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?
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)
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
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
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
Editor's Notes
Eligibility criteria for the ToGA trial include: &gt;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.