Land mark trials gastric cancer

1. Land mark studies in
Metastatic Gastric Cancer
Prof.Ahmed M Badheeb, MD.
Professor Of Oncology and Internal
Medicine

2. TAX 325

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

4. CF
(23
0)
DCF EOX FC-T =ToGA
RR 25.4
%
36.7
%
48%
4% CR
TTP 3.7
M
5.6 m 7
OS 8.6
M
9.2 m 11.2
1-yr.
OS
31.6
%
40.2
%
2-
yr.O
S
8.8
%
18.4
%

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

6. 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?

7. REAL 2

8. 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)

9. 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

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

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

12. Cunningham, NEJM 2008, v358, p 44

13. CALGB 80403 / ECOG E1206

14. CALGB 80403 / ECOG E1206: Schema
Stratification:
ECOG 0-1 vs 2
ADC vs. SCC
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
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)

15. CALGB 80403/ECOG 1206: Response
ECF-C
N=64
IC-C
N=68
FOLFOX-C
N=69
Response
CR 0 1 ( 1%) 2 ( 3%)
PR 37 (58%) 30 (44%) 35 (51%)
SD 15 (23%) 23 (34%) 19 (28%)
PD 4 ( 6%) 10 (15%) 8 (12%)
Not eval / unknown 5 / 3 (8% /5%) 2 / 2 (3% /3%) 3 / 2 (4% /3%)
Objective Response Rate*
(CR+PR)/total 57.8 45.6 53.6
(90% C.I.) 46.8 68.3 35.2 56.3 43.1 64.0
p vs. H0<0.25 <.0001 <.0001 <.0001
Response duration (mos)
median 6.1 5.3 5.7
range 0.5 - 22.7 0.5 - 20.1 2.4 - 18.2
*RECIST - confirmed; restaging every 6 weeks

16. 0 5 10 15 20 25
Months from Study Entry
0.00.20.40.60.81.0
ProportionSurviving
ECF-C (n=67)
IC-C (n=71)
FOLFOX-C (n=72)
CALGB 80403/ECOG 1206: Overall Survival by Arm

17. ToGA

18. 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

19. 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

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

21. 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

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

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

24. ToGA trial design
HER2-positive
advanced GC
(n=584)
5-FU or capecitabinea
+ cisplatin
(n=290)
R
a
Chosen at investigator’s discretion
GEJ, gastroesophageal junction
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
Phase III, randomized, open-label, international, multicenter study
1
Bang et al; Abstract 4556, ASCO 2009
3807 patients screened1
810 HER2-positive (22.1%)

25. 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

26. ToGA trial end points
 Primary end point:
− 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

27. Main patient selection criteria
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
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

28. Patient demographics and baseline
characteristics
Characteristic 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 a
n=287; b
n=293

29. Primary end point: OS
Time (months)
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
0
1
0
0
0
No.
at risk
11.1 13.8
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36
Event
FC + T
FC
Events
167
182
HR
0.74
95% CI
0.60, 0.91
p value
0.0046
Median
OS
13.8
11.1
T, trastuzumab

30. Secondary end point: PFS
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34
Event
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
0
2
0
0
0
5.5 6.7
No.
at risk
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Time (months)
FC + T
FC
Events
226
235
HR
0.71
95% CI
0.59, 0.85
p value
0.0002
Median
PFS
6.7
5.5

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

32. 11
3
OS in IHC2+/FISH+ or IHC3+
(exploratory analysis)
1.0
0.8
0.6
0.4
0.2
0.0
363432302826242220181614121086420
Time (months)
11.8 16.0
FC + T
FC
Events
120
136
HR
0.65
95% CI
0.51, 0.83
Median
OS
16.0
11.8
Event
0.1
0.3
0.5
0.7
0.9
218
198
4
0
5
3
12
4
20
11
228
218
196
170
170
141
142
112
122
96
100
75
84
53
65
39
51
28
1
0
0
0
No.
at risk
39
20
28
13

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

34. Safety: cardiac AEs
a
Measured at baseline and every 12 weeks; MI, myocardial infarction
Cardiac event, n (%) F+C
(n=290)
F+C + trastuzumab
(n=294)
All Grade 3/4 All Grade 3/4
Cardiac AEs, total 18 (6) 9 (3) 17 (6) 4 (1)
Cardiac failure 2 (<1) 2 (<1) 1 (<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 2 (<1) 2 (<1)

35. 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

36. AVAGAST
Avastin
PFS +, OS not

37. AVAGAST: A Randomized Double-Blind
Placebo- Controlled Phase III Study
Starting dose of bev/placebo: 30 minutes, subsequent doses: 15 minutes
Capecitabine*/Cisplatin (XP)
+ Placebo q3w
Capecitabine*/Cisplatin (XP)
+ Bevacizumab q3w
Locally advanced
or metastatic
gastric cancer
R
*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
Stratification factors:
1. Geographic region
2. Fluoropirimidine backbone
3. Disease status

38. Patient Characteristics (I)
Number of patients N=774 (%)
XP + Placebo
N=387
XP + Bev
N=387
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)
20 (5)
367 (95)
*1 additional patient had an ECOG PS of 4

39. Patient Characteristics (II)
Number of patients N=774 (%)
XP + Placebo
N=387
XP + Bev
N=387
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)
311 (80)
76 (20)
Metastatic sites, n
0
1
≥2
8 (2)
131 (34)
247 (64)
8 (2)
131 (34)
247 (64)
Prior gastrectomy Yes 107 (28) 110 (28)
Liver metastasis Yes 126 (33) 130 (34)

40. Overall Survival
387
387
343
355
271
291
204
232
146
178
98
104
15
19
XP + Placebo
XP + Bev
Number at risk
54
50
0
0
XP + Placebo
XP + Bev
HR = 0.87
95% CI 0.73–1.03
p = 0.1002
Survival rate
3 9 15 18 21 240
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

41. Progression-Free Survival
387
387
279
306
145
201
86
123
55
71
32
38
3
3
15
11
0
0
XP + Placebo
XP + Bev
Number at risk
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 21 240 6 12
5.3
6.7
Study month

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