AVADO

1
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

• 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 2007357266676
4
AVADO double-blind, placebo-controlled trial
All patientsgiven optionto receive
bevacizumabwith 2nd-linechemotherapy
Treat withplacebo/bevacizumabto
diseaseprogression
Docetaxel 100mg/m2 placebo q3w

• 1st-line locally recurrent
• or mBC (n705)
• 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

• Primary endpoint progression-free survival
• Secondary endpoints overall response rate,
  duration of response, time to treatment failure,
  overall survival, safety, quality of life

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 01
• 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 017.5)
• Analysis
• intent-to-treat population (all randomized
  patients), n736
• safety population (patients receiving at least
  one dose of study therapy), n730

8
AVADO patient characteristics(ITT population),
mg/kg q3w DFI disease-free interval
9
AVADO progression-free survival(ITT population)
Bev 15 docetaxel (n247)
Bev 7.5 docetaxel (n248)
Placebo docetaxel (n241)
Placebo docetaxel (n241)
HR 95 CI (unstratified)
HR 95 CI (unstratified)
0.72 (0.570.90)p0.0099
0.79 (0.630.98)p0.0318
HR 95 CI (stratified)
HR 95 CI (stratified)
0.69 (0.540.89)p0.0035
0.61 (0.480.78)plt0.0001
8.8
8.0
8.7
8.0
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 syndromeATE
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 (n248)
Bev 15 docetaxel (n247)
Placebo docetaxel (n241)
Placebo docetaxel (n241)
HR 95 CI
0.61 (0.480.78)plt0.0001
HR 95 CI
0.69 (0.540.89)p0.0035
8.8
8.0
8.7
8.0
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)
Paclitaxel (n354)
Treat to disease progression
Previously untreated locally recurrent or
mBC (n722)
No cross over permitted
Paclitaxel bevacizumab 10mg/kg q2w (n368)
Treat to disease progression
Paclitaxel 90mg/m2/w for 3 weeks of a 4-week
cycle

• Primary endpoint progression-free survival
• other endpoints overall response rate, overall
  survival, quality of life

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 (n354) Bev paclitaxel (n368)
HR0.48
HR0.42
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(n525)
Bestresponse ()
IRF assessment(n472)
60 50 40 30 20 10 0
Bev paclitaxel
50
Paclitaxel
48
23
22
CR PRplt0.0001
CR PRplt0.0001
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
armsEvents 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