Metastatic Gastric Cancer John L. Marshall, MD Lombardi Cancer Center Georgetown University Washington DC

Gastric cancer: a global disease 4th most common malignant disease ~ 930,000 2nd most common cause of cancer-related death worldwide ~700,000 Falling incidence of distal gastric cancer Increasing incidence of proximal gastric cancer Wide geographical variation Incidence (males) 20 / 100 000 10 - 20 / 100 000 <10 / 100 000 www.cancer.gov Kamangar F et al. J Clin Oncol 2006;24:2137–50 2

(trend to perioperative CT (5FU/Xeloda or combination) Neo-adjuvant and adjuvant therapy for gastric cancer: different strategies Peri-operative Chemotherapy (ECF- 5FU/cisplatin) Post-operative Chemoradiotherapy (trend to perioperative CT in academic centers) Postoperative CT Post-operative Chemotherapy (5FU/Xeloda or combination) 3

North American Perspective We see more proximal tumors Surgery first dominates in community hospitals Chemotherapy first dominates in academic centers We are unsure what to do with radiation Our patients are typically quite ill from the beginning

State of the Art More than one disease Gastric- low acid Esophageal – tobacco, alcohol GE Junction- high acid Different cancers in different parts of the world Asia ≠ Western No regional or global standards Surgical differences Chemotherapy differences Sequence of therapy differences (Chemo, Surgery, Radiation)

Esophagogastric Cancer: Siewart Classification From Siewart, J Surg Onc 2005, v. 90: 139

Role of Docetaxel: V 325 Phase III Stratification Factors: Docetaxel 75 mg/m2 IV over 1 hr R A N D O M I Z E Liver Involvement Cisplatin 75 mg/m2 IV over 1-3 hrs both on Day 1 only 5-FU 750 mg/m2/day by CIV over 5 days Days 1-5 Prior Gastrectomy Cycles repeated every 3 weeks Measurable vs Evaluable Disease Cisplatin 100 mg/m2/IV over 1-3 hrs Weight Loss (>5%) in Prior 3 Months 5-FU 1000 mg/m2/day by CIV over 5 days Days 1-5 Cycles repeated every 4 weeks Centers Adequate hydration and anti-emetics required, No Prophylactic Growth Factors Response assessment every 8 weeks independent of treatment schedule

Results: TAX 325 DCF (227) CF (230) 36.7% ORR (P=0.02) 25.4% 5.6 months Med. TTP (p=0.0004) 3.7 months 9.2 months Med. Survival (HR=1.29, p=0.02) 8.6 months 40.2% 1-yr. Survival 31.6% 18.4% 2-yr. Survival 8.8%

Toxicity: TAX 325 DCF (221) CF (224) 82% 57% 66% 20% 30% 13% 8% 21% Gr. 3-4 Toxicity (% of Pts) CF (224) 82% Neutropenia 57% 66% Received GCSF 20% 30% Neutro. Fever/Infect. 13% Diarrhea 8% 21% Stomatitis 27% 15% Vomiting 19% Neurologic 3% 3.6 % Death from Toxicity 5.4 %

DCF is too toxic- and not worth it mDCF vs DCF Shah et al: ASCO 4014, 2010 DCF is “spicy”- requires G-CSF mDCF less so 72 patients randomized mDCF had a better survival Does dose intensity matter in GI cancers?

Advanced Gastric Cancer: REAL-2 Cunningham, NEJM 2008, v 358, p. 36 1002 pts with unresectable esophageal/ gastric cancer enrolled 6/00-5/05 63 yo (22-83) 81% male 78% metastatic 40% gastric, 35% esophageal, 25% GEJ 90% adenoCA 11% PS2 Primary endpoint: Survival non-inferiority design (23% boundary)

REAL-2 2x2 design (ECF, EOF, ECX, EOX) Cycles repeated every 21 days Epirubicin 50 mg/m2 IV D#1 Cisplatin 60 mg/m2 IV D#1 or Oxaliplatin 130 mg/m2 IV D#1 5-Fluorouracil 200 mg/m2/d IVCI or Capecitabine 625 mg/m2 PO BID

Cunningham, NEJM 2008, v358, p. 42

Cunningham, NEJM 2008, v 358, p. 41

Cunningham, NEJM 2008, v358, p 44

CALGB 80403 / ECOG E1206: Schema Stratification: ECOG 0-1 vs 2 ARM A: (ECF + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Epirubicin 50 mg/m2 IV, day 1 Cisplatin 60mg/m2 IV, day 1 Fluorouracil 200mg/m2/day, days 1-21 ARM B: (IC + cetuximab); 1 cycle = 21 days Cetuximab 400  250mg/m2 IV, weekly Cisplatin 30 mg/m2 IV, days 1 and 8 Irinotecan 65 mg/m2 IV, days 1 and 8 Stratification: ECOG 0-1 vs 2 ADC vs. SCC ARM C: (FOLFOX + cetuximab); 1 cycle = 14 days Cetuximab 400  250mg/m2 IV, weekly Oxaliplatin 85 mg/m2 IV, day 1 Leucovorin 400 mg/m2, day 1 Fluorouracil 400 mg/m2 IV bolus, day 1 Fluorouracil 2400 mg/m2 IV over 46hrs (days 1-2)

CALGB 80403/ECOG 1206: Response *RECIST - confirmed; restaging every 6 weeks

CALGB 80403/ECOG 1206: Overall Survival by Arm

The ToGA trial: A phase III study of trastuzumab added to standard chemotherapy in first-line human epidermal growth factor receptor 2 (HER2)-positive advanced gastric cancer

HER2 and trastuzumab mechanism of action HER2 receptor trastuzumab Trastuzumab Inhibits HER2-mediated signalling in HER2-positive tumors Prevents HER2 activation by blocking extracellular domain cleavage Activates antibody-dependent cellular cytotoxicity

The Rules for EGFR Targeting Breast- HER2 overexpression Colon- KRAS Lung- ATP binding site mutations Gastric- Do we actually know?

HER2 testing HER2 testing in breast cancer is well established Recent evidence shows that same techniques with some modifications are also valid for assessing HER2 status in stomach cancer 1. Hoffmann 2008

HER2 testing – 2 main methods Immunohistochemistry (IHC) Shows how much of the HER2 protein is present in the tumour sample HER2-negative HER2-positive

HER2 testing – 2 main methods Fluorescence in-situ hybridization (FISH) Measures the amount of the HER2/neu gene in each cell HER2-negative HER2-positive

ToGA trial design Phase III, randomized, open-label, international, multicenter study 5-FU or capecitabinea + cisplatin (n=290) 3807 patients screened1 810 HER2-positive (22.1%) HER2-positive advanced GC (n=584) R 5-FU or capecitabinea + cisplatin + trastuzumab (n=294) Stratification factors advanced vs metastatic GC vs GEJ measurable vs non-measurable ECOG PS 0-1 vs 2 capecitabine vs 5-FU Eligibility criteria for the ToGA trial include: >18 years of age, HER2-positive histologically confirmed gastric cancer or gastro-oesophageal adenocarcinoma, with inoperable, locally advanced or recurrent and/or metastatic disease. The ToGA trial planned to recruit 584 patients. An additional 10 patients, who had already signed the informed consent form when the screening cut-off was reached, were allowed to enter the trial, resulting in a total of 594 patients recruited. The primary end point is overall survival in the two treatment arms. Secondary end points include progression-free survival, overall response rate, clinical benefit rate, duration of response and safety profile. aChosen at investigator’s discretion GEJ, gastroesophageal junction 1Bang et al; Abstract 4556, ASCO 2009

Treatment regimens Capecitabine 1000 mg/m2 bid d1-14 q3w x 6 5-Fluorouracil 800 mg/m2/day continuous iv infusion d1-5 q3w x 6 Cisplatin 80 mg/m2 q3w x 6 Trastuzumab 8 mg/kg loading dose followed by 6 mg/kg q3w until PD

ToGA trial end points Primary end point: Secondary end points overall survival Secondary end points PFS, TTP, ORR, Clinical Benefit Rate, Duration of Response, QoL, safety, pain intensity, analgesic consumption, weight change, pharmacokinetics Sample size assumptions median OS improvement from 10 to 13 months (HR 0.77) α-level = 0.05, 80% power required sample size: 584 patients randomized 1:1 Analyses 1st pre-planned interim analysis after 230 events (50%) 2nd interim analysis after 345 events (75%) considered final by Independent Data Monitoring Committee

Main patient selection criteria Inclusion criteria Adenocarcinoma of stomach or GEJ Inoperable locally advanced and/or metastatic disease Measurable (RECIST), or non-measurable evaluable disease HER2-positive tumor (centrally assessed) IHC 3+ and/or FISH+ Adequate organ function and ECOG performance status ≤2 Written informed consent Exclusion criteria Previous adjuvant chemotherapy within 6 months Chemotherapy for advanced disease Congestive heart failure or baseline LVEF <50% Creatinine clearance <60 mL/min IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction

Patient demographics and baseline characteristics F+C n=290 F+C + trastuzumab n=294 Sex, % Male / Female 75 / 25 77 / 23 Age, median (range) years 59.0 (21-82) 61.0 (23-83) Weight, median (range) kg 60.3 (28-105) 61.5 (35-110) Region, n (%) Asia C/S America Europe Other 166 (56) 26 (9) 95 (32) 9 (3) 158 (53) 27 (9) 99 (33) 14 (5) Type of GC (central assessment) Intestinal Diffuse Mixed 74.2a 8.7a 17.1a 76.8b 8.9b 14.3b Prior gastrectomy 21.4 24.1 Highest recruitment was from Korea, Japan, China and Russia F, fluoropyrimidine; C, cisplatin an=287; bn=293

Primary end point: OS Event 1.0 Median OS 13.8 11.1 0.9 Events 167 182 HR 0.74 95% CI 0.60, 0.91 p value 0.0046 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 11.1 13.8 0.1 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 294 290 277 266 246 223 209 185 173 143 147 117 113 90 90 64 71 47 56 32 43 24 30 16 21 14 13 7 12 6 6 5 4 1 T, trastuzumab

Secondary end point: PFS Event 1.0 Median PFS 6.7 5.5 Events 226 235 HR 0.71 95% CI 0.59, 0.85 p value 0.0002 0.9 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 0.1 5.5 6.7 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months) No. at risk 294 290 258 238 201 182 141 99 95 62 60 33 41 17 28 7 21 5 13 3 9 3 8 2 6 2 6 1 6 1 4 2

Secondary end point: tumor response rate Intent to treat Patients (%) p=0.0017 F+C + trastuzumab p=0.0145 F+C 47.3% 41.8% 34.5% 32.1% p=0.0599 5.4% 2.4% CR PR ORR ORR= CR + PR CR, complete response; PR, partial response

OS in IHC2+/FISH+ or IHC3+ (exploratory analysis) Event 1.0 Median OS 16.0 11.8 Events 120 136 HR 0.65 95% CI 0.51, 0.83 0.9 0.8 FC + T 0.7 FC 0.6 0.5 0.4 0.3 0.2 0.1 11.8 16.0 0.0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 Time (months) No. at risk 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

Safety: non-hematological AEs F+C n=290 F+C + trastuzumab n=294 All Grade 3/4 Nausea Vomiting Fatigue Diarrhea Constipation Asthenia Stomatitis Weight decrease Abdominal pain 63 46 28 32 18 15 14 7 8 2 4 3 1 67 50 35 37 26 19 24 23 16 6 9 <1 AEs occurring in >10% of patients

Safety: cardiac AEs Cardiac event, n (%) F+C (n=290) F+C + trastuzumab (n=294) All Grade 3/4 Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1) Cardiac failure 2 (<1) 1 (<1) Asymptomatic LVEF dropsa <50% <50% and by 10% 2 (1.1) 2 (1.1) 14 (5.9) 11 (4.6) Cardiac AEs leading to death 2 (<1) Cardiac arrest; cardio-respiratory arrest 2 (<1) Acute MI; angina unstable and cardiac failure Cardiac AEs related to treatment aMeasured at baseline and every 12 weeks; MI, myocardial infarction

Summary ToGA met the primary end point trastuzumab reduces the risk of death by 26% when combined with a reference chemotherapy (HR 0.74) prolongs the median survival by nearly 3 months (11.1 to 13.8 months; p=0.0046) in patients with HER2-positive advanced GC All secondary efficacy parameters (PFS, TTP, ORR, CBR, DoR) were also significantly improved Addition of trastuzumab to chemotherapy was well tolerated: there was no difference in overall safety profile, including cardiac AEs, between treatment arms

AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III Study Capecitabine*/Cisplatin (XP) + Placebo q3w Locally advanced or metastatic gastric cancer 1:1 R Capecitabine*/Cisplatin (XP) + Bevacizumab q3w Stratification factors: 1. Geographic region 2. Fluoropirimidine backbone 3. Disease status *5-FU also allowed if cape contraindicated Cape 1000 mg/m2 oral bid, d1–14, 1-week rest Cisplatin 80 mg/m2 d1 Bevacizumab 7.5 mg/kg d1 Maximum of 6 cycles of cisplatin Cape and bevacizumab/placebo until PD Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes 37

Patient Characteristics (I) Number of patients N=774 (%) XP + Placebo N=387 XP + Bev Gender Male 258 (67) 257 (66) Age, years Median (range) 59 (22–82) 58 (22–81) ECOG PS 0–1 ≥2 367 (95) 20 (5) 365 (94) 22* (6) Region Asia Europe Pan-America 188 (49) 124 (32) 75 (19) 188 (49) 125 (32) 74 (19) Fluoropyrimidine Capecitabine 5-FU 365 (94) 22 (6) 364 (94) 23 (6) Disease status Locally advanced Metastatic 9 (2) 378 (98) *1 additional patient had an ECOG PS of 4 38

Patient Characteristics (II) Number of patients N=774 (%) XP + Placebo N=387 XP + Bev Primary site Stomach GEJ 338 (87) 49 (13) 333 (86) 54 (14) Histologic type Intestinal Diffuse Mixed 135 (35) 206 (53) 26 (7) 155 (40) 176 (46) 35 (9) Disease measurability Measurable Evaluable 297 (77) 90 (23) (80) 76 (20) Metastatic sites, n 1 ≥2 8 (2) 131 (34) 247 (64) Prior gastrectomy Yes 107 (28) 110 (28) Liver metastasis 126 (33) 130 (34) 39

Overall Survival 12.1 10.1 XP + Placebo XP + Bev HR = 0.87 95% CI 0.73–1.03 p = 0.1002 Survival rate 3 9 15 18 21 24 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 6 12 Study month 10.1 12.1 Number at risk XP + Placebo XP + Bev 387 343 355 271 291 204 232 146 178 98 104 54 50 15 19 40

Progression-Free Survival XP + Placebo XP + Bev HR = 0.80 95% CI 0.68–0.93 p = 0.0037 Progression-free survival rate 0.0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 3 9 15 18 21 24 6 12 5.3 6.7 Study month Number at risk XP + Placebo XP + Bev 387 279 306 145 201 86 123 55 71 32 38 15 11 3 41

Conclusion and Questions FOLFOX or XELOX- a new standard? Established role of Herceptin New role of Avastin? PFS +, OS not Should we use Avastin beyond progression