TOGA trial

1. Dr Mebanshanbor Garod
(MS General Surgery, FMAS,
FEBS Surgical Oncology)
Surgical Oncology Dept.,
NEIGRIHMS, Shillong

2. • 4th most common malignant disease ~ 930,000
• One of the most common cause of cancer-related death worldwide ~700,000
• Wide geographical variation
Gastric cancer: a global disease
www.cancer.gov
Kamangar F et al. J Clin Oncol 2006;24:2137–50
20/100000
<10/100000
10 - 20/100000
Incidence

3. Advanced Gastric Cancer
 Although gastric cancer is relatively chemosensitive (RR
30 - 40%), chemotherapy prolongs median survival with
only 4 - 6 months (3 - 4 to 7 - 10 months).
 Problems: -short response duration
-low CR rate
-toxic and/or “heavy” regimen
 Chemotherapy improves outcome in selected patients

4. Chemotherapy for advanced
gastric cancer
 There is no universal standard treatment,
but
 fluoropyrimidine (capecitabine / 5-FU) / platinum
(cisplatin / oxaliplatin)-based chemotherapy
considered as a reference regimen
 epirubicin or docetaxel sometimes added
 Regional differences
 Bologicals are under investigation

5. Rationale for trastuzumab in GC
 Some gastric adenocarcinomas are HER2 positive (7-
34%)
 Trastuzumab is effective against HER2-overexpressing
GC cell lines in vitro and in vivo
 Role well established in breast cancer
Fujimoto-Ouchi et al 2007; Gravalos & Jimeno 2008

6. 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

7. ToGA trial design
HER2-positive
advanced GC
(n=584)
5-FU or capecitabinea
+ cisplatin
(n=290)
R
5-FU or capecitabinea
+ cisplatin
+ trastuzumab
(n=294)
 Stratification factors
− advanced vs metastatic
− GC vs GEJ
− ECOG PS 0-1 vs 2
− capecitabine vs 5-FU
Randomized, open-label, international, multicenter study
1Bang et al; Abstract 4556, ASCO 2009
3807 patients screened1
810 HER2-positive (22.1%)

9. Surgical specimen staining pattern.

10. Human epidermal growth factor receptor 2
expression in gastric and breast tumors

11. Treatment regimens
 5-Fluorouracil
800 mg/m2/day continuous iv infusion d1-5 q3w x
6cycles
OR
Capecitabine
1000 mg/m2 bid d1-14 q3w x 6cycles
 Cisplatin
80 mg/m2 q3w x 6cycles
 Trastuzumab
8 mg/kg loading dose followed by 6 mg/kg q3w until PD,
unacceptable toxicity or withdrawal of consent.

12. ToGA trial end points
 Primary end point:
− overall survival
 Secondary end points
− PFS, TTP, ORR, Duration of Response and safety.
 Sample size assumptions
− sample size: 584 patients randomized 1:1
− median OS improvement from 10 to 13 months (HR 0.77)
 Analyses
− by Independent Data Monitoring Committee

13. Selection Criteria
Exclusion criteria
• Previous adjuvant chemotherapy within 6 months
• Congestive heart failure or baseline LVEF <50%
• Disrupted upper GI integrity or UGI bleed or malabsorption syndrome
• Brain mets
• Creatinine clearance <60 mL/min
IHC, immunohistochemistry; FISH, fluorescence in situ hybridization; LVEF, left ventricular ejection fraction;;
ECOG, Eastern Cooperative Oncology Group
Inclusion criteria
• >18 years ; informed consent.
• ECOG performance status ≤2;Adequate organ function
• Adenocarcinoma of stomach or GEJ
• Inoperable locally advanced and/or metastatic disease
• HER2-positive tumors (IHC 3+ and/or FISH+)

14. 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 an=287; bn=293

15. Stratification factors
Characteristic, % F+C
n=290
F+C + trastuzumab
n=294
Metastatic disease 96.6 96.6
Primary site
Stomach
GE junction
83.4
16.6
80.3
19.7
ECOG PS
0
1
2
36.2
54.5
9.3
34.4
55.4
10.2
Fluoropyrimidine
Capecitabine
5-FU
87.9
12.1
87.1
12.9

16. 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

17. 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

18. Efficacy: OS by HER2 status
Subgroup Median OS
(months)
All 11.1 13.8vs
Pre-planned analysis
IHC0/FISH+
IHC1+/FISH+
IHC2+/FISH+
IHC3+/FISH+
IHC3+/FISH-
7.2
10.2
10.8
12.3
17.7
10.6
8.7
12.3
17.9
17.5
0.2 0.4 0.6 1 2 3 4 5
vs
vs
vs
vs
vs
0.92
1.24
0.75
0.58
0.83
0.48, 1.76
0.70, 2.20
0.51, 1.11
0.41, 0.81
0.20, 3.38
Hazard
ratio
95% CI
0.74 0.60, 0.91
Risk ratioFavors T Favors no T
584
61
70
159
256
15
N

19. 2nd-line treatment received after
progression
Treatment, n (%) F+C
n=290
F+C + trastuzumab
n=294
Patients receiving any therapy 131 (45) 122 (42)
Chemotherapy 124 (43) 113 (38)
Cytotoxic therapy received by >5% of patients
Docetaxel
Paclitaxel
5-FU
Irinotecan
Cisplatin
Oxaliplatin
S-1
40 (14)
35 (12)
52 (18)
56 (19)
21 (7)
20 (7)
21 (7)
38 (13)
38 (13)
53 (18)
47 (16)
21 (7)
14 (5)
22 (7)
HER2 targeting therapy
Lapatinib
Trastuzumab
3 (1)
2 (<1)
4 (1)
3 (1)
Radiotherapy 17 (6) 17 (6)
Surgery 13 (4) 8 (3)

20. Cause of death
F+C
n=290
F+C + trastuzumab
n=294
Total deaths, n (%) 182 (63) 167 (57)
Deaths due to progressive disease, n (%) 167 (57) 148 (50)
60-day mortality, n (%) 20 (7) 15 (5)
Treatment-related mortality, n (%) 3a (1) 10b (3)
aSepsis, pancytopenia, unknown
bPneumonia (2), myocardial infarction, angina unstable and cardiac failure in same patient,
gastric hemorrhage, depressed level of consciousness, thrombocytopenia, renal failure, unknown (2)

21. Safety: hematological AEs
(NCI_CTCAE)
AE, %
F+C
n=290
F+C + trastuzumab
n=294
All Grade 3/4 All Grade 3/4
Neutropenia
Febrile neutropenia
Anemia
Thrombocytopenia
57
3
21
11
30
3
10
3
53
5
28
16
27
5
12
5
AE, adverse event; NCI-CTCAE national cancer institute-common terminology criteria for adverse events

22. 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

23. Safety: cardiac AEs
aMeasured 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)

24. Limitations of the trial
 Open label
 Her-2 testing:
 Centrally done: logistic issues
 Trastuzumab was continued till
progression of disease whereas
chemotherapy was for 6 cycles

25.  Chemo used were 5FU/capecitabine
and cisplatin ; now, standard of care
includes epirubicicn, 5FU and cisplatin.
 No details of distal gastric growth.
 Cost not mentioned.

26. 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, DoR)
were also significantly improved

27.  Addition of trastuzumab to chemotherapy
was well tolerated: there was no difference
in overall safety profile, including cardiac
AEs, between treatment arms
 Her-2 testing centrally done
 Separate criteria
 Independent data monitoring committee

28. ToGA study: Conclusions
 Trastuzumab is the first biological to show a
survival benefit in advanced gastric cancer
 Trastuzumab in combination with
chemotherapy is a new treatment option for
patients with HER2-positive advanced gastric
adenocarcinoma

29. Thank you…