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Introduction

RIBBON-1: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy with or without Bevacizumab for First-Line Treatment of HER2-Negative Locally Recurrent or Metastatic Breast Cancer.

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Introduction

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  1. RIBBON-1: A Randomized, Double-Blind, Placebo-Controlled, Phase III Trial of Chemotherapy with or without Bevacizumab for First-Line Treatment of HER2-Negative Locally Recurrent or Metastatic Breast Cancer N. Robert, V. Dieras, J. Glaspy, A. Brufsky, I. Bondarenko, O. Lipatov, E. Perez, D. Yardley, J. O’Shaughnessy, X. Zhou, S. Phan Fairfax Northern Virginia Hematology Oncology, U.S. Oncology, Fairfax, VA; Institut Curie, Paris, France; UCLA TORI, Los Angeles, CA; Univ. of Pittsburgh, Pittsburgh, PA; State Medical Academy, Dnepropetrovsk, Ukraine; Bashkirian Republican Clinical Oncology, Ufa, Russia; Mayo Clinic, Jacksonville, FL; Sarah Cannon Cancer Center, Nashville, TN; Baylor-Sammons Cancer Center, Texas Oncology, U.S. Oncology, Dallas, TX; Genentech, South San Francisco, CA

  2. Introduction • Bevacizumab (BV), a monoclonal antibody, directly inhibits vascular endothelial growth factor (VEGF), a central mediator of angiogenesis. • Two previous Phase III trials demonstrated that BV + 1st line taxanes (paclitaxel and docetaxel) improved progression-free survival (PFS) for metastatic breast cancer (MBC) patients. • RIBBON-1 was designed to demonstrate the clinical benefit of combining BV with other chemotherapies used for MBC.

  3. Study Design • Previously untreated MBC • (n=1237) • Stratification Factors: • Disease-free interval • Previous adjuvant chemotherapy • Number of metastatic sites • Cape, T or Anthra CHOICE OFCHEMO BY INVESTIGATOR Chemo +bevacizumabq3w Optional2nd-line Chemo+ bevacizumab Treat until PD Capecitabine or TaxaneorAnthracycline RANDOMIZE 2:1 Chemo +placeboq3w • Capecitabine (1000 mg/m2 BID x 14d) • Taxane (docetaxel q3w or protein-bound paclitaxel q3w) • Anthracycline-based chemotherapy (AC, EC, FAC, FEC) • Placebo or bevacizumab (15 mg/kg q3w)

  4. Key Eligibility Criteria • Age ≥18 years • ECOG performance status 0 or 1 • Histologically confirmed, locally recurrent or MBC • No prior chemotherapy for locally recurrent or MBC • HER2-negative MBC • ≥12 months since any prior adjuvant chemotherapy

  5. Study Endpoints • Primary endpoint: • PFS, as assessed by investigator • Secondary endpoints: • PFS, by independent review committee (IRC) • Objective response rate (ORR) • Overall survival (OS) & 1-year survival rate • Safety

  6. Statistical Design and Analyses * 300 pts treated with taxane, 300 pts with anthracycline Cape + bevacizumab n=409 CHOICE OFCHEMO BY INVESTIGATOR Cape + placebo n=206 Capecitabineor TaxaneorAnthracycline EFFICACYANALYSIS RANDOMIZE T/Anthra + bevacizumab n=415 T/Anthra + placebo n=207

  7. Study Conduct • Conducted at >200 sites in 22 countries • Accrued 1237 patients from Dec 2005 to Aug 2007 • Data cutoff date: July 31, 2008 • Median follow-up • Capecitabine: 15.6 months • Taxane and anthracycline: 19.2 months

  8. Patient Characteristics All data as %, unless otherwise noted.

  9. RESULTS

  10. Capecitabine: PFS by Investigator INV IRC

  11. Taxane/Anthra: PFS by Investigator INV IRC

  12. Exploratory Endpoint:PFS by Chemotherapy Subgroups PFS = PFS by investigator

  13. Analysis of PFS by stratification factors: Cape and T/Anthra Cohorts Cape T/Anthra + BV better + PL better + BV better + PL better Total n Hazard Ratio Total n Hazard Ratio Baseline Factor All Patients 615 0.67 Disease-free interval (mo) ≤12 154 0.81 >12 461 0.63 Number of metastatic sites <3 345 0.63 ≥3 270 0.74 Prior adjuvant chemotherapy Yes 444 0.64 No 171 0.80 622 0.66 239 0.62383 0.69 341 0.65281 0.64 283 0.67339 0.64

  14. Objective Response Rate Cape p=0.0097 T/Anthra p=0.0054 51.3 37.9 35.4 % 23.6 PL BV PL BV Measurable disease (n) 161 325 177 345 Includes only patients with measurable disease at baseline.

  15. Overall Survival

  16. Safety Summary * AEs previously shown to be associated with BV ** Excludes AEs related to MBC progression

  17. Selected Grade ≥3 AEs VTE=venous thromboembolism

  18. Summary • For the pre-specified Cape and T/Anthra cohorts, the addition of bevacizumab led to a statistically significant improvement in: • PFS (by investigator) • PFS (by IRC) • ORR • No difference was noted in OS • Safety: • Incidence of bevacizumab-related adverse events consistent with prior studies • No new bevacizumab-related safety signals in each of the chemotherapy groups

  19. Conclusions • RIBBON-1 provides a third randomized Phase III trial demonstrating the efficacy and safety of combining bevacizumab, a direct VEGF inhibitor, with first-line chemotherapy for MBC. • RIBBON-1 establishes the efficacy of combining bevacizumab with non-taxane chemotherapies used for first-line treatment of MBC. • The safety profile of bevacizumab in combination with these chemotherapies was consistent with that reported from prior Phase III trials.

  20. Acknowledgments • 1237 patients and the RIBBON-1 investigators from:

  21. Back-ups

  22. Chemotherapy Regimens • Investigator chose from the following protocol specified chemotherapy regimens prior to randomization: • Capecitabine: • Capecitabine 1000 mg/m2 BID x 14d started q21d • Taxanes: • Docetaxel 75 or 100 mg/m2 q21d • Protein-bound paclitaxel 260 mg/m2 q21d • Anthracyclines: • AC (doxorubicin 50 or 60 mg/m2, cyclophosphamide 500 or 600 mg/m2) q21d • FAC (5-FU 500 or 600 mg/m2, doxorubicin 50 or 60 mg/m2, cyclophosphamide 500 or 600 mg/m2) q21d • EC (epirubicin 90 or 100 mg/m2, cyclosphosphamide 500 or 600 mg/m2) q21d • FEC (5-FU 500 or 600 mg/m2, epirubicin 90 or 100 mg/m2, cyclophosphamide 500 or 600 mg/m2) q21d

  23. Second-line Usage of Bevacizumab • Per protocol, at the time of disease progression, all patients were offered option of receiving bevacizumab with a 2nd line chemotherapy chosen by the investigator

  24. Analysis of PFS by stratification factors: Cape and T/Anthra Cohorts Cape T/Anthra + BV better + PL better + BV better + PL better Total n Hazard Ratio Total n Hazard Ratio Baseline Factor All Patients 615 0.67 Hormone receptor status Positive 458 0.69 Negative 143 0.70 Time from diagnosis of primary cancerto diagnosis of locally recurrent ormetastatic disease (months) ≤ 24 205 0.76 > 24 408 0.63 622 0.66 459 0.61142 0.78 262 0.65358 0.67 0.2 0.5 1 2 0.2 0.5 1 2

  25. Subgroup Analyses of PFS T/Anthra Cohorts T/Anthra + BV better + PL better Total n Hazard Ratio Baseline Factor All Patients 622 0.66 Taxane Docetaxel 181 0.78 Abraxane 124 0.65 Anthracycline-based Chemotherapy Doxorubicin-based 236 0.63 Epirubicin-based 74 0.46

  26. Clinical Summary of Cardiac Toxicity: Anthracycline Cohort • Grade 3 and 4 Events • Two patients with clinical CHF (Grade 3, Grade 4) • One patient with non-specific symptoms • Two patients with measurement error • One patient with progressive disease

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