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

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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.

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: National Cancer Institute

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, National Cancer Institute

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+

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.

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,* % Median PFS, mos Median OS, mos yr OS, % *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.

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 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 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:

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

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 deaths Off therapy for adverse event or consent withdrawal4937 Van Cutsem E, et al. J Clin Oncol. 2006;24:

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 mg/m 2  Change dose and schedule to CRC-like schedules –FOLFOX or FOLFIRI –FOLFOX has emerged as US Intergroup Standard

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 Bleiberg [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 Ross [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 Van Cutsem [3] EOX Epirubicin 50 mg/m 2 Day 1 Oxaliplatin 130 mg/m 2 Day 1 Capecitabine 625 mg/m 2 BID Cunningham [4] 1. Bleiberg H, et al. Eur J Cancer. 1997;33: Ross P, et al. J Clin Oncol. 2002;20: Van Cutsem E, et al. J Clin Oncol. 2006;24: Cunningham D, et al. N Engl J Med. 2008;358:36-46.

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

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: Kim IJ, et al. Hum Genet. 2003;114: Galizia G, et al. World J Surg. 2007;31: Dragovich T, et al. J Clin Oncol. 2006;24: Chan JA, et al. Ann Oncol. 2011;[Epub ahead of print]. 6. Mammano E, et al. Anticancer Res. 2006;26: Yano T, et al. Oncol Rep. 2006;15:65-71.

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:

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:

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: *Chemotherapy plus trastuzumab: n = 293; chemotherapy alone: n = 287.

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 , Copyright 2010, with permission from Elsevier. Bang YJ, et al. ASCO Abstract 4556.

clinicaloptions.com/oncology Role of HER2 in Gastric Cancer HER2 Positivity Worldwide Bang YJ, et al. ASCO Abstract Reprinted with permission. HER2 positivity in ToGA: 22.1% Asian/Pacific Europe South/Middle America Other Patients, % 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)

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

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

clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Events ToGA Primary Endpoint: OS Mos Pts at Risk, n Survival Probability FC + T FC HR % CI P Value.0046 Median OS 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 , Copyright 2010, with permission from Elsevier.

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: ) OutcomeChemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) HR (95% CI)P Value Median OS, mos ( ).0046 Median PFS, mos ( ).0002 ORR, %  CR  PR Bang YJ, et al. Lancet. 2010;376:

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 ( ) Preplanned analysis  IHC 0/FISH+ (n = 61)10.6 vs ( )  IHC 1+/FISH+ (n = 70)8.7 vs ( )  IHC 2+/FISH+ (n = 159)12.3 vs ( )  IHC 3+/FISH+ (n = 256)17.9 vs ( )  IHC3+/FISH- (n = 15)17.5 vs ( ) Exploratory analysis  IHC 0 or 1+/FISH+ (n = 131)10.0 vs ( )  IHC 2+/FISH+ or IHC 3+ (n = 446)16.0 vs ( ) Bang YJ, et al. Lancet. 2010;376: *HR 1 favors chemotherapy alone.

clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Events Mos Pts at Risk, n Survival Probability FC + T FC HR % CI Median OS 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 , Copyright 2010, with permission from Elsevier.

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: *Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187.

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 , Copyright 2005, with permission from Elsevier.

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. NCT LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer  Primary endpoint: OS (was PFS)  Data expected mid-2012

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. NCT

Clinical Application

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

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

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:

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

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

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

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

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!

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?

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

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

clinicaloptions.com/oncology Role of HER2 in Gastric Cancer Median OS Increased to > 1 Yr With Trastuzumab-Based Therapy 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: Vanhoefer U, et al. J Clin Oncol. 2000;18: Ajani JA, et al. J Clin Oncol. 2010;28: Van Cutsem E, et al. J Clin Oncol. 2006;24: Dank M, et al. Ann Oncol. 2008;19: Cunningham D, et al. N Engl J Med. 2008;358: Kang YK, et al. Ann Oncol. 2009;20: Bang YJ, et al. Lancet. 2010;376:

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