y-k kang, a ohtsu, e van cutsem, sy rha, a sawaki sr park, h-y lim, j wu, b langer, ma shah
DESCRIPTION
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 - PowerPoint PPT PresentationTRANSCRIPT
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
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)
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
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
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=387XP + 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 AsiaEuropePan-America
188 (49)124 (32)75 (19)
188 (49)125 (32)74 (19)
Fluoropyrimidine Capecitabine5-FU
365 (94)22 (6)
364 (94)23 (6)
Disease status Locally advancedMetastatic
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=387XP + Bev
N=387
Primary siteStomachGEJ
338 (87)49 (13)
333 (86)54 (14)
Histologic typeIntestinalDiffuseMixed
135 (35)206 (53)26 (7)
155 (40)176 (46)35 (9)
Disease measurability
MeasurableEvaluable
297 (77)90 (23)
311 (80)76 (20)
Metastatic sites, n01≥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
387387
343355
271291
204232
146178
98104
1519
XP + PlaceboXP + Bev
Number at risk
5450
00
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
Progression-Free Survival
387387
279306
145201
86123
5571
3238
33
1511
00
XP + PlaceboXP + 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
Best Overall Response: Measurable Disease Population XP + Placebo
N=387XP + Bev
N=387
Patients with measurable disease 297 311
Overall response 111 (37%) 143 (46%)
95% CI 31.9–43.1 40.3–51.7
Difference 9%
95% CI 0.6–16.6
P value (2) 0.0315
Complete response 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
Pan-America
2
No
Disease status
ECOG performance
Prior gastrectomy
Region
Site of primary disease
No. of metastatic sites at baseline
Disease measurability
Histologic type
All
Locally advanced*
Metastatic
0
Yes
Europe
All
1
Asia
StomachGE junction
1
Measurable
Non-measurable
IntestinalDiffuseMixed
SubgroupCategory
2Hazard Ratio
0 1
* 29 patients with locally advanced disease only
Regional Differences in Efficacy
RegionXP + PlaceboMedian, mo
XP + BevMedian, mo
Delta, mo
Hazard Ratio 95% CI
OS 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
PFS 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
Patient Characteristics by Region% of patients Asia Europe Pan-America
Age <65 72 68 77
≥65 28 32 23
ECOG PS 0–1 97 91 96
2 3* 9 4
Primary site Stomach 94 78 84
GEJ 6 22 16
Extent of disease Metastatic 99 95 92
Locally advanced 1 5 8
Prior gastrectomy yes 32 23 27
no 68 77 73
Measurable lesion yes 73 88 77
no 27 12 23
Liver metastasis yes 27 37 42
no 73 63 58
*1 additional patient had an ECOG PS of 4
Second-Line Therapy by Region
RegionPatients entered
Patients receiving second-line treatment %
Asia 376 248 66
Europe 249 78 31
Pan-America 149 32 21
Most Frequent Grade 3–5 AEs (≥5%)% of patients
XP + PlaceboN=381
XP + BevN=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 + BevReversible 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