AVAGAST: a randomized, double-blind
placebo-controlled, phase III study of
first-line capecitabine and cisplatin +
bevacizumab or placebo in patients
with advanced gastric cancer (AGC)
Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki
SR Park, H-Y Lim, J Wu, B Langer, MA Shah
on behalf of AVAGAST investigators
Rationale for Bevacizumab in AGC
• Angiogenesis important for tumor growth,
progression and metastases
• Vascular endothelial growth factor (VEGF):
– Critical growth factor for tumor angiogenesis
– Over-expressed and prognostic for many human tumors
• Bevacizumab:
– Humanized monoclonal antibody to VEGF
– Effective and safe in mCRC and other tumor types
– Promising results in Phase II studies in AGC1
1Shah
et al. J Clin Oncol 2006;23:2574–2576
AVAGAST: A Randomized Double-Blind
Placebo- Controlled Phase III Study
Capecitabine*/Cisplatin (XP)
Locally advanced
or metastatic
gastric cancer
+ Placebo q3w
R
Capecitabine*/Cisplatin (XP)
+ Bevacizumab q3w
*5-FU also allowed if cape contraindicated
Stratification factors:
Cape 1000 mg/m2 oral bid, d1–14, 1-week rest
1. Geographic region
2. Fluoropirimidine backbone
3. Disease status
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
Endpoints and Statistical Assumptions
• Primary: overall survival
• Secondary: PFS, TTP, ORR, duration of
response, safety, QoL, biomarkers
• Statistical assumptions
 Median overall survival improvement from 10.0
to 12.8 months (HR 0.78)
 Two-sided α-level = 0.05, 80% power
 Required sample size: 760 patients for 517 deaths
(with interim analysis)
Main Eligibility Criteria
• Metastatic or inoperable, locally advanced adenocarcinoma
of the stomach or gastro-esophageal junction (GEJ)
• Measurable or evaluable disease
• ECOG performance status 0–2
• No previous chemotherapy for metastatic/locally advanced
gastric cancer
• If adjuvant chemotherapy, completed at least 6 months prior
to randomization
• No previous platinum or antiangiogenic therapy
• No history of other malignancies
Trial Conduct
• From September 2007 to December 2008, 774
patients were enrolled
• A total of 93 centers in 17 countries were involved
• Interim analysis
– Planned at 345 events, but not performed according to
protocol as analysis date too close to anticipated final
analysis
• Data cutoff for final analysis
– November 2009
– After 509 events
Patient Characteristics (I)
Number of patients N=774 (%)
XP + Placebo
N=387
XP + Bev
N=387
258 (67)
257 (66)
59 (22–82)
58 (22–81)
Gender
Male
Age, years
Median (range)
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
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)
Overall Survival
Survival rate
XP + Placebo
1.0
XP + Bev
0.9
0.8
HR = 0.87
0.7
95% CI 0.73–1.03
0.6
p = 0.1002
12.1
0.5
10.1
0.4
0.3
0.2
0.1
0.0
0
3
6
9
15
18
21
24
98
104
54
50
15
19
0
0
Study month
Number at risk
XP + Placebo 387
XP + Bev
387
12
343
355
271
291
204
232
146
178
Progression-Free Survival
Progression-free survival rate
XP + Placebo
1.0
XP + Bev
0.9
0.8
HR = 0.80
0.7
95% CI 0.68–0.93
0.6
6.7
0.5
p = 0.0037
5.3
0.4
0.3
0.2
0.1
0.0
0
3
6
9
15
18
21
24
32
38
15
11
3
3
0
0
Study month
Number at risk
XP + Placebo 387
XP + Bev
387
12
279
306
145
201
86
123
55
71
Best Overall Response: Measurable Disease
Population
XP + Placebo
N=387
XP + Bev
N=387
297
311
Overall response
111 (37%)
143 (46%)
95% CI
31.9–43.1
40.3–51.7
Patients with measurable disease
Difference
95% CI
9%
0.6–16.6
P value (2)
Complete response
0.0315
3 (1%)
5 (2%)
Partial response
108 (36%)
138 (44%)
Stable disease
90 (30%)
93 (30%)
Progressive disease
63 (21%)
44 (14%)
Not assessable
33 (11%)
31 (10%)
Overall Survival: Subgroup Analysis
Category
All
Subgroup
All
Asia
Region
Europe
Pan-America
ECOG performance
Site of primary disease
Histologic type
Disease status
Disease measurability
Prior gastrectomy
No. of metastatic sites at baseline
0
1
Stomach
GE junction
Intestinal
Diffuse
Mixed
Locally advanced*
Metastatic
Measurable
Non-measurable
Yes
No
1
2
0
1
Hazard Ratio
2
* 29 patients with locally advanced disease only
Regional Differences in Efficacy
XP + Placebo
Median, mo
XP + Bev
Median, mo
Delta,
mo
Hazard
Ratio
95% CI
Asia
12.1
13.9
1.8
0.97
0.75–1.25
Europe
8.6
11.1
2.5
0.85
0.63–1.14
America
6.8
11.5
4.7
0.63
0.43–0.94
Asia
5.6
6.7
1.1
0.92
0.74–1.14
Europe
4.4
6.9
2.5
0.71
0.54–0.93
America
4.4
5.9
1.5
0.65
0.46–0.93
Region
OS
PFS
Patient Characteristics by Region
% of patients
Age
ECOG PS
Primary site
Extent of disease
Prior gastrectomy
Measurable lesion
Liver metastasis
Asia
Europe
Pan-America
<65
72
68
77
≥65
28
32
23
0–1
97
91
96
2
3*
9
4
Stomach
94
78
84
GEJ
6
22
16
Metastatic
99
95
92
Locally advanced
1
5
8
yes
32
23
27
no
68
77
73
yes
73
88
77
no
27
12
23
yes
27
37
42
no
73
63
58
*1 additional patient had an ECOG PS of 4
Second-Line Therapy by Region
Patients
entered
Patients receiving
second-line treatment
%
Asia
376
248
66
Europe
249
78
31
Pan-America
149
32
21
Region
Most Frequent Grade 3–5 AEs (≥5%)
% of patients
XP + Placebo
N=381
XP + Bev
N=386
Neutropenia
37
35
Febrile neutropenia
4
5
Anemia
14
10
Decreased appetite
11
8
Nausea
10
7
Vomiting
9
6
Diarrhea
4
8
Hypokalemia
6
3
Asthenia
6
5
Hand-foot syndrome
3
6
Hypertension
<1
6
Pulmonary embolism
5
3
Fatigue
4
5
AEs of Special Interest to Bevacizumab
% of patients
XP + Placebo (N=381)
XP + Bev (N=386)
Total
G1
G2
G3
G4
G5
Total
G1
G2
G3
G4
G5
Patients with ≥1 AE
(all body systems)
39
19
14
9
4
2
50
30
17
17
3
1
VTEs
12
<1
2
6
3
<1
10
<1
3
4
3
–
ATEs
2
<1
–
1
1
–
2
<1
<1
<1
<1
–
Bleeding
15
11
2
3
<1
<1
26
21
2
3
<1
<1
Hypertension
13
6
7
<1
–
–
21
7
9
6
–
–
Proteinuria
6
2
3
–
–
–
7
3
4
<1
–
–
Wound
complications
<1
<1
<1
–
–
–
2
<1
<1
<1
–
–
GI perforations
<1
–
<1
–
–
<1
2
–
–
2
–
<1
CHF
<1
–
–
<1
–
–
<1
–
<1
<1
–
<1
Fistula/abscess in 2 patients on XP + Bev
Reversible posterior leukoencephalopathy syndrome in 2 patients on XP + Bev
AVAGAST Summary & Conclusions
•
Primary endpoint of OS not met
•
Secondary efficacy endpoints (PFS, best ORR)
significantly improved, indicating clinical activity of
bev + chemo in AGC
•
Heterogeneous efficacy results in both treatment
arms across geographic regions
 Hypothesis generating with regard to tumor burden,
patient status, practice patterns, genetics?
•
No unexpected / new safety signals for bev
•
Further analysis ongoing, including preplanned
biomarker analysis
Acknowledgments
• Patients and their families
• Investigators, study coordinators and nurses
at 93 centers in 17 countries
• AVAGAST study team at Genentech, Roche &
Chugai