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AVADO

A randomized, double-blind study of bevacizumab in combination with docetaxel as first-line treatment of patients with HER2-negative locally recurrent or metastatic breast cancer: efficacy and safety. AVADO. David Miles Mount Vernon Cancer Centre, Middlesex, United Kingdom.

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AVADO

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  1. A randomized, double-blind study of bevacizumab in combination with docetaxel as first-line treatment of patients with HER2-negative locally recurrent or metastatic breast cancer: efficacy and safety AVADO David Miles Mount Vernon Cancer Centre, Middlesex,United Kingdom On behalf of the AVADO investigators

  2. Disclosure • ASCO General COI Yes, I have Consultant or Advisory Role to disclose • Roche Yes, I have Honoraria to disclose • Roche

  3. Introduction • Bevacizumab is a monoclonal antibody to vascular endothelial growth factor (VEGF) that inhibits tumor angiogenesis • In a phase III trial (E2100) the addition of bevacizumab to first-line paclitaxel significantly increased progression-free survival (PFS) in patients with metastatic breast cancer (mBC)1 • Docetaxel is a widely used and active taxane in mBC • AVADO was designed to investigate the addition of bevacizumab to docetaxel in first-line mBC 1. Miller et al. N Engl J Med 2007;357:2666–76

  4. AVADO: double-blind, placebo-controlled trial • Primary endpoint: progression-free survival • Secondary endpoints: overall response rate, duration of response, time to treatment failure, overall survival, safety, quality of life Treat withplacebo/bevacizumabto diseaseprogression All patientsgiven optionto receive bevacizumabwith 2nd-linechemotherapy Docetaxel* 100mg/m2+ placebo q3w • 1st-line locally recurrent • or mBC (n=705) • Stratification factors: • region • prior taxane/time to relapse since adjuvant chemo • measurable disease • hormone receptor status Docetaxel* + bevacizumab 7.5mg/kg q3w Docetaxel* + bevacizumab 15mg/kg q3w *Docetaxel was administered for a maximum of nine cycles, but earlier discontinuation was permitted

  5. AVADO: key eligibility criteria • Women aged ≥18 years • ECOG PS 0–1 • No prior chemotherapy for locally recurrent or mBC • Prior adjuvant chemotherapy permitted if relapse ≥6 months since last dose (≥12 months if taxane-based) • HER2-negative

  6. AVADO: statistical design • Sample size assumptions were based upon • 80% power to detect PFS hazard ratio of 0.7 • median 6.0 vs 8.6 months • 705 patients required • Planned analyses were • to compare PFS between each bevacizumab-containing arm versus control using a closed-test procedure (unstratified test) • to investigate PFS with censoring for non-protocol antineoplastic therapy given prior to progression (stratified test)

  7. AVADO: results • 736 patients recruited from 104 sites in 26 countries between March 2006 and April 2007 • Data cut-off 31 October 2007 • Median follow-up = 10.2 months (range 0–17.5) • Analysis • intent-to-treat population (all randomized patients), n=736 • safety population (patients receiving at least one dose of study therapy), n=730

  8. AVADO: patient characteristics(ITT population), % †mg/kg q3w; DFI = disease-free interval

  9. AVADO: progression-free survival(ITT population) Placebo +docetaxel (n=241) Bev 15† +docetaxel (n=247) Placebo +docetaxel (n=241) Bev 7.5† +docetaxel (n=248) HR + 95% CI (unstratified) HR + 95% CI (unstratified) 0.72 (0.57–0.90)p=0.0099 0.79 (0.63–0.98)p=0.0318 HR + 95% CI (stratified*) HR + 95% CI (stratified*) 0.61 (0.48–0.78)p<0.0001 0.69 (0.54–0.89)p=0.0035 8.0 8.8 8.0 8.7 Median Median PFS estimate PFS estimate 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 6 12 18 0 6 12 18 Months Months †mg/kg q3w; *Data censored for non-protocol therapy before PD

  10. AVADO: PFS subgroup analysis(ITT population) Favors bevacizumab Favors placebo 0.25 0.5 1 2 4 †mg/kg q3w

  11. AVADO: response(patients with measurable disease), % †mg/kg q3w

  12. AVADO: overall survival* (ITT population) Cut-off for final survival analysis 24 months after last patient recruited (April 2009) *Unstratified analysis; †mg/kg q3w; NR = not reached

  13. AVADO: safety summary †mg/kg q3w; *during study phase; ‡not mutually exclusive

  14. AVADO: selected key grade ≥3 adverse events,* % *With a ≥2% difference in incidence between study arms; †mg/kg q3w

  15. AVADO: grade ≥3 adverse events of special interest,* % *Protocol-defined; †mg/kg q3w; RPLS = reversible posterior leukoencephalopathy syndrome;ATE = arterial thromboembolic event; VTE = venous thromboembolic event

  16. AVADO: conclusions • Double-blind, placebo-controlled trial AVADO confirms the clinical benefit of combining first-line bevacizumab with taxane chemotherapy for patients with HER2-negative mBC • Both the 7.5 and 15mg/kg doses significantly increase PFS and response rate compared with placebo • Overall survival data are not yet mature • No new safety signals were detected and bevacizumab had limited impact on the toxicity profile of docetaxel 100mg/m2

  17. Acknowledgements • All patients participating • AVADO investigators and study personnel • The study sponsor, F. Hoffmann-La Roche

  18. BACK-UP SLIDES

  19. AVADO: progression-free survival (stratified analysis) Bev 7.5†+ docetaxel (n=248) Placebo + docetaxel (n=241) Bev 15†+ docetaxel (n=247) Placebo + docetaxel (n=241) HR + 95% CI* 0.69 (0.54–0.89)p=0.0035 HR + 95% CI* 0.61 (0.48–0.78)p<0.0001 8.0 8.7 8.0 8.8 Median Median PFS estimate PFS estimate 1.0 0.8 0.6 0.4 0.2 0 1.0 0.8 0.6 0.4 0.2 0 0 6 12 18 0 6 12 18 Months Months †mg/kg q3w; *Data censored for non-protocol therapy prior to PD (ITT population)

  20. AVADO: PFS subgroup analysis(ITT population) Favors bevacizumab Favors placebo 0.25 0.5 1 2 4 †mg/kg q3w

  21. AVADO: patients starting docetaxel at each cycle,* % Patients, % Placebo + docetaxel Bev 7.5† + docetaxel Bev 15† + docetaxel Cycle number *Safety population; †mg/kg q3w

  22. AVADO: patients starting bevacizumab/placebo at each cycle,* % Patients, % Placebo + docetaxel Bev 7.5† + docetaxel Bev 15† + docetaxel Cycle number *Safety population; †mg/kg q3w

  23. Phase III trial of bevacizumab + paclitaxel in first-line mBC (E2100) Primary endpoint: progression-free survival other endpoints: overall response rate, overall survival, quality of life Treat to disease progression* Paclitaxel (n=354) Previously untreated locally recurrent or mBC (n=722) *No cross over permitted Paclitaxel + bevacizumab 10mg/kg q2w (n=368) Treat to disease progression Paclitaxel: 90mg/m2/w for 3 weeks of a 4-week cycle Miller, et al. NEJM 2007

  24. E2100: significant progression-free survival increase confirmed by Independent Review Facility (IRF) PFS estimate 1.0 0.8 0.6 0.4 0.2 0 PFS byinvestigator PFS by IRF* Paclitaxel (n=354) Bev + paclitaxel (n=368) HR=0.42 HR=0.48 5.8 11.4 11.3 5.8 0 6 12 18 24 30 36 42 48 54 Month Cameron D. EJC Suppl. 2008; Avastin SmPC 2008 *Scans available for 90% of patients

  25. E2100: objective response(patients with measurable disease) Investigator assessment(n=525) Bestresponse (%) IRF assessment(n=472) 60 50 40 30 20 10 0 Bev + paclitaxel 50 Paclitaxel 48 23 22 CR + PRp<0.0001 CR + PRp<0.0001 Cameron D. EJC Suppl. 2008

  26. E2100: no new safety signals *Includes NCI AdEERS mandatory collection in the bevacizumab plus paclitaxel arm only which does not allow a valid comparison between the two arms†Events were double counted where applicable ‡Two additional patients died from myocardial infarction in the bevacizumab plus paclitaxel arm Miles D. EJC Suppl. 2008; Avastin SmPC 2008

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