Treatment of HER2-Positive Gastroesophageal Carcinoma Manish A. Shah, MD Director, Gastrointestinal Oncology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York This program is supported by an educational donation from

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 Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options Disclaimer The materials published on the Clinical Care Options Web site reflect the views of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.

Program Faculty Program Director: Manish A. Shah, MD Director, Gastrointestinal Oncology Weill Cornell Medical College NewYork-Presbyterian Hospital New York, New York

Faculty Disclosure Manish A. Shah, MD, has disclosed that he has received consulting fees and contracted research support from Genentech and sanofi-aventis.

Gastroesophageal Cancer: Treatment Overview Surgery is primary treatment for medically fit, resectable cases[1] For advanced disease, treatment may include perioperative chemotherapy or preoperative chemoradiation Postoperative treatment options Chemoradiation (fluoropyrimidine-based or capecitabine) Palliative chemotherapy or best supportive care Recurrent or metastatic disease Chemotherapy Palliative chemotherapy, clinical trial, or best supportive care Significant need exists for deeper understanding of tumor subtypes, biomarkers for treatment response[2] 1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. 2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392.

Gastroesophageal Cancer: Systemic Therapy for Metastatic Disease First-line options[1] DCF/modified DCF ECF/modified DCF Single agent or combination regimens (fluoropyrimidine or taxane based) Trastuzumab + standard chemotherapy for HER2- positive tumors Second-line options[1] Trastuzumab + standard chemotherapy for HER2- positive tumors if no first-line trastuzumab Paclitaxel or docetaxel Single agent irinotecan or irinotecan-based combination Phase III trials under way with other targeted agents[2] DCF, docetaxel, cisplatin, and 5-fluorouracil; ECF, epirubicin, cisplatin, and 5-fluorouracil. 1. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011. 2. Power DG, et al. Cancer Treat Rev. 2010;36:384-392.

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

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] HGF/c-Met: over/aberrant expression reported in various human cancers, including gastric cancer[8] EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.   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;22:1367-1373. 6. Mammano E, et al. Anticancer Res. 2006;26:3547-3550. 7. Yano T, et al. Oncol Rep. 2006;15:65-71. 8. Birchmeier C, et al. Nat Rev Mol Cell Biol. 2003;4:915-925.

ToGA: Trastuzumab + Chemotherapy in Advanced HER2+ Gastric Cancer Rationale: a subpopulation of gastric cancers overexpress HER2 Primary endpoint: OS Stratified by ECOG PS, advanced vs metastatic, gastric vs GEJ, measurable disease, capecitabine vs 5-FU 5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 + Trastuzumab 6 mg/kg q3w until PD (8 mg/kg loading dose) (n = 294) Patients with advanced gastric cancer screened for HER2 status (N = 3803) Patients with HER2-positive advanced gastric cancer (n = 810; 22% of successful screenings) R 5-FU or Capecitabine* + Cisplatin 80 mg/m2 q3w x 6 (n = 290) 5-FU, 5-fluorouracil; ECOG, Eastern Cooperative Oncology Group; GEJ, gastroesophageal junction; OS, overall survival; PD, progressive disease; PS, performance score; R, randomization.   (n = 584) *Selected at investigator’s discretion: 5-FU 800 mg/m2/day infusional on Days 1-5 q3w x 6; capecitabine 1000 mg/m2 BID on Days 1-14 q3w x 6. Bang YJ, et al. Lancet. 2010;376:687-697.

ToGA: Efficacy Outcome Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) HR (95% CI) P Value Median OS, mos 13.8 11.1 0.74 (0.60-0.91) .0046 Median PFS, mos 6.7 5.5 0.71 (0.59-0.85) .0002 ORR, % 47 35 -- .0017 CR 5 2 .0599 PR 42 32 .0145 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) CI, confidence interval; CR, complete response; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; PFS, progression-free survival; PR, partial response; ORR, overall response rate; OS, overall survival.   Bang YJ, et al. Lancet. 2010;376:687-697.

Median OS, Mos (CT + T vs CT Alone) ToGA: OS by HER2 Status HER2 Status Subgroup Median OS, Mos (CT + T vs CT Alone) HR* (95% CI) All patients (N = 584) 13.8 vs 11.1 0.74 (0.60-0.91) Preplanned analysis IHC 0/FISH+ (n = 61) 10.6 vs 7.2 0.92 (0.48-1.76) IHC 1+/FISH+ (n = 70) 8.7 vs 10.2 1.24 (0.70-2.20) IHC 2+/FISH+ (n = 159) 12.3 vs 10.8 0.75 (0.51-1.11) IHC 3+/FISH+ (n = 256) 17.9 vs 12.3 0.58 (0.41-0.81) IHC3+/FISH- (n = 15) 17.5 vs 17.7 0.83 (0.20-3.38) Exploratory analysis IHC 0 or 1+/FISH+ (n = 131) 10.0 vs 8.7 1.07 (0.70-1.62) IHC 2+/FISH+ or IHC 3+ (n = 446) 16.0 vs 11.8 0.65 (0.51-0.83) CI, confidence interval; CT, chemotherapy; CT + T, chemotherapy + trastuzumab; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival.   *HR < 1 favors chemotherapy + trastuzumab; HR > 1 favors chemotherapy alone. Bang YJ, et al. Lancet. 2010;376:687-697.

ToGA: OS in IHC 2+/FISH+ or IHC 3+ (Exploratory Analysis) 1.0 Events, n 120 136 Median OS, Mos 16.0 11.8 0.9 HR 0.65 95% CI 0.51-0.83 0.8 FC + T 0.7 FC 0.6 Survival Probability 0.5 0.4 0.3 0.2 0.1 11.8 16.0 CI, confidence interval; FC, 5-fluorouracil, cisplatin; FC + T, 5-fluorouracil, cisplatin + trastuzumab; FISH, fluorescence in situ hybridization; HR, hazard ratio; IHC, immunohistochemistry; OS, overall survival.   2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Mos Pts at Risk, n FC + T 228 218 218 198 196 170 170 141 142 112 122 96 100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 1 FC Bang YJ, et al. Lancet. 2010;376:687-697.

ToGA: Select Toxicities Adverse Event, % Chemotherapy + Trastuzumab (n = 294) Chemotherapy Alone (n = 290) Grade 3/4 hematologic events Neutropenia 27 30 Anemia 12 10 Grade 3/4 nonhematologic events Diarrhea 9 4 Nausea 7 Cardiac events 6 Grade 3/4 1 3 LVEF reduction of ≥ 10% to absolute value < 50%* 5 LVEF, left ventricular ejection fraction.   *Chemotherapy plus trastuzumab: n = 237; chemotherapy alone: n = 187. Bang YJ, et al. Lancet. 2010;376:687-697.

ToGA: HER2 Positivity by IHC Score Surgical Specimen Staining Pattern Biopsy Specimen Staining Pattern HER2 Overexpr. Assessment 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 regardless of % of tumor cells stained 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 regardless 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 regardless of % of tumor cells stained Positive FISH, fluorescence in situ hybridization; IHC, immunohistochemistry.   *FISH or other in situ hybridization method recommended by NCCN guidelines panel. Bang YJ, et al. Lancet. 2010;376:687-697. NCCN. Clinical practice guidelines in oncology: gastric cancer, v2. 2011.

HER2 Testing in Gastroesophageal Cancer HER2 more heterogeneous in gastric vs breast cancer Objectives Evaluate IHC-FISH concordance in processed samples Determine applicability of ASCO/CAP HER2 breast cancer scoring system to gastroesophageal carcinomas FISH IHC 0 IHC 1+ IHC 2+ IHC 3+ Total, n (%) Positive (HER2/CEP17 > 2.2) 1 3 16 (100) 20 (15) Negative (HER2/CEP17 < 1.8) 60 (97) 39 (93) 4 103 (77) Equivocal (HER2/CEP17 1.8-2.2) 2 (1.9; 2.0)* 2 (2.1; 1.8)* 1 (2.1)* 5 (4) Failure 2 64 (48) 44 (33) 8 (6) 17 (13) 133 ASCO/CAP, American Society of Clinical Oncology/College of American Pathologists; FISH, fluorescence in situ hybridization; IHC, immunohistochemistry. *Data in parentheses show individual values, not percentages. Tafe LJ, et al. Arch Pathol Lab Med. 2011;135:1460-1465.

Median OS Increased to > 1 Yr With Trastuzumab-Based Therapy 12 mos BSC[1] FAMTX[2] C + S1[3] CF[4] IF[5] EOF[6] DCF[4] ECF[6] ECX[6] BSC, best supportive care; C + S1, cisplatin + S1; CF, cisplatin, 5-fluorouracil; DCF, docetaxel, cisplatin, 5-fluorouracil; ECF, epirubicin, cisplatin, 5-fluorouracil; ECX, epirubicin, cisplatin, capecitabine; EOF, epirubicin, oxaliplatin, 5-fluorouracil; EOX, epirubicin, oxaliplatin, capecitabine; FAMTX, methotrexate, 5-fluorouracil, doxorubicin; FISH, fluorescence in situ hybridization; IF, irinotecan, 5-fluorouracil; IHC, immunohistochemistry; OS, overall survival; XP, capecitabine, cisplatin; XP/FP, capecitabine or 5-fluorouracil plus cisplatin.   XP[7] EOX[6] Trastuzumab + XP/FP[8] HER2 IHC 2+/FISH+ or IHC 3+ 5 10 15 Median OS in Patients With Advanced Gastric Cancer (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. 16 16

Definition of HER2 Positivity for Gastroesophageal Carcinoma HER2-Positivity Requirements for Approved Trastuzumab Use US European Union IHC 3+ or FISH+ (ratio > 2.0) IHC 2+ and FISH+ (ratio > 2.0)

Prognostic Role of HER2 in Gastric Cancer Prognostic value of HER2 controversial with > 20 yrs of conflicting data Systematic literature analysis involving 12,749 patients in 42 studies[1] 71% of studies demonstrated association between HER2 positivity and poor survival (40%) or clinicopathologic features (31%; eg, serosal invasion, LN metastases, disease stage, or distant metastases) However, multivariate analyses performed in only ~ 50% of studies Systematic literature review involving 11,337 patients in 49 studies included 35 studies evaluating effect of HER2 overexpression on survival[2] 57%: no effect on OS 6%: significantly longer OS with HER2 overexpression 37%: significantly poorer OS with HER2 overexpression 1. Jørgensen JT, et al. J Cancer. 2012;3:137-144. 2. Chua TC, et al. Int J Cancer. 2012;130:2845-2856.

Gastric Cancer Surgical cure rates are high with lesions limited to the mucosa or submucosa (ie, T1) However, for patients with stage II or higher, 5-yr survival remains poor Patients increasingly presenting with T1 N0 disease, but proportion remains low 40% to 50% of patients will present with unresectable disease Overall 5-yr survival remains low This is a bad disease After surgery, chances of long-term survival for most patients remains < 50%. Can we do better??

Gastric INT 116: Postoperative Chemoradiotherapy vs Surgery Alone 20% were GEJ tumors Similar survival benefit in this subset 100 OS 80 60 Chemoradiotherapy Patients (%) 40 20 Surgery only 24 48 72 96 120 Mos After Registration Macdonald JS, et al. N Engl J Med. 2001;345:725-730.

Meta-analysis: Surgery vs Surgery + Any Adj CT in Resectable GC Survival benefit for addition of chemotherapy 100 Any chemotherapy Surgery alone 90 80 70 60 Survival (%) 50 40 30 20 HR: 0.82 (95% CI: 0.76-0.90; P < .001) 10 1 2 3 4 5 6 7 8 9 10 Yrs From Randomization Pts at Risk, n Any chemotherapy Surgery along 1924 1857 1688 1568 1385 1300 1217 1092 1080 952 929 782 709 583 526 407 390 267 297 172 243 138 GASTRIC Group, et al. JAMA. 2010;303:1729-1737. 21

Chemotherapy in Resectable Gastric Cancer Addition of pre/peri/postsurgery chemotherapy consistently demonstrates benefit vs surgery alone Study Regimens Primary Endpoint Primary Endpoint Results P Value CLASSIC[1] Surgery vs surgery + adjuvant capecitabine/oxaliplatin 3-yr DFS 59% vs 74% < .0001 MAGIC[2] Surgery vs surgery + periop ECF 5-yr OS 23% vs 36% .009 Sakuramoto et al[3] Surgery vs surgery + adjuvant S-1 3-yr OS 70% vs 80% .003 1. Bang YJ, et al. Lancet. 2012;379:315-321. 2. Cunningham D, et al. N Engl J Med. 2006;355:11-20. 3. Sakuramoto S, et al. N Engl J Med. 2007;357:1810-1820.

Chemotherapy in Resectable Gastric Cancer However, resounding lack of progress in improving patient outcomes with any specific CT/CRT regimen vs any other chemotherapy regimen Study Regimens Primary Endpoint Primary Endpoint Results P Value CALGB 80101[1] Postop 5-FU/LV CRT vs ECF CRT OS 37 vs 38 mos .80 ARTIST[2] Postop CT vs CRT (capecitabine/cisplatin) 3-yr DFS 74% vs 78% .086 1. Fuchs CS, et al. ASCO 2011. Abstract 4003. 2. Lee J, et al. J Clin Oncol. 2012;30:268-273.

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

LOGiC: Phase III Trial of Lapatinib + CapeOx in HER2+ Gastric Cancer CapeOx + Lapatinib Patients with HER2-amplified locally advanced, unresectable, or metastatic gastric, esophageal, or GEJ cancer (Planned N = 535) CapeOx + Placebo CapeOx, capecitabine + oxaliplatin; GEJ, gastroesophageal junction; OS, overall survival; PFS, progression-free survival.   Primary endpoint: OS (was PFS) Data expected mid-2012 ClinicalTrials.gov. NCT00680901.

Pertuzumab & Trastuzumab Bind Distinct Epitopes on HER2 Extracellular Domain Activates ADCC Prevents HER2 domain cleavage Inhibits HER2-mediated signaling pathways Activates ADCC Has a major effect on role of HER2 as a coreceptor with HER3 or EGFR Inhibits multiple HER- mediated signaling pathways ADCC, antibody-dependent cellular cytotoxicity; EGFR, epidermal growth factor receptor.   Hubbard SR. Cancer Cell 2005;7:287-288. 26

Paclitaxel + Lapatinib Second-line Paclitaxel + Lapatinib vs Paclitaxel for Advanced Gastric Cancer Paclitaxel + Lapatinib Patients with HER2-amplified gastric cancer and PD after 1 previous 5-FU and/or cisplatin regimen (N = 273) Paclitaxel Primary endpoint Initial pilot analysis: tolerability to determine optimal dosing Randomized part: OS ClinicalTrials.gov. NCT00486954.

Phase II Studies of Targeted Agents in HER2-Positive Disease PF-00299804, pan-EGFR inhibitor (NCT01152853) AUY922, Hsp90 inhibitor (NCT01402401) Pertuzumab + trastuzumab + chemotherapy (NCT01461057) Bevacizumab + trastuzumab + docetaxel, oxaliplatin and capecitabine chemotherapy (NCT01359397) Bevacizumab + trastuzumab + capecitabine and oxaliplatin (NCT01191697) Afatinib (NCT01522768) ClinicalTrials.gov.

Summary HER2 represents the first validated target in gastric and gastroesophageal junction adenocarcinoma All patients with metastatic gastric/GEJ adenocarcinoma who are HER2 positive should be considered for trastuzumab-based therapy There are few data on the use of trastuzumab in the pre- operative or adjuvant setting, or on its continued use after progression on trastuzumab-based therapy Drug development targeting HER2 in gastric cancer is active and ongoing

Go Online for More CCO Coverage of Chicago 2012! Capsule Summaries of all the key data, plus CME-certified Slidesets exploring the clinical implications of these findings Downloadable slides: for use as a study resource or in your noncommericial presentations clinicaloptions.com/oncology