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