFS, toxicity & PROs Gefitinib 500mg od (n=225) Gefitinib 500mg od (n=225) Placebo (n=225) Simple randomisation Multi-centre Double-blind – patients, clinicians and trial office staff blinded to trial treatment Treated until progression Regular CT scans

38. Overall Survival Overall Survival ESMO 29th Sept 2012

39. Progression free survival ESMO 29th Sept 2012 Days on protocol therapy Placebo: median 35; IQR 27 to 62; range 0 to 372 Gefitinib: median 42; IQR 27 to 91; range 0 to 680

40. EGFR Inhibition for Gastric Cancers Three negative randomized trials Anything to biomarkers? –REAL-3 does not show anything predictive, only prognostic, but numbers are low –EXPAND – 97% tumor sample acquisition – will this help us learn anything? –Gefitinib – biomarker studies also pending – are TKI’s different than antibodies? Squamous vs. adenocarcinomas? –Small randomized phase II of cetuximab for SCC showed potential benefit – like head and neck? Lordick, et al, ASCO 2008, n = 66, RR 19 vs. 13%, PFS 5.7 vs. 3.6 mo, OS 9.5 vs. 5.5 mo

41. PI3K/Akt/mTOR Pathway in Gastric Cancer The PI3K/Akt/mTOR pathway, a key regulator of cell proliferation, growth, survival, metabolism, and angiogenesis, is dysregulated in 50%-60% of gastric cancers 1-3 Everolimus, an oral mTOR inhibitor, showed efficacy in preclinical models of gastric cancer 1,4-6 41 mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase. 1 Xu DZ et al. BMC Cancer. 2010;10:536; 2 Lang SA et al. Cancer. 2007;120:1803-10; 3 Yu G et al. Clin Cancer Res. 2009;15:1821-29; 4 Taguchi F et al. Invest New Drugs. 2011;29:1198-205; 5 Cejka D et al. Anticancer Res. 2008;28:3901-08; 6 Jaeger-Lansky A et al. Cancer Biol Ther. 2010;9:919-27; 7 Doi T et al. J Clin Oncol. 2010;28:1904-1910. In a phase 2 study of 53 patients with previously treated advanced gastric cancer, everolimus showed promising efficacy and acceptable tolerability 7

42. Phase 3 GRANITE-1 Study Design Everolimus 10 mg PO daily + BSC* (n = 439) Placebo PO daily + BSC (n = 217) SCREEN Treatment until disease progression or intolerable toxicity Stratification by region: Asia vs rest of world Stratification by number of lines of previous systemic chemotherapy (1 vs 2) Safety follow-up: EOT + 28 d Survival follow-up: every 3 mo RANDOMIZE (N = 656) BSC, best supportive care; EOT, end of treatment; PO, orally. ClinicalTrials.gov identifier: NCT00879333. 2 1 Van Cutsem GI ASCO 2012

43. Overall Survival (FAS) Van Cutsem GI ASCO 2012

44. Overall Survival by Stratification Factors (FAS) Van Cutsem GI ASCO 2012 ROW, rest of world. Prior chemotherapy Region Cross-class. of strata Hazard Ratio (95% CI) 0.80.6 Everolimus 10 mg/d Placebo In favor of 1.01.21.4 All (N = 656)0.90 (0.75-1.08) 2 (n = 343)0.90 (0.70-1.15) Asia (n = 363)0.96 (0.75-1.23) ROW (n = 293)0.85 (0.65-1.10) 1 prior chemo & ROW (n = 167)0.91 (0.64-1.31) 2 prior chemo & ROW (n = 126)0.74 (0.50-1.09) 1 (n = 313)0.94 (0.73-1.23) 0.98 (0.71-1.35)2 prior chemo & Asia (n = 217) 0.94 (0.63-1.39)1 prior chemo & Asia (n = 146)

45. Progression-Free Survival (FAS) Van Cutsem GI ASCO 2012

46. Rationale for Targeting MET  Met is a receptor tyrosine kinase.  Following binding to its only known ligand, hepatic growth factor (HGF), Met receptors dimerize, leading to growth, migration and survival signals  Met is amplified, mutated, overexpressed in many tumors  Met expression is associated with a worse prognosis in many cancers including NSCLC, colorectal, gastric, and breast cancers  Met pathway also implicated in resistance to bevacizumab in colorectal cancer patients and resistance to EGFR inhibitors

47. Activation of Met in Cancer MUTANT METAUTOCRINE HGFINCREASED MET OtherFocal Amp Paracrine HGF LUNG HCC (Childhood) PAPIL. RENAL (Hereditary & Sporadic) GLIOMA OSTEOSARCOMA PANCREATIC GASTRIC BREAST COLORECTAL ESOPHAGEAL GASTRIC GLIOMA HNSCC LUNG MELANOMA MESOTHELIOMA OVARIAN PANCREATIC RENAL GASTRIC LUNG Met CRC

48. Met Pathway and Targeted Agents Appleman (2011) JCO ePub

49. 1+ 2+ 3+  Intensity of Met staining on tumor cells scored on 0–3+ scale Development of Met IHC as a Diagnostic ‘Met High’ is defined as: ≥50% tumor cells with a staining intensity of 2 + or 3 + 1+ 2+ 3+

50. AMG-102 for gastric cancer Met receptor overexpression is associated with poor prognosis for gastric cancer patients Update on randomized phase II trial –ECX plus AMG-102 (rilotumumab) at 7.5 or 15 mg/kg (n = 82) vs. ECX plus placebo (n = 39) Met high defined as > 50% tumor cells positive for Met expression (n = 27 vs. 11) Oliner ASCO 2012

51. Clinical Efficacy in the Intent-to-Treat Population* *Results based on the updated analysis with data cutoff of April 1, 2011. † Adjusted for baseline randomization stratification variables (ECOG status [0 or 1] and disease extent [locally advanced or metastatic]). Iveson T, et al. European Multidisciplinary Cancer Congress, September 23-27, 2011, Stockholm, Sweden; abstract #6504. Median Months (80% CI) HR † (80% CI)P Value Rilotumumab + ECX (n = 82)5.6 (4.9–6.9)0.64 (0.48–0.85)0.045 Placebo + ECX (n = 39)4.2 (3.7–4.6) Progression-Free Survival Overall Survival Median Months (80% CI) HR † (80% CI)P Value Rilotumumab + ECX (n = 82)11.1 (9.5–12.1)0.73 (0.53–1.01)0.215 Placebo + ECX (n = 39)8.9 (5.7–10.6) HR 0.64 HR 0.73 Oliner ASCO 2012

52. Improved PFS and OS in MET High Patients Progression-Free Survival Overall Survival *HR adjusted for baseline disease extent and ECOG PS. MET-evaluable OS HR, 0.95 ITT OS HR, 0.73 Median Months (80% CI) HR * (95% CI)P Value Rilotumumab + ECX (n = 27)6.9 (5.1–7.5)0.51 (0.24–1.10)0.085 Placebo + ECX (n = 11)4.6 (3.7–5.2) Median Months (80% CI) HR + (95% CI)P Value Rilotumumab + ECX (n = 27)11.1 (9.2–13.3)0.29 (0.11–0.76)0.012 Placebo + ECX (n = 11)5.7 (4.5–10.4) HR 0.51 HR 0.29 Oliner ASCO 2012

53. Targeted Agents for Gastric and Esophageal Cancers They are in testing, and some look promising We are going to have to come to terms with the epidemiology of this disease to target the right populations in trials Biomarkers are essential, though we do not quite know what we are doing yet But we are continuing to move forward!