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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, 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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  1. 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

  2. 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

  3. 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

  4. 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)

  5. 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

  6. 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

  7. Patient Characteristics (I) *1 additional patient had an ECOG PS of 4

  8. Patient Characteristics (II)

  9. 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

  10. 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

  11. Best Overall Response: Measurable Disease Population

  12. 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

  13. Regional Differences in Efficacy

  14. Patient Characteristics by Region *1 additional patient had an ECOG PS of 4

  15. Second-Line Therapy by Region

  16. Most Frequent Grade 3–5 AEs (≥5%)

  17. AEs of Special Interest to Bevacizumab Fistula/abscess in 2 patients on XP + Bev Reversible posterior leukoencephalopathy syndrome in 2 patients on XP + Bev

  18. 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

  19. 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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