1. Efficacy results from 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
Eric Van Cutsem*
Y-K Kang, HC Chung, L Shen, A Sawaki, F Lordick, J Hill, M Lehle, A Feyereislova, Y-J Bang
*University Hospital Gasthuisberg, Leuven, Belgium

2. Disclosure slide Research funding/advisory board: Amgen Merck KGaA
Novartis
Pfizer
Roche
Sanofi-Aventis

3. Rationale for trastuzumab in HER2-positive GC
There is no universal standard treatment, but
fluoropyrimidine (capecitabine / 5-FU) / platinum (cisplatin / oxaliplatin)-based chemotherapy considered as reference regimen
epirubicin or docetaxel sometimes added
biologicals are under investigation
Unmet need for new treatment options in advanced gastric cancer
Some gastric adenocarcinomas are HER2 positive
Trastuzumab is effective against HER2-overexpressing GC cell lines in vitro and in vivo
References
Ross JS, McKenna BJ. Cancer Invest 2001; 19: 554–568.
Shinohara H et al. J Surg Res 2002; 102: 169–177.
Allgayer H et al. J Clin Oncol 2000; 18: 2201–2209.
Fujimoto-Ouchi K et al. Cancer Chemother Pharmacol 2007; 59:
Slamon DJ et al. N Engl J Med 2001; 344:
Marty M et al. J Clin Oncol 2005; 23:
Smith I et al. Lancet 2007; 369:
Gravalos C, Jimeno A. Ann Oncol 2008; 19:
Fujimoto-Ouchi et al 2007; Gravalos & Jimeno 2008

4. 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

5. 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

6. 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

7. 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
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.

8. 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

9. 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

10. Stratification factors
Characteristic, %
F+C n=290
F+C + trastuzumab n=294
Metastatic disease
96.6
Measurable disease
88.6
91.5
Primary site Stomach GE junction
ECOG PS 0 1 2
Fluoropyrimidine Capecitabine 5-FU

11. 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

12. 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

13. 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

14. Efficacy: OS subgroup analysis
Category
Subgroup N
95% CI HR
All
584
0.60, 0.91
0.74
GEJ
Primary site
106
0.42, 1.08
0.67
Stomach
478
0.60, 0.96
0.76
0-1
ECOG PS
527
0.56, 0.89
0.71 2 57
0.51, 1.79
0.96
Fluoropyrimidine
5-FU 73
0.40, 1.23
0.70
Capecitabine
511
0.60, 0.95
0.75
279
0.84
<60
Age group
0.62, 1.14
>60
305
0.49, 0.88
0.66
Region
Asia
319
0.61, 1.11
0.82
C/S America 52
0.21, 0.90
0.44
Europe
190
0.44, 0.89
0.63
Other 23
0.48, 3.08
1.22
Diffuse
GC type 51
0.56, 2.05
1.07
Intestinal
438
0.54, 0.88
0.69
Mixed 91
0.51, 1.46
0.86 No
Yes
Prior gastrectomy
451
133
0.72
0.81
0.57, 0.91
0.49, 1.34
1-2
No. metastatic sites
298
0.68, 1.26
0.93
>2
285
0.43, 0.77
0.57
HER2 result
IHC 0/FISH+ 61
0.48, 1.76
0.92
IHC 1+/FISH+ 70
0.70, 2.20
1.24
IHC 2+/FISH+
159
0.51, 1.11
0.75
IHC 3+/FISH+
256
0.41, 0.81
0.58
IHC 3+/FISH- 15
0.20, 3.38
0.83
0.2
0.4
0.6 1 2 3 4 5
Favors T
Risk ratio
Favors no T

15. Efficacy: OS by HER2 status
Subgroup
Median OS (months)
Hazard ratio
95% CI
0.2
0.4
0.6 1 2 3 4 5 N
All
584
11.1 vs
13.8
0.74
0.60, 0.91
Pre-planned analysis
IHC0/FISH+
IHC1+/FISH+
IHC2+/FISH+
IHC3+/FISH+
IHC3+/FISH- 61 70
159
256 15
7.2
10.2
10.8
12.3
17.7 vs
10.6
8.7
12.3
17.9
17.5
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
Exploratory analysis
IHC0 or 1+/FISH+
IHC2+/FISH+ or IHC3+
131
446
8.7
11.8 vs
10.0
16.0
1.07
0.65
0.70, 1.62
0.51, 0.83
Favors T
Risk ratio
Favors no T

16. 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

17. Exposure to trial treatments
F+C n=290
F+C + trastuzumab n=294
Median
Range
Trastuzumab Cycles Treatment duration, months Dose intensity, % 8
4.9
100.1
Cisplatin Cycles Treatment duration, months Dose intensity, % 5
3.4
91.1 6
3.5
89.4
Capecitabine Cycles Treatment duration, months Dose intensity, %
3.9
86.7
85.9
5-FU Cycles Treatment duration, months Dose intensity, % 4
2.9
95.7
3.6
98.3
Treatment duration converted from days to months by dividing by 365/12=30.416

18. 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)
38 (13)
53 (18)
47 (16)
14 (5)
22 (7)
HER2 targeting therapy Lapatinib Trastuzumab
3 (1) 2 (<1)
4 (1) 3 (1)
Radiotherapy
17 (6)
Surgery
13 (4)
8 (3)

19. 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 (%)
148 (50)
60-day mortality, n (%)
20 (7)
15 (5)
Treatment-related mortality, n (%)
3a (1)
10b (3)
Treatment related deaths
3 in chemotherapy arm: sepsis, death, pancytopenia.
10 in trastuzumab + chemotherapy arm: 2 pneumonia, 1 MI, 1 angina unstable and 1 cardiac failure in same patient,  1 gastric haemorrhage, 2x death, 1 depressed level of consciousness, 1 thrombocytopenia, 1 renal failure.
Please note that 1 patient reported death due to angina unstable and cardiac failure, investigator could not identify which one lead to death. The events ´death´ are unknown cases although queried several times.
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)

20. Safety: hematological AEs
F+C n=290
F+C + trastuzumab n=294
All
Grade 3/4
Neutropenia
Febrile neutropenia
Anemia
Thrombocytopenia 57 3 21 11 30 10 53 5 28 16 27 12
AE, adverse event

21. 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

22. 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

23. 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

24. 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

25. ToGA trial: acknowledgements to
the patients
the investigators, co-investigators, and study teams at the 142 centers in 24 countries (Asia, Australia, Europe, Latin-America, South Africa)
the study team at Roche
my team in Leuven
my wife and 3 daughters 25