1. Copyright © 2011 Research To Practice. All rights reserved. Case presented by Dr Morganstein (Prof Van Cutsem) 78 yo woman with Stage IV GE adenocarcinoma found in 1/2010 – mets to liver, bone, nodes –Carboplatin/irinotecan x 2 cycles  progressive somnolence  hemorrhagic brain mets = resected 4/2010: HER2-positive (IHC 3+, FISH amplified = 6.9) –FOLFOX + trastuzumab  PET/CT 4 mos later = CR and PS improved significantly –Neurotoxicity  d/c oxaliplatin  on 5-FU/LV/trast Recent PET/CT = near CR, mild activity at GE jnx

2. Copyright © 2011 Research To Practice. All rights reserved. HER2-positive (IHC3+ or FISH+), inoperable, locally advanced, recurrent or metastatic GE junction or gastric adenocarcinoma ToGA: Trial Schema FC Fluoropyrimidine (F) (5-FU or capecitabine at investigator discretion) + Cisplatin (C) R FC + Trastuzumab (T) Primary Analysis: N = 584 5-FU = 800 mg/m 2 /day continuous infusion d1-5 q3wks x 6 Capecitabine = 1,000 mg/m 2 bid d1-14 q3wks x 6 Cisplatin = 80 mg/m 2 q3wks x 6 Trastuzumab = 8 mg/kg loading dose followed by 6 mg/kg q3wks until PD Bang YJ et al. Lancet 2010;376(9742):687-97.

3. Copyright © 2011 Research To Practice. All rights reserved. ALL Patients 584 0.74 0.60 - 0.91 IHC 0 / FISH+ 61 0.92 0.48 - 1.76 IHC 1+ / FISH+ 70 1.24 0.70 - 2.20 IHC 2+ / FISH+ 159 0.75 0.51 - 1.11 IHC 3+ / FISH+ 256 0.58 0.41 - 0.81 IHC 3+ / FISH- 15 0.83 0.20 - 3.38 0.2 0.4 0.6 1 2 3 4 5 Favors Therapy Impact Risk Ratio Favors No Therapy Impact Number Hazard 95% Confidence Of Patients Ratio Limits Relative Impact of HER2 Status by IHC or FISH in the ToGA Trial 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 2011, with permission from Elsevier.

4. Copyright © 2011 Research To Practice. All rights reserved. Case presented by Dr Morganstein (Prof Van Cutsem) 78 yo woman with Stage IV GE adenocarcinoma found in 1/2010 – mets to liver, bone, nodes –Carboplatin/irinotecan x 2 cycles  progressive somnolence  hemorrhagic brain mets = resected 4/2010: HER2-positive (IHC 3+, FISH amplified = 6.9) –FOLFOX + trastuzumab  PET/CT 4 mos later = CR and PS improved significantly –Neurotoxicity  d/c oxaliplatin  on 5-FU/LV/trast Recent PET/CT = near CR, mild activity at GE jnx

5. Copyright © 2011 Research To Practice. All rights reserved. Comparison of HER2 Testing in Breast and Gastric/GEJ Cancers Breast CancerGastric/GE Junction Cancer IHC Membranous Staining Pattern 3+ requires full circumferential staining pattern 3+ score allowed for cases with loss of apical membrane staining Required Percent of Membranous Staining ASCO – CAP Guidelines: 30% Trastuzumab Package Insert: 10% Biopsies: no percentage required. Any cell cluster with membranous staining is HER2+ Resections: 10% Heterogeneity of HER2 Positivity Well-described; judged as moderate, can influence HER2 test results especially when core biopsies are assessed More severe than for breast cancer; especially important for endoscopic biopsies

6. Copyright © 2011 Research To Practice. All rights reserved. Gastric Cancer Gastroesophageal Junction Cancer Breast Cancer Continuous Complete 360 Degree Membranous HER2 Staining Incomplete Staining With Loss of Apical Membrane HER2 Expression Marked Heterogeneity of HER2 Immunostaining Courtesy of Jeffrey S Ross, MD Comparison of HER2 IHC Slide Scoring in Gastric/GEJ and Breast Cancers

7. Copyright © 2011 Research To Practice. All rights reserved. FISH positive/IHC 2+ FISH positive/IHC 3+ FISH positive/IHC 1+ FISH positive/ IHC 0 FISH no result/ IHC 3+ FISH positive/ IHC no result FISH negative/IHC 3+ ToGA: HER2 Status of Enrolled Patients Bang YJ et al. Lancet 2010;376(9742):687-97.

8. Copyright © 2011 Research To Practice. All rights reserved. ToGA: Pre-Planned and Post-Hoc Exploratory Analyses of Patients Stratified by HER2 Status 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 2011, with permission from Elsevier.

9. Copyright © 2011 Research To Practice. All rights reserved. Case presented by Dr Morganstein (Prof Van Cutsem) 78 yo woman with Stage IV GE adenocarcinoma found in 1/2010 – mets to liver, bone, nodes –Carboplatin/irinotecan x 2 cycles  progressive somnolence  hemorrhagic brain mets = resected 4/2010: HER2-positive (IHC 3+, FISH amplified = 6.9) –FOLFOX + trastuzumab  PET/CT 4 mos later = CR and PS improved significantly –Neurotoxicity  d/c oxaliplatin  on 5-FU/LV/trast Recent PET/CT = near CR, mild activity at GE jnx