Post on 05-Jan-2016
description
AVADO
David Miles
Mount Vernon Cancer Centre, Middlesex,United Kingdom
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
On behalf of the AVADO investigators
Disclosure
ASCO General COI
Yes, I have Consultant or Advisory Role to disclose
– Roche
Yes, I have Honoraria to disclose
– Roche
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
Docetaxel* 100mg/m2 + placebo q3w
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
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
All patientsgiven optionto receive
bevacizumabwith 2nd-line
chemotherapy
1st-line locally recurrentor mBC (n=705)
Stratification factors:• region• prior taxane/time to
relapse since adjuvant chemo
• measurable disease• hormone receptor
status
Treat withplacebo/
bevacizumabto disease
progression
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
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)
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
AVADO: patient characteristics(ITT population), %
Placebo +docetaxel(n=241)
Bev 7.5†
+ docetaxel(n=248)
Bev 15† + docetaxel
(n=247)
Median age, years (range)
55.0 (29–83)
54.0 (26–83)
55.0 (27–76)
ECOG PS 0/1 62/38 61/39 61/39
ER/PgR positive 78 78 76
DFI ≥12 months 82 75 81
Adjuvant chemotherapyTaxaneAnthracycline
651555
651553
681755
≥3 metastatic sites 41 49 49
SitesBoneLiverLung
595038
604042
554648
Measurable disease 86 81 83
†mg/kg q3w; DFI = disease-free interval
Bev 15† +docetaxel (n=247)
HR + 95% CI (unstratified)
Bev 7.5† +docetaxel (n=248)
1.0
0.8
0.6
0.4
0.2
0
Months
PFS estimate
0 6 12 18
1.0
0.8
0.6
0.4
0.2
0
Months0 6 12 18
AVADO: progression-free survival(ITT population)
†mg/kg q3w;
HR + 95% CI (stratified*) 0.69 (0.54–0.89)p=0.0035
0.79 (0.63–0.98)p=0.0318
Placebo +docetaxel (n=241)
Median 8.78.0
HR + 95% CI (stratified*) 0.61 (0.48–0.78)p<0.0001
Median 8.88.0
0.72 (0.57–0.90)p=0.0099
HR + 95% CI (unstratified)
Placebo +docetaxel (n=241)
PFS estimate
*Data censored for non-protocol therapy before PD
Bev 7.5†
Baseline risk factor n HR
All patients 489 0.79
ER/PgR combined
Negative
Positive
105
382
0.76
0.78
Prior adjuvant chemotherapy
Yes
No
318
171
0.67
1.04
Prior taxane therapy
Yes
No
73
416
0.59
0.84
Measurable disease at baseline Yes
No
408
81
0.76
1.14
0.25 0.5 1 2 4
Favors bevacizumab
Favors placebo
AVADO: PFS subgroup analysis(ITT population)
Bev 15†
n HR
488 0.72
111
376
0.60
0.73
323
165
0.65
0.85
77
411
0.42
0.77
413
75
0.70
0.89
†mg/kg q3w
AVADO: response(patients with measurable disease), %
Placebo + docetaxel
(n=207)
Bev 7.5† + docetaxel
(n=201)
Bev 15† + docetaxel
(n=206)
Overall response rate 44 55 63
p value (vs control) – 0.0295 0.0001
Best responseCR
PR
SD
PD
1
44
39
12
3
52
35
5
1
62
25
4
†mg/kg q3w
AVADO: overall survival* (ITT population)
Placebo + docetaxel
(n=241)
Bev 7.5† + docetaxel
(n=248)
Bev 15† + docetaxel
(n=247)
Deaths, n (%) 50 (21) 49 (20) 37 (15)
Median overall survival, months
Hazard ratio
(95% CI)
NR
–
NR
0.92
(0.62–1.37)
NR
0.68
(0.45–1.04)
1-year survival, %
Patients still at risk, n
73
63
78
73
83
79
*Unstratified analysis; †mg/kg q3w; NR = not reached
Cut-off for final survival analysis 24 months after last patient recruited (April 2009)
AVADO: safety summary
%
Placebo + docetaxel
(n=233)
Bev 7.5† + docetaxel
(n=250)
Bev 15† + docetaxel
(n=247)
Any AE 99.6 100.0 99.6
Any grade ≥3 AE 67.0 74.8 74.1
AEs leading to death* 2.6 1.6 1.6
AEs leading to discontinuation‡ ofDocetaxelBevacizumab or placebo
24.011.2
20.8 8.0
24.311.7
†mg/kg q3w; *during study phase; ‡not mutually exclusive
AVADO: selected key grade ≥3 adverse events,* %
Adverse event, %Placebo +
docetaxel (n=233) Bev 7.5† +
docetaxel (n=250)Bev 15† +
docetaxel (n=247)
Diarrhea 3.4 6.8 6.9
Fatigue 5.2 8.4 6.5
Palmar-plantar erythema 0.9 5.2 6.1
Mucosal inflammation 0.4 4.0 4.9
Peripheral sensory
neuropathy 1.7 3.2 4.5
Stomatitis 0.4 2.8 3.2
Myalgia 0.9 1.2 3.6
Skin exfoliation 0 2.4 1.2
Anemia 2.6 0.4 1.2
Infection 3.0 0.8 0.4
*With a ≥2% difference in incidence between study arms; †mg/kg q3w
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
Adverse event, %Placebo +
docetaxel (n=233)Bev 7.5† +
docetaxel (n=250)Bev 15† +
docetaxel (n=247)
All 31.3 35.2 36.4
Neutropenia 17.2 19.2 19.8
Febrile neutropenia 12.0 15.2 16.6
VTE 3.4 1.2 1.2
Hypertension 1.3 0.4 3.2
Bleeding 0.9 1.2 1.2
Wound-healing complication 0.9 0.4 0.4
GI perforation 0.9 0.4 0.4
CHF 0 0.8 0
ATE 0.4 0 0
Proteinuria 0 0 0.4
RPLS 0 0 0
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
Acknowledgements
All patients participating
AVADO investigators and study personnel
The study sponsor, F. Hoffmann-La Roche
1.0
0.8
0.6
0.4
0.2
00 6 12 18
Months
AVADO: progression-free survival (stratified analysis)
1.0
0.8
0.6
0.4
0.2
00 6 12 18
Months
Median 8.88.0Median 8.78.0
HR + 95% CI* 0.61 (0.48–0.78)p<0.0001
Bev 15† + docetaxel
(n=247)
Placebo + docetaxel
(n=241)
†mg/kg q3w; *Data censored for non-protocol therapy prior to PD (ITT population)
HR + 95% CI* 0.69 (0.54–0.89)p=0.0035
Bev 7.5† + docetaxel
(n=248)
Placebo + docetaxel
(n=241)
PFS estimate PFS estimate
Bev 7.5†
Baseline risk factor n HR
All patients 489 0.79
Age
<65 years
≥65 years
410
79
0.81
0.62
Disease-free interval
≤24 months
>24 months
188
301
0.70
0.83
Number of metastatic sites
<3
≥3
264
221
0.73
0.79
0.25 0.5 1 2 4
Favors bevacizumab
Favors placebo
AVADO: PFS subgroup analysis(ITT population)
Bev 15†
n HR
488 0.72
402
86
0.73
0.62
161
327
0.62
0.79
263
221
0.77
0.65
†mg/kg q3w
AVADO: patients starting docetaxel at each cycle,* %
0
20
40
60
80
100
1–3 4–6 7–9Cycle number
Placebo + docetaxelBev 7.5† + docetaxelBev 15† + docetaxel
Patients, %
*Safety population; †mg/kg q3w
AVADO: patients starting bevacizumab/placebo at each cycle,* %
0
20
40
60
80
100
1–3 4–6 7–9 10–14 15–18 10+
Patients, %
Cycle number*Safety population; †mg/kg q3w
Placebo + docetaxelBev 7.5† + docetaxelBev 15† + docetaxel
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
Paclitaxel(n=354)
Paclitaxel + bevacizumab10mg/kg q2w
(n=368)
Treat to disease progression*
Treat to disease progression
*No cross over permitted
Paclitaxel:90mg/m2/w for 3 weeks of a 4-week cycle
Miller, et al. NEJM 2007
Previously untreated locally recurrent or mBC
(n=722)
E2100: significant progression-free survival increase
*Scans available for 90% of patients Cameron D. EJC Suppl. 2008; Avastin SmPC 2008
11.4
HR=0.48
Paclitaxel (n=354)
Bev + paclitaxel (n=368)
PFS byinvestigator
5.811.3
HR=0.42
PFS by IRF*
5.8
0 6 12 18 24 30 36 42 48 54Month
PFS estimate1.0
0.8
0.6
0.4
0.2
0
confirmed by Independent Review Facility (IRF)
E2100: objective response(patients with measurable disease)
Cameron D. EJC Suppl. 2008
Bestresponse (%)
Investigator assessment
(n=525)
IRF assessment(n=472)
50
2223
48 Paclitaxel
Bev + paclitaxel
CR + PRp<0.0001
CR + PRp<0.0001
60
50
40
30
20
10
0
E2100: no new safety signals
Miles D. EJC Suppl. 2008; Avastin SmPC 2008
Selected grade 3/4 adverse events,* %
Paclitaxel(n=348)
Bev + paclitaxel (n=363)
Grade 3 Grade 4 Grade 3 Grade 4
Sensory neuropathy 17.0 0.6 23.7 0.6
Fatigue 4.9 0.3 10.5 0.2
Infection + grade 3/4 neutropenia 1.1 0.3 2.8 0
Hypertension 1.4 0 15.4 0.6
Arterial thromboembolic events† ‡ 0 0 1.1 1.9
Venous thromboembolic events 2.3 2.0 2.8 0.3
Bleeding 0.3 0 1.7 0.6
Proteinuria 0 0 1.9 1.1
Left ventricular dysfunction† 0 0 1.9 0.3*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