AVAGAST: a randomized, double-blind placebo-controlled, phase III study of first-line capecitabine a...
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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 Presentation


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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

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Y-K Kang, A Ohtsu, E Van Cutsem, SY Rha, A Sawaki SR Park, H-Y Lim, J Wu, B Langer, MA Shah

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Y k kang a ohtsu e van cutsem sy rha a sawaki sr park h y lim j wu b langer ma shah

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, MAShah

on behalf of AVAGAST investigators


Rationale for bevacizumab in 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

AVAGAST: A Randomized Double-Blind Placebo- Controlled Phase III Study

Capecitabine*/Cisplatin (XP)

+ Placebo q3w

Locally advanced

or metastatic gastric cancer

R

Capecitabine*/Cisplatin (XP)

+ Bevacizumab q3w

Stratification factors:

1. Geographic region

2. Fluoropirimidine backbone

3. Disease status

*5-FU also allowed if cape contraindicated

Cape 1000mg/m2oral bid, d1–14, 1-week rest

Cisplatin 80mg/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

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

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

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

Patient Characteristics (I)

*1 additional patient had an ECOG PS of 4


Patient characteristics ii

Patient Characteristics (II)


Overall survival

Overall Survival

Survival rate

XP + Placebo

XP + Bev

1.0

HR = 0.87

95% CI 0.73–1.03

p = 0.1002

0.9

0.8

0.7

12.1

0.6

0.5

10.1

0.4

0.3

0.2

0.1

0.0

12

0

15

18

21

24

3

9

6

Study month

Number at risk

54

50

0

0

XP + Placebo

XP + Bev

387

387

343

355

271

291

204

232

146

178

98

104

15

19


Progression free survival

Progression-Free Survival

Progression-free survival rate

XP + Placebo

XP + Bev

1.0

HR = 0.80

95% CI 0.68–0.93

p = 0.0037

0.9

0.8

0.7

6.7

0.6

0.5

5.3

0.4

0.3

0.2

0.1

0.0

12

0

15

18

21

24

3

9

6

Study month

Number at risk

15

11

0

0

XP + Placebo

XP + Bev

387

387

279

306

145

201

86

123

55

71

32

38

3

3


Best overall response measurable disease population

Best Overall Response: Measurable Disease Population


Overall survival subgroup analysis

Overall Survival: Subgroup Analysis

Category

Subgroup

All

All

Asia

Region

Europe

Pan-America

0

ECOG performance

1

Stomach

Site of primary disease

GE junction

Intestinal

Histologic type

Diffuse

Mixed

Locally advanced*

Disease status

Metastatic

Measurable

Disease measurability

Non-measurable

Yes

Prior gastrectomy

No

1

No. of metastatic sites at baseline

2

0

1

2

Hazard Ratio

* 29 patients with locally advanced disease only


Regional differences in efficacy

Regional Differences in Efficacy


Patient characteristics by region

Patient Characteristics by Region

*1 additional patient had an ECOG PS of 4


Second line therapy by region

Second-Line Therapy by Region


Most frequent grade 3 5 aes 5

Most Frequent Grade 3–5 AEs (≥5%)


Aes of special interest to bevacizumab

AEs of Special Interest to Bevacizumab

Fistula/abscess in 2 patients on XP + Bev

Reversible posterior leukoencephalopathy syndrome in 2 patients on XP + Bev


Avagast summary conclusions

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

Acknowledgments

  • Patients and their families

  • Investigators, study coordinators and nurses at 93 centers in 17 countries

  • AVAGAST study team at Genentech, Roche & Chugai


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