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

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Angiogenesis important for tumor growth, progression and metastases

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Vascular endothelial growth factor (VEGF):

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Critical growth factor for tumor angiogenesis

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Over-expressed and prognostic for many human tumors

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Bevacizumab:

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Humanized monoclonal antibody to VEGF

– –

Effective and safe in mCRC and other tumor types Promising results in Phase II studies in AGC 1 1 Shah et al. J Clin Oncol 2006;23:2574 –2576

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 1000 mg/m 2 oral bid, d1 –14, 1-week rest Cisplatin 80 mg/m 2 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

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Primary: overall survival

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Secondary: PFS, TTP, ORR, duration of response, safety, QoL, biomarkers

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Statistical assumptions

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Median overall survival improvement from 10.0 to 12.8 months (HR 0.78)

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Two sided α-level = 0.05, 80% power

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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 gastric cancer –2 No previous chemotherapy for metastatic/locally advanced If adjuvant chemotherapy, completed at least 6 months prior to randomization No previous platinum or antiangiogenic therapy No history of other malignancies

Trial Conduct

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From September 2007 to December 2008, 774 patients were enrolled

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A total of 93 centers in 17 countries were involved

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Interim analysis

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Planned at 345 events, but not performed according to protocol as analysis date too close to anticipated final analysis

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Data cutoff for final analysis

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November 2009

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After 509 events

Patient Characteristics (I)

Number of patients N=774 (%) Gender Male Age, years Median (range) XP + Placebo N=387 258 (67) 59 (22 –82) ECOG PS 0 –1 ≥2 367 (95) 20 (5) Region Fluoropyrimidine Asia Europe Pan-America Capecitabine 5-FU 188 (49) 124 (32) 75 (19) 365 (94) 22 (6) Disease status Locally advanced Metastatic 9 (2) 378 (98) XP + Bev N=387 257 (66) 58 (22 –81) 365 (94) 22 * (6) 188 (49) 125 (32) 74 (19) 364 (94) 23 (6) 20 (5) 367 (95) *1 additional patient had an ECOG PS of 4

Patient Characteristics (II)

Number of patients N=774 (%) Primary site Stomach GEJ Histologic type Intestinal Diffuse Mixed XP + Placebo N=387 338 (87) 49 (13) 135 (35) 206 (53) 26 (7) Disease measurability Metastatic sites, n Prior gastrectomy Liver metastasis Measurable Evaluable 0 1 ≥2 Yes Yes 297 (77) 90 (23) 8 (2) 131 (34) 247 (64) 107 (28) 126 (33) XP + Bev N=387 333 (86) 54 (14) 155 (40) 176 (46) 35 (9) 311 (80) 76 (20) 8 (2) 131 (34) 247 (64) 110 (28) 130 (34)

Overall Survival

Survival rate 1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.0

0 Number at risk XP + Placebo XP + Bev 387 387 3 343 355 6 271 291 10.1

12.1

9 204 232 12 Study month 146 178 15 98 104 XP + Placebo XP + Bev HR = 0.87

95% CI 0.73

–1.03 p = 0.1002

18 54 50 21 15 19 24 0 0

Progression-Free Survival

Progression-free survival rate 1.0

0.9

0.8

0.7

0.6

6.7

0.5

0.4

0.3

5.3

0.2

0.1

0.0

Number at risk 0 XP + Placebo XP + Bev 387 387 3 279 306 6 145 201 9 86 123 12 Study month 55 71 15 32 38 XP + Placebo XP + Bev HR = 0.80

95% CI 0.68

–0.93 p = 0.0037

18 15 11 21 3 3 24 0 0

Best Overall Response:

Measurable Disease Population XP + Placebo N=387 XP + Bev N=387 Patients with measurable disease Overall response 95% CI Difference 95% CI P value (

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2 ) Complete response Partial response Stable disease Progressive disease Not assessable 297 0.0315

311 111 (37%) 31.9

–43.1

9% 0.6

–16.6

143 (46%) 40.3

–51.7

3 (1%) 108 (36%) 90 (30%) 63 (21%) 33 (11%) 5 (2%) 138 (44%) 93 (30%) 44 (14%) 31 (10%)

Overall Survival: Subgroup Analysis

Category All Subgroup All Region Asia Europe Pan-America ECOG performance Site of primary disease Histologic type 0

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1 Stomach GE junction Intestinal Diffuse Mixed Disease status Disease measurability Prior gastrectomy No. of metastatic sites at baseline Locally advanced* Metastatic Measurable Non-measurable Yes No

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1

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2 0 1 Hazard Ratio 2 * 29 patients with locally advanced disease only

Regional Differences in Efficacy

OS Region Asia Europe America PFS Asia Europe America XP + Placebo Median, mo XP + Bev Median, mo 12.1

13.9

8.6

6.8

5.6

4.4

4.4

11.1

11.5

6.7

6.9

5.9

Delta, mo Hazard Ratio 1.8

0.97

95% CI 0.75

–1.25

2.5

4.7

1.1

0.85

0.63

0.92

0.63

–1.14

0.43

–0.94

0.74

–1.14

2.5

1.5

0.71

0.65

0.54

–0.93

0.46

–0.93

Patient Characteristics by Region

% of patients Age ECOG PS Primary site Extent of disease Prior gastrectomy Measurable lesion Liver metastasis yes no yes no yes no <65 ≥65 0 –1 2 Stomach GEJ Metastatic Locally advanced 32 68 73 27 27 73 Asia 72 28 97 3* 94 6 99 1 Europe 68 32 91 9 78 22 95 5 23 77 88 12 37 63 Pan-America 77 23 96 4 84 16 92 8 27 73 77 23 42 58 *1 additional patient had an ECOG PS of 4

Second-Line Therapy by Region

Region Asia Europe Pan-America Patients entered Patients receiving second-line treatment 376 249 149 248 78 32 % 66 31 21

Most Frequent Grade 3 –5 AEs (≥5%)

% of patients Neutropenia Febrile neutropenia Anemia Decreased appetite Nausea Vomiting Diarrhea Hypokalemia Asthenia Hand-foot syndrome Hypertension Pulmonary embolism Fatigue XP + Placebo N=381 37 4 14 11 10 9 4 6 6 3 <1 5 4 XP + Bev N=386 35 5 10 8 7 6 3 5 6 8 3 5 6

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) VTEs ATEs 39 12 2 19 <1 <1 14 2 – 9 6 1 4 3 1 2 <1 – 50 10 2 30 <1 <1 17 3 <1 17 4 <1 3 3 <1 1 – – Bleeding Hypertension Proteinuria Wound complications GI perforations CHF 15 13 6 <1 <1 <1 11 6 2 <1 – – 2 7 3 <1 <1 – 3 <1 – – – <1 <1 – – – – – <1 – – – <1 – 26 21 7 2 2 <1 21 7 3 <1 – – 2 9 4 <1 – <1 3 6 <1 <1 2 <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

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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

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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

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Patients and their families

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

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AVAGAST study team at Genentech, Roche & Chugai