Monday Night with Research To Practice: An 8-Part Live CME Webcast Series

1. Monday Night with Research To Practice: An 8-Part Live CME Webcast Series Part VI: HER2-Positive Gastric CancerMonday, October 25, 20107:30 PM - 8:30 PM ET

2. Jaffer A Ajani, MD Professor of Medicine Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston, Texas Jeffrey S Ross, MD Cyrus Strong Merrill Professor and Chair Department of Pathology and Laboratory Medicine Albany Medical College Albany, New York Neil Love, MDModerator Research To PracticeMiami, Florida

3. Disclosures for Moderator Neil Love, MD Dr Love is president and CEO of Research To Practice, which receives funds in the form of educational grants to develop CME activities from the following commercial interests: Abraxis BioScience, Allos Therapeutics, Amgen Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc, Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals Inc, Bristol-Myers Squibb Company, Celgene Corporation, Cephalon Inc, Eisai Inc, EMD Serono Inc, Genentech BioOncology, Genomic Health Inc, Lilly USA LLC, Millennium Pharmaceuticals Inc, Myriad Genetics Inc, Novartis Pharmaceuticals Corporation, OSI Oncology, Sanofi-Aventis and Spectrum Pharmaceuticals Inc.

4. Disclosures for Jaffer A Ajani, MD

5. Disclosures for Jeffrey S Ross, MD

6. A 47 year old man with history of inflammatory bowel disease and intrahepatic sclerosing cholangitis Patient presented with epigastric pain Endoscopy and CT scans: Mass in lower esophagus, GE junction, proximal stomach, lung metastasis Case History: Dr Ajani

7. Initial PET Evaluation

12. 1) Would you want HER2 testing done before deciding on a treatment plan? Yes, in almost all situations Yes, in some situations Yes, but it’s difficult to get the pathologist to do it No

13. 2) What treatment would you generally recommend if the patient’s tumor was HER2-negative? DCF or DCF modification ECF or ECF modification Irinotecan plus cisplatin Irinotecan plus fluoropyrimidine Oxaliplatin plus fluoropyrimidine Cisplatin plus fluoropyrimidine Paclitaxel-based regimen Other

14. Case History: Dr Ajani (continued) The patient’s tumor is HER2-positive (IHC3+, FISH-positive)

15. 3) Would you recommend trastuzumab-based therapy for this patient? Yes No

16. 4) If you would recommend trastuzumab, which chemotherapy regimen would you use? No chemotherapy – trastuzumab alone DCF or DCF modification ECF or ECF modification Irinotecan plus cisplatin Irinotecan plus fluoropyrimidine Oxaliplatin plus fluoropyrimidine Cisplatin plus fluoropyrimidine Paclitaxel-based regimen Other

17. Case History: Dr Ajani (continued) Patient treated with Docetaxel 40 mg/m2 q2wks Capecitabine 1,500 mg/m2 7d on/7d off Oxaliplatin 85 mg/m2 q2wks Trastuzumab 6 mg/kg q3wks

18. Response Evaluation in 10/2008

19. Patient Continues Trastuzumab as of 10/2010

20. Trastuzumab in Combination with Chemotherapy versus Chemotherapy Alone for Treatment of HER2-Positive Advanced Gastric or GE Junction Cancer (ToGA): A Phase 3, Open-Label, Randomised Controlled Trial Bang YJ et al. Lancet 2010;376(9742):687-97.

21. ToGA: Trial Schema Primary Analysis: N = 584 FC Fluoropyrimidine (F) (5-FU or capecitabine at investigator discretion) + Cisplatin (C) HER2-positive (IHC3+ or FISH+), inoperable, locally advanced, recurrent or metastatic GE junction or gastric adenocarcinoma R FC + Trastuzumab (T) 5-FU = 800 mg/m2/day continuous infusion d1-5 q3wks x 6 Capecitabine = 1,000 mg/m2 bid d1-14 q3wks x 6 Cisplatin = 80 mg/m2 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.

23. Efficacy of Trastuzumab + Chemotherapy versus Chemotherapy Alone in HER2-Positive Advanced Gastric or GE Junction Tumors Bang YJ et al. Lancet 2010;376(9742):687-97.

24. ToGA: Median Overall Survival Bang YJ et al. Lancet 2010;376(9742):687-97.

25. ToGA: Progression-Free Survival Bang YJ et al. Lancet 2010;376(9742):687-97.

26. Cardiac Safety of Trastuzumab + Chemotherapy versus Chemotherapy Alone in HER2-Positive Advanced Gastric or GE Junction Tumors Bang YJ et al. Lancet 2010;376(9742):687-97.

27. Quality of Life Results from a Phase III Study of Trastuzumab Plus Chemotherapy as First-Line Therapy in Patients with HER2-Positive Advanced Gastric and Gastro-Oesophageal Junction Cancer Ohtsu A et al. Proc 12th WCGC 2010;Abstract O-0011.

28. ToGA QoL Analysis: Proportion of Patients with Global Health Status, Physical Functioning, Nausea and Vomiting, Dysphagia and Pain Intensity Scores Improving by at Least 10% from Baseline at Week 37 Global health status Physical functioning Nausea/vomiting Dysphagia Pain intensity Chemotherapy alone Trastuzumab + chemotherapy 0% 10% 20% 30% 40% 50% 60% 70% Ohtsu A et al. Proc 12th WCGC 2010;Abstract O-0011.

29. ToGA ASCO 2009 Discussion: Trastuzumab in Gastro-Oesophageal Cancer – Future Directions (David Cunningham, MD) • Efficacy of trastuzumab monotherapy? • Maintenance monotherapy after triplet regimens? • Continuation beyond progression in association with second-line therapy as in breast cancer (Von Minckwitz et al, JCO 2009)? • Role of trastuzumab in the perioperative setting? • Other potential biomarkers to further select patients (currently under evaluation in breast cancer)?

30. Ongoing Studies of Targeting HER2-Positive Metastatic or Unresectable Gastric Cancer www.clinicaltrials.gov, October 2010

31. Interim Safety Analysis from TYTAN: A Phase III Asian Study of Lapatinib in Combination with Paclitaxel as Second-Line Therapy in Gastric Cancer Satoh T et al. Proc ASCO 2010;Abstract 4057.

32. A Phase III Study of CapeOX +/- Lapatinib in FISH-Positive HER2 Locally Advanced/Metastatic Upper Gastrointestinal Adenocarcinoma: Interim Safety Results Hecht JR et al. ProcECCO-15 2009;Abstract 6584.

33. Phase II Multi-Center Study of Perioperative Chemotherapy/Trastuzumab (NCT01130337) Accrual: N = 45 Preoperative Therapy x 3 Cycles Capecitabine + Oxaliplatin (CAPOX) Trastuzumab Eligibility Locally advanced, resectable HER2+ gastric or GE junction adenocarcinoma Surgery If complete resection, R0 or microscopic R1 Postoperative Therapy x 3 Cycles CAPOX Trastuzumab Trastuzumab completion to 12 months www.clinicaltrials.gov, October 2010

34. Signal Transduction by the HER Family Promotes Proliferation, Survival, and Invasiveness Receptor specific ligands HER2 HER1, HER2, HER3, or HER4 HER3 HER4 HER2 VEGF HER1 (EGFR) PI3K P SOS Plasma membrane P Tyrosine kinase domains RAS P Akt RAF P MAPK MEK Cytoplasm Cell proliferation Cell survival Cell mobility and invasiveness Nucleus 34 Transcription

35. Lapatinib, a Dual EGFR and HER2 Kinase Inhibitor, Selectively Inhibits HER2-Amplified Human Gastric Cancer Cells and is Synergistic with Trastuzumab In Vitro and In Vivo Wainberg ZA et al. Clin Cancer Res 2010;16(5):1509-19.

36. Synergistic Antitumor Activity of Lapatinib and Trastuzumab in Combination (N87 Xenograft) Tumor volume (mm3) Reprinted with permission: Wainberg ZA E et al. Clin Cancer Res 2010;16(5):1509-19.

38. Case History: Dr Ajani A 56 year old man presents with abdominal pain and dyspepsia Investigations revealed a GE junction mass with liver and adrenal masses as well Biopsy of GE junction mass shows HER2-positive (by FISH) moderately differentiated adenocarcinoma Patient treated with: Docetaxel 40 mg/m2 q2wks Capecitabine 1,500 mg/m2/d 7d on/7d off Oxaliplatin 85 mg/m2 q2wks Trastuzumab 6 mg/kg q3wks

39. Initial CT Evaluation

40. Recent Evaluation in 8/2010 Patient continues on trastuzumab as of 10/2010 and remains free of obvious cancer

41. Approximately How Many New Patients With Gastric Cancer Do You See Per Year? 0 6% 19% 1-4 Patients 5-9 34% 10-15 33% >15 8% Median = 5 patients Patterns of Care Survey of US-Based Medical Oncologists (n = 100)

42. How Many Patients With Gastric Cancer Have You Treated With Trastuzumab +/- Chemo? 0 55% Patients 1-2 38% 7% ≥3 Patterns of Care Survey of US-Based Medical Oncologists (n = 94)

43. Which Chemotherapy Did You Generally Administer With Trastuzumab? Platinum/fluoropyrimidine Single-agent chemo Platinum/taxane Platinum/fluoropyrimidine/taxane fluoropyrimidine/taxane Other 41% 31% 10% 10% 2% 6% Patterns of Care Survey of US-Based Medical Oncologists (n = 42)

44. In General, How Long Did You Continue The Trastuzumab? Until disease 63% progression Six cycles 31% Indefinitely 5% One year 1% Patterns of Care Survey of US-Based Medical Oncologists (n = 42)

45. Neal Fishbach, MDFairfield, CT I’ve tested every patient with metastatic gastric cancer whom I have cared for recently, and all 10 patients have been HER2-negative. I don’t know whether there is a lot of geographic variation, but I haven’t seen a lot of HER2 positivity in gastric cancer.

46. Karen Green, MDWhite Plains, NY In a patient with HER2-positive gastric cancer who initially responds to trastuzumab plus chemotherapy and is subsequently maintained on trastuzumab alone, but then progresses, does the panel feel that there is a role for continuing the trastuzumab as is done in breast cancer, or at least changing to another anti-HER2-directed therapy?

48. Richard Polkinghorn, MDBrunswick, ME How should we interpret the results of HER2 testing in gastric cancer? What’s considered positive? If the specimen is less than IHC3+, is it considered HER2-negative? Or should we use FISH?

49. Case History: Dr Ross • A 67 year old woman with history of low grade ductal carcinoma of the breast seven years ago presents with dysphagia • Endoscopy: polypoid mass beneath gastroesophageal sphincter • Punch biopsies (three): Gastric adenocarcinoma, intestinal type. HER2-negative

50. Case History: Dr Ross (continued) • Patient undergoes primary surgery, and histopathology from surgical specimen shows • Moderately differentiated intestinal type adenocarcinoma • Invasion of muscularis propria • 1/32 regional lymph nodes+ • All margins negative • T2N1 tumor