1. Axel Grothey, MD Professor, Oncology Mayo Clinic Rochester, Minnesota Role of HER2 in Gastroesophageal Cancer This program is supported by an educational grant from

2. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer About These Slides  Our thanks to the presenters who gave permission to include their original data  Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent  These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.

3. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Disclosure Axel Grothey, MD, has disclosed that he has received contracted research support from Bayer, Daiichi, and Genentech.

4. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Gastric Cancer: A Global Disease  Fourth most common malignant disease: ~ 930,000 cases/yr  Second most common cause of cancer-related death worldwide: ~ 700,000 deaths/yr  Decreasing incidence of distal gastric cancer  Increasing incidence of proximal gastric cancer  Wide geographic variation  20/100,000 < 10/100,000  10 to  20/100,000 Incidence (Males) Kamangar F, et al. J Clin Oncol. 2006;24:2137-2150. National Cancer Institute. 2010.

5. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Esophageal and Gastric Carcinoma US Incidence in 2010  37,640 new cases estimated [1] –Gastric: 21,000 (56%); esophagus: 16,640 (44%)  Increase in esophageal, GEJ, cardia adeno [2] –Obesity, GERD, Barrett’s, tobacco, EtOH –Are adenocarcinomas of the distal esophagus, GEJ, and upper stomach the same?  Decline in gastric cancer, SCC incidence [2]  4.4% of US cancer deaths [1] –Esophageal: 88% fatality rate; gastric: 50% fatality rate  Male > female 1. Altekruse SF, et al. SEER Cancer Statistics Review, 1975-2007. 2. National Cancer Institute. 2010.

6. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Metastatic Gastroesophageal Cancer  Long-standing search for a true standard regimen  Multiple combinations are feasible in the first-line setting  No data as to whether combinations are better than sequential therapy  Active agents –Fluoropyrimidines, platinums, taxanes, irinotecan, (anthracyclines), trastuzumab in HER2+

7. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer ECF (n = 249)ECX (n = 241) EOF (n = 235)EOX (n = 239) Epirubicin50 mg/m 2 IV 3 weekly Cisplatin 60 mg/m 2 IV 3 weekly 5-FU 200 mg/m 2 /day IV given continuously Epirubicin 50 mg/m 2 IV 3 weekly Cisplatin 60 mg/m 2 IV 3 weekly Capecitabine625 mg/m 2 BID PO continuously Epirubicin 50 mg/m 2 IV 3 weekly Oxaliplatin130 mg/m 2 IV 3 weekly 5-FU 200 mg/m 2 /day IV given continuously Epirubicin 50 mg/m 2 IV 3 weekly Oxaliplatin130 mg/m 2 IV 3 weekly Capecitabine 625 mg/m 2 BID PO continuously REAL-2: Phase III Capecitabine vs 5-FU and Oxaliplatin vs Cisplatin  2 x 2 randomization, 8 cycles –Noninferiority of X over F and O over C for OS –Assuming 1-yr survival of 35% for ECF, 80% power to detect noninferiority with 1-sided α of 5% Cunningham D, et al. N Engl J Med. 2008;358:36-46.

8. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer REAL 2: Efficacy  Median follow-up: 17.1 mos Outcome (ITT)ECF (n = 263) ECX (n = 250) EOF (n = 245) EOX (n = 244) ORR,* %40.746.442.447.9 Median PFS, mos6.26.76.57.0 Median OS, mos9.9 9.311.2 1-yr OS, %37.740.840.446.8 *Patients evaluable for ORR: n = 246 for ECF; n = 237 for ECX; n = 231 for EOF; n = 234 for EOX. Cunningham D, et al. N Engl J Med. 2008;358:36-46.

9. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer TAX325: Phase III Docetaxel/Cisplatin/5-FU (DCF) vs Cisplatin/5-FU (CF)  Primary endpoint: TTP from 4 → 6 mos  Secondary endpoints: OS, RR, safety, QoL, clinical benefit Patients with advanced gastric cancer and no previous palliative chemotherapy (N = 457) DCF Docetaxel 75 mg/m 2 IV over 1 hr on Day 1 + Cisplatin 75 mg/m 2 IV over 1-3 hrs on Day 1 + 5-FU 750 mg/m 2 /day by CIV over 5 days q3w (n = 227) CF Cisplatin 100 mg/m 2 IV over 1-3 hrs on Day 1 + 5-FU 1000 mg/m 2 /day by CIV over 5 days q4w (n = 230) R Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.

10. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer DCF vs CF: Efficacy Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997. ParameterDCF (n = 221)* CF (n = 224)* P Value Median age, yrs55 -- Metastatic disease, %9697-- ORR, %3725.01 Median TTP, mos5.63.7≤.001 Median OS, mos9.28.6.02 *Full analysis population (treated patients).

11. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer DCF vs CF: Toxicity Adverse Event, %DCF (n = 221) CF (n = 224) Grade 3/4  Stomatitis2127  Diarrhea198  Nausea1417  Vomiting1417  Neutropenia8257 All-grade neutropenic fever and/or neutropenic infection2912 Toxic deaths3.65.4 Off therapy for adverse event or consent withdrawal4937 Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997.

12. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer DCF: Supportive Care, Dose Modifications  Prophylactic use of growth factors  Reduce doses –Docetaxel to 60 mg/m 2 –Cisplatin to 60 mg/m 2 –5-FU to 500-600 mg/m 2  Change dose and schedule to CRC-like schedules –FOLFOX or FOLFIRI –FOLFOX has emerged as US Intergroup Standard

13. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Phase III Data of Chemotherapy Regimens in Advanced Gastroesophageal Cancer RegimenORR, %Median TTP/PFS/FFS, Mos Median OS, Mos Reference CF Cisplatin 100 mg/m 2 Day 1 5-FU 1000 mg/m 2 CIV Days 1-5 35--8.3Bleiberg [1] ECF Epirubicin 50 mg/m 2 Day 1 Cisplatin 60 mg/m 2 Day 1 5-FU 200 mg/m 2 /day CIV Days 1-21 427.09.4Ross [2] DCF Docetaxel 75 mg/m 2 Day 1 Cisplatin 75 mg/m 2 Day 1 5-FU 750 mg/m 2 /day CIV Days 1-5 375.69.2Van Cutsem [3] EOX Epirubicin 50 mg/m 2 Day 1 Oxaliplatin 130 mg/m 2 Day 1 Capecitabine 625 mg/m 2 BID 487.011.2Cunningham [4] 1. Bleiberg H, et al. Eur J Cancer. 1997;33:1216-1220. 2. Ross P, et al. J Clin Oncol. 2002;20:1996-2004. 3. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997. 4. Cunningham D, et al. N Engl J Med. 2008;358:36-46.

14. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Targeted Therapies  Conventional, cytotoxic chemotherapy has limited benefit  Targeted agents: attempt to block specific tumor growth pathways –Monoclonal antibodies –Tyrosine kinase inhibitors –Soluble receptors to growth factors –Inhibition of pathways involved in protein synthesis and degradation

15. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Molecular Targets: Esophagogastric Cancer  KRAS mutation: < 5% to 10% [1,2]  BRAF mutation: < 5% [1,2]  EGFR overexpression: ~ 50% to 80% [3,4] –TKIs inactive [4] –Cetuximab monotherapy inactive [5]  EGFR mutation: very low [4,6]  HER2 overexpression: 10% to 25% [7] 1. Lee SH, et al. Oncogene. 2003;22:6942-6945. 2. Kim IJ, et al. Hum Genet. 2003;114:118-120. 3. Galizia G, et al. World J Surg. 2007;31:1458-1468. 4. Dragovich T, et al. J Clin Oncol. 2006;24:4922-4927. 5. Chan JA, et al. Ann Oncol. 2011;[Epub ahead of print]. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550. 7. Yano T, et al. Oncol Rep. 2006;15:65-71.

16. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer: ToGA  Rationale: a subpopulation of gastric cancers overexpress HER2  Primary endpoint: OS *Selected at investigator’s discretion: 5-FU 800 mg/m 2 /day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m 2 BID on Days 1-14 q3w x 6. (n = 584) R Patients with advanced gastric cancer screened for HER2 status (N = 3803) Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU Patients with HER2+ advanced gastric cancer (n = 810; 22% of successful screenings) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) 5-FU or Capecitabine* + Cisplatin 80 mg/m 2 q3w x 6 (n = 290) Bang YJ, et al. Lancet. 2010;376:687-697.

17. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer ToGA: Main Patient Selection Criteria  Inclusion criteria –Adenocarcinoma of stomach or GEJ –Inoperable locally advanced, recurrent, and/or metastatic disease –Measurable (RECIST) or nonmeasurable evaluable disease –HER2+ tumor (centrally assessed) –IHC 3+ and/or FISH+ –Adequate organ function and ECOG PS ≤ 2 –Written informed consent  Exclusion criteria –Previous adjuvant chemotherapy within 6 mos –Chemotherapy for advanced disease –Congestive heart failure or baseline LVEF < 50% –Creatinine clearance < 60 mL/min Bang YJ, et al. Lancet. 2010;376:687-697.

18. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Patient Demographics and Baseline Characteristics CharacteristicChemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) Male, %7775 Mean age, yrs (SD)59.4 (10.8)58.5 (11.2) Race, %  Asian5154  White3936 Type of gastric cancer (central assessment),* %  Intestinal7774  Diffuse99  Mixed1417 Previous gastrectomy, %2421 Bang YJ, et al. Lancet. 2010;376:687-697. *Chemotherapy plus trastuzumab: n = 293; chemotherapy alone: n = 287.

19. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer HER2 Positivity IHC Score Surgical Specimen Staining Pattern Biopsy Specimen Staining Pattern HER2 Overexpr. Assessment 0 No reactivity or membranous reactivity in < 10% of tumor cells No reactivity or no membranous reactivity in any tumor cell Negative 1+ Faint or barely perceptible membranous reactivity in ≥ 10% of tumor cells; cells are reactive only in part of their membrane Tumor cell cluster with faint or barely perceptible membranous reactivity irrespective of % of tumor cells stained Negative 2+ Weak to moderate complete, basolateral or lateral membranous reactivity in ≥ 10% of tumor cells Tumor cell cluster with weak to moderate complete, basolateral or lateral membranous reactivity irrespective of % of tumor cells stained Equivocal 3+ Strong complete, basolateral or lateral membranous reactivity in ≥ 10% of tumor cells Tumor cell cluster with strong complete, basolateral or lateral membranous reactivity irrespective of % of tumor cells stained Positive Reprinted from The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 687-697, Copyright 2010, with permission from Elsevier. Bang YJ, et al. ASCO 2009. Abstract 4556.

20. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer HER2 Positivity Worldwide Bang YJ, et al. ASCO 2009. Abstract 4556. Reprinted with permission. HER2 positivity in ToGA: 22.1% Asian/Pacific Europe South/Middle America Other Patients, % 35 30 25 20 15 10 5 0 Australia (n = 61)Japan (n = 410) Korea (n = 687) China (n = 590)India (n = 118)Taiwan (n = 34) South Africa (n = 27) Russia (n = 459)Mexico (n = 67) Guatemala (n = 53) Panama (n = 40)Brazil (n = 97)Peru (n = 168)Costa Rica (n = 59)Denmark (n = 33)Italy ( n = 99)France (n = 78)UK (n = 132)Germany (n = 173)Portugal (n = 67)Spain (n = 122)Belgium (n = 14)Turkey (n = 58)Finland (n = 21)

21. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer HER2 Positivity Histological Type Bang YJ, et al. ASCO 2009. Abstract 4556. Reprinted with permission SubtypeHER2 Positivity (%)P Value Histological typeIntestinal Diffuse Mixed 32.2 6.1 20.4 <.001 LocalizationGEJ Gastric 33.2 20.9 <.002 Histological subtype and tumor sublocalization are important factors for HER2 expression/amplification in gastric cancer

22. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer HER2 Positivity GEJ vs Gastric Cancer Gastric cancer GEJ cancer 100 80 60 40 20 0 Samples (%) BelgiumDenmarkFinlandFranceGermanyUKAustraliaPortugalMexicoItalyIndiaSpainPanamaCosta RicaChinaRussiaTurkeyPeruBrazilGuatemalaJapanKoreaTaiwanSouth Africa N = 2759; *P <.001Gastric CancerGEJ CancerTotal HER2 positive, %20.933.2*21.3 Bang YJ, et al. ASCO 2009. Abstract 4556. Reprinted with permission

23. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Events 167 182 ToGA Primary Endpoint: OS Mos 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 Pts at Risk, n 11.113.8 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 024681012141618202224262830323436 Survival Probability FC + T FC HR 0.74 95% CI 0.60-0.91 P Value.0046 Median OS 13.8 11.1 Reprinted from The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 687-697, Copyright 2010, with permission from Elsevier.

24. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer ToGA: Efficacy Outcome  Preplanned subgroup analysis indicated improved OS benefit with increasing HER2 expression by IHC  Exploratory analysis of IHC 2+/FISH+ and IHC 3+ cohort demonstrated a 4-mo increase in OS with trastuzumab –HR: 0.65 (95% CI: 0.51-0.83) OutcomeChemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) HR (95% CI)P Value Median OS, mos13.811.10.74 (0.60-0.91).0046 Median PFS, mos6.75.50.71 (0.59-0.85).0002 ORR, %4735-.0017  CR52-.0599  PR4232-.0145 Bang YJ, et al. Lancet. 2010;376:687-697.

25. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer ToGA: OS by HER2 Status HER2 Status SubgroupMedian OS, Mos (CT + T vs CT Alone) HR* (95% CI) All patients (N = 584)13.8 vs 11.10.74 (0.60-0.91) Preplanned analysis  IHC 0/FISH+ (n = 61)10.6 vs 7.20.92 (0.48-1.76)  IHC 1+/FISH+ (n = 70)8.7 vs 10.21.24 (0.70-2.20)  IHC 2+/FISH+ (n = 159)12.3 vs 10.80.75 (0.51-1.11)  IHC 3+/FISH+ (n = 256)17.9 vs 12.30.58 (0.41-0.81)  IHC3+/FISH- (n = 15)17.5 vs 17.70.83 (0.20-3.38) Exploratory analysis  IHC 0 or 1+/FISH+ (n = 131)10.0 vs 8.71.07 (0.70-1.62)  IHC 2+/FISH+ or IHC 3+ (n = 446)16.0 vs 11.80.65 (0.51-0.83) Bang YJ, et al. Lancet. 2010;376:687-697. *HR 1 favors chemotherapy alone.

26. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Events 120 136 Mos 228 218 198 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5353 4040 1010 0000 Pts at Risk, n 11.816.0 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 024681012141618202224262830323436 Survival Probability FC + T FC HR 0.65 95% CI 0.51-0.83 Median OS 16.0 11.8 ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis) Reprinted from The Lancet, 376(9742), Bang YJ, et al., Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. 687-697, Copyright 2010, with permission from Elsevier.

27. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer ToGA: Select Toxicities Adverse Event, %Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) Grade 3/4 hematologic events  Neutropenia2730  Anemia1210 Grade 3/4 nonhematologic events  Diarrhea94  Nausea77 Cardiac events66  Grade 3/413 LVEF reduction of ≥ 10% to absolute value < 50%* 51 Bang YJ, et al. Lancet. 2010;376:687-697. *Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187.

28. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Pertuzumab & Trastuzumab Bind Distinct Epitopes on HER2 Extracellular Domain  Activates ADCC  Prevents HER2 domain cleavage  Inhibits HER2-mediated signaling pathways  Activates antibody-dependent cellular cytotoxicity (ADCC)  Has a major effect on role of HER2 as a coreceptor with HER3 or EGFR  Inhibits multiple HER-mediated signaling pathways Trastuzumab-HER2 ComplexPertuzumab-HER2 Complex Trastuzumab Dimerization domain Pertuzumab Reprinted from Cancer Cell, Vol. 7/4, Hubbard SR. EGF receptor inhibition: attacks on multiple fronts.287- 288, Copyright 2005, with permission from Elsevier.

29. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer (Planned N = 535) CapeOx + Lapatinib CapeOx + Placebo ClinicalTrials.gov. NCT00680901. LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer  Primary endpoint: OS (was PFS)  Data expected mid-2012

30. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer RTOG 1010: Neoadjuvant Phase III Trial in Esophageal/GEJ Adenocarcinoma  Primary endpoint: DFS (15 → 27 mos; HR: 0.56) Patients with confirmed HER2- overexpressing esophageal or GEJ adenocarcinoma (Planned N = 160) Radiation (50.4 Gy) + Paclitaxel + Carboplatin + Trastuzumab Radiation (50.4 Gy) + Paclitaxel + Carboplatin Stratified by presence of adenopathy and involved celiac nodes Surgery 5-8 wks after radiation completion Maintenance Trastuzumab q3w x 13 Principal investigator: H. Safran, Providence, RI. ClinicalTrials.gov. NCT01196390.

31. Clinical Application

32. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Patient History and Presentation of Disease  Personal history –61-yr-old female consultant from Iowa –Healthy, good performance score  Disease presentation –Developed dysphagia –EGD revealed mass at the gastroesophageal junction –Biopsies confirmed ACA –CT scan showed multiple intrahepatic metastases  Patient consulted Mayo Clinic

33. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer CT Scans Before Treatment

34. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Treatment  Discussed palliative situation, identified goal of therapy to extend her life and maintain her 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] 1. Hofmann M, et al. Histopathology. 2008;52:797-805.

35. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Treatment  From cycle 2 on, trastuzumab added to capecitabine and oxaliplatin –Epirubicin dropped  Excellent tolerability of therapy  CT scans every 3 cycles (9 wks); no treatment delays

36. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer CT Scans Before and After Treatment Mar 23, 2010Jun 25, 2010 Jan 19, 2010

37. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer CT Scans Before and After Treatment Mar 23, 2010Jun 25, 2010 Jan 19, 2010

38. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Clinical Course  Appointment on June 28, 2010  Patient doing very well –No dysphagia –Felt energetic –Only relevant adverse effect at this point: grade 2 sensory neurotoxicity from oxaliplatin (~ 750 mg/m 2 cumulative dose)  Continued trastuzumab + capecitabine, but oxaliplatin omitted from therapy, treatment cycles every 3 wks  Continue assessment every 9 wks

39. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Clinical Course  November 2010: tumor progression, patient still asymptomatic  Start second-line therapy with docetaxel –Progressive disease after two 3-weekly cycles  Start third-line therapy with FOLFIRI (patient still in excellent performance score) –Feb 2011: PR after four 2-weekly cycles!

40. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Advanced Gastroesophageal Cancer: Summary  Chemotherapy backbone –2-drug regimens preferred (FOLFIRI, FOLFOX, XELOX, Cape-Cis) –Marginal benefit for 3-drug regimens (docetaxel + CF) –ECF/EOX: Is E needed in metastatic disease?

41. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Advanced Gastroesophageal Cancer: Summary  Molecular-targeted therapies –VEGF, EGFR/HER pathways targeted –Phase II and III development with chemo, chemoRT –Molecular markers to select therapy –HER2+ → trastuzumab should be used

42. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer FDA Approval for Trastuzumab  October 21, 2010 FDA approval for trastuzumab in combination with chemotherapy (cisplatin plus either capecitabine or 5- fluorouracil) for HER2-positive metastatic cancer of the stomach or gastroesophageal junction, in patients who have not received prior treatment for metastatic disease  Note –No specific diagnostic test for HER2 mentioned –No required HER2 expression level specified

43. clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Median OS Increased to > 1 Yr With Trastuzumab-Based Therapy 0 5 10 15 Trastuzumab + XP/FP [8] EOX [6] XP [7] ECX [6] ECF [6] DCF [4] EOF [6] IF [5] CF [4] FAMTX [2] BSC [1] C + S1 [3] HER2 IHC 2+/FISH+ or IHC 3+ Median OS in Patients With Advanced Gastric Cancer (Mos) 12 mos 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. 2010;28:1547-1553. 4. Van Cutsem E, et al. J Clin Oncol. 2006;24:4991-4997. 5. Dank M, et al. Ann Oncol. 2008;19:1450-1457. 6. Cunningham D, et al. N Engl J Med. 2008;358:36-46. 7. Kang YK, et al. Ann Oncol. 2009;20:666-673. 8. Bang YJ, et al. Lancet. 2010;376:687-697.

44. More Hematology/Oncology Available Online Expert Roundtable Video “HER2 Expression in Gastric Cancer— Best Practices and Optimal Patient Care” In this exclusive video, Axel Grothey, MD; Michael F. Press, MD, PhD; and Eric Van Cutsem, MD, PhD, provide practical guidance on HER2 testing and how HER2- targeted agents can be safely integrated into optimal therapeutic approaches. clinicaloptions.com/oncology