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

2. 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 /
10 - 20 /
<10 /
Kamangar F et al. J Clin Oncol 2006;24:2137–50 2

3. (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

4. 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

5. 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)

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

7. 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

8. 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%

9. 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 %

10. 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?

11. 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)

12. 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

13. Cunningham, NEJM 2008, v358, p. 42

14. Cunningham, NEJM 2008, v 358, p. 41

15. Cunningham, NEJM 2008, v358, p 44

16. 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)

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

18. CALGB 80403/ECOG 1206: Overall Survival by Arm

19. 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

20. 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

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

22. 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

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

24. 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

25. 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

26. 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

27. 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

28. 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

29. 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 a
76.8b 8.9b b
Prior gastrectomy
21.4
24.1
Highest recruitment was from Korea, Japan, China and Russia
F, fluoropyrimidine; C, cisplatin an=287; bn=293

30. Primary end point: OS Event 1.0 Median OS 13.8 11.1 0.9 Events 167 182HR
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

31. Secondary end point: PFS
Event
1.0
Median PFS
Events 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

32. 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

33. OS in IHC2+/FISH+ or IHC3+ (exploratory analysis)
Event
1.0
Median OS
Events 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
122 96
100 75 84 53 65 39 51 28 39 20 28 13 20 11 12 4 11 3 5 3 4 1

34. 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

35. 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

36. 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 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

37. 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

38. 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

39. 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

40. Overall Survival 12.1 10.1 XP + Placebo XP + Bev HR = 0.87
95% CI 0.73–1.03
p =
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

41. Progression-Free Survival
XP + Placebo
XP + Bev
HR = 0.80
95% CI 0.68–0.93
p =
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

42. 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