bevacizumab bei mbc. avastin - fachkurzinformation avastin® 25 mg/ml konzentrat zur herstellung...
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Bevacizumab bei mBC
Avastin - FachkurzinformationAvastin® 25 mg/ml Konzentrat zur Herstellung einer Infusionslösung.
Qualitative und quantitative Zusammensetzung: Jeder Milliliter enthält 25 mg Bevacizumab. Jede Durchstechflasche enthält 100 mg Bevacizumab in 4 ml bzw. 400 mg in 16 ml, entsprechend 1,4 bis 16,5 mg/ml bei Verdünnung gemäß Empfehlung. Bevacizumab ist ein rekombinanter humanisierter monoklonaler Antikörper, der mittels DNA-Technologie aus Ovarialzellen des chinesischen Hamsters (CHO-Zellen) gewonnen wird.
Anwendungsgebiete: Avastin (Bevacizumab) wird in Kombination mit einer Chemotherapie auf Fluoropyrimidin-Basis zur Behandlung von Patienten mit metastasiertem Kolon- oder Rektumkarzinom angewendet.
Avastin wird in Kombination mit Paclitaxel zur First-Line-Behandlung von Patienten mit metastasiertem Mammakarzinom angewendet. Zu weiteren Informationen wie auch zum HER2-Status siehe veröffentlichte Fachinformation Abschnitt 5.1 „Pharmakodynamische Eigenschaften“.
Avastin wird zusätzlich zu einer Platin-haltigen Chemotherapie zur First-Line-Behandlung von Patienten mit inoperablem fortgeschrittenem, metastasiertem oder rezidivierendem nicht kleinzelligem Bronchialkarzinom, außer bei vorwiegender Plattenepithel-Histologie, angewendet.
Avastin wird in Kombination mit Interferon alfa-2a zur First-Line-Behandlung von Patienten mit fortgeschrittenem und/oder metastasiertem Nierenzellkarzinom angewendet.
Gegenanzeigen: - Überempfindlichkeit gegen den arzneilich wirksamen Bestandteil oder einen der sonstigen Bestandteile. - Überempfindlichkeit gegen CHO-Zellprodukte oder andere rekombinante humane oder humanisierte Antikörper. - Schwangerschaft (siehe veröffentlichte Fachinformation Abschnitt 4.6 „Fertilität, Schwangerschaft und Stillzeit“).
Liste der sonstigen Bestandteile: α,α-Trehalose 2 H2O, Natriumphosphat, Polysorbat 20, Wasser für Injektionszwecke.
Inhaber der Zulassung: Roche Registration Limited, 6 Falcon Way, Shire Park, Welwyn Garden City, AL7 1TW, Vereinigtes Königreich.
Verschreibungspflicht/Apothekenpflicht: rezept- und apothekenpflichtig, wiederholte Abgabe verboten.
Pharmakotherapeutische Gruppe: Monoklonale Antikörper; ATC-Code: L01X C07.
Besondere Warnhinweise und Vorsichtsmaßnahmen für die Anwendung, Wechselwirkungen mit anderen Arzneimitteln und sonstige Wechselwirkungen sowie Informationen zu Schwangerschaft und Stillzeit und zu Nebenwirkungen sind der veröffentlichten Fachinformation zu entnehmen.
3 positive Phase III Studien: konsistenter Benefit von First-Line Bevacizumab in mBC
•E21001,2
: open-label phase III trial
– Combining Avastin with weekly paclitaxel doubled PFS and ORR in patients with mBC, leading to its regulatory approval in this setting
•AVADO3,4
: double-blind, placebo-controlled, phase III trial
•RIBBON-15: double-blind, placebo-controlled, phase III trial
– Combining Avastin with standard chemotherapy (taxane, anthracycline-based combination or Xeloda) significantly improved PFS and ORR
– The benefit of Avastin extends to a wide range of chemotherapy options in the first-line setting
1Miller et al. NEJM 2007; 2Gray et al. JCO 2009; 3Miles et al. ASCO 2008; 4Avastin SmPC 2009; 5Robert et al. ASCO 2009
A randomised phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer
KD Miller, M Wang, J Gralow, M Dickler, MA Cobleigh, EA Perez,TN Shenkier, NE Davidson
Indiana University Cancer Center, Dana Farber Cancer Institute, Pudget Sound Oncology Consortium, Memorial Sloan Kettering Cancer Center, Rush-Presbyterian-St. Luke’s Medical Center, Mayo Clinic, British Columbia Cancer Agency, Vancouver Cancer Center, Johns Hopkins Oncology Center
E2100
E2100: Phase III Avastin + Paclitaxel
•Primary endpoint: PFS
– Other endpoints: ORR, OS, quality of life, safety
Previouslyuntreated LR/mBC
N=722
Stratification factors:• Disease-free interval• No. of metastatic sites• Adjuvant chemotherapy
(yes vs no)• ER status
Paclitaxela
Paclitaxela + Avastin10 mg/kg q2w
Treat to disease progression*
Treat to disease progression
*No crossover permitted
a90 mg/m2 weekly for 3 weeks of a 4-week cycleMiller et al. NEJM 2007
Phase III Avastin + Paclitaxel (E2100) Einschlusskriterien
– Lokal rezidivierendes oder metastasiertes Mammakarzinom
• HER2+ nur nach vorheriger Behandlung mit Herceptin (Trastuzumab) oder Kontraindikation
– Keine vorangegangene Chemotherapie in der Indikation MBC
• adjuvant Taxane erlaubt bei einem disease-free interval >12 Monate
– ECOG PS 0 oder 1
– Keine Antitumor-Therapie innerhalb von 21 Tagen
– Keine ZNS-Metastasen (CT oder MRI erforderlich)
– Keine signifikante Proteinurie (>500mg/24 h)
– Keine therapeutische Antikoagulation
HER = human epidermal growth factor receptor CT = computed tomographyMRI = magnetic resonance imaging
Miller KD, et al. Breast Cancer Res Treat 2005;94:S6(Abstract 3)
Paclitaxel(n=354)
Avastin + paclitaxel(n=368)
Median age, years (range) 55 (27–85) 56 (29–84)
ER positive, % 63 61
PgR positive, % 45 45
HER2 positive, % 1.7 2.4
Disease-free interval, % ≤24 months>24 months
4159
41
59
Number of metastatic sites, %<3≥3
52
48
57
43
Prior taxane therapy, % 19 20
Prior anthracycline therapy, % 51 50
Gray et al. JCO 2009
E2100: Baseline Characteristics
11.4
0 6 12 18 24 30 36
PF
S e
stim
ate
HR=0.483
p<0.0001
Paclitaxel (n=354)
Avastin + paclitaxel (n=368)
PFS by investigator
5.811.3
HR=0.421
p<0.0001
PFS by IRFa
5.8
Months
1.0
0.8
0.6
0.4
0.2
0.0
aScans available for 90% of patients
E2100: PFS (confirmed by Independent Review)
Gray et al. JCO 2009
Publikation Fachinfo
Herceptin + chemotherapy
E2100: Avastin + paclitaxel in context
DocetaxelChan 1999
DoxorubicinChan 1999
PaclitaxelSeidman 2004
Vinorelbine Muñoz 2006
Doxorubicin + paclitaxelJassem 2001
Xeloda + docetaxelO’Shaughnessy 2002
Gemcitabine + paclitaxelAlbain 2004
FECZielinski 2005
Epirubicin + docetaxelPacilio 2006
Avastin + paclitaxelE2100 2007
PaclitaxelE2100 2007
Time (months)
Monotherapy
Combinationchemotherapy
Median PFS / TTP
0 2 4 6 8 10 12 14
Avastin + chemotherapy(E2100)
9 months
Herceptin + docetaxelMarty 2005
5.8
11.7
9.0
9.0
5.2
6.1
8.3
4.1
6.0
5.3
6.5
11.4
DocetaxelMarty 2005
6.1
Baseline risk factor Total nHazard ratio (95% CI)
Number of metastatic sites <3 ≥3
514208
0.530.56
(0.41–0.69)(0.38–0.81)
Disease-free interval (months) ≤24 months >24 months
296426
0.580.50
(0.42–0.79)(0.38–0.67)
ER status Positive Negative
446265
0.590.44
(0.44–0.78)(0.31–0.61)
ER/PR/HER2 combined Negative All others
232490
0.490.57
(0.34–0.70)(0.44–0.75)
Prior adjuvant chemotherapy Yes No
475247
0.470.70
(0.36–0.61)(0.49–1.01)
Prior taxane therapy Yes No
142580
0.330.60
(0.20–0.54)(0.47–0.76)
Prior anthracycline therapy Yes No
364358
0.460.64
(0.34–0.62)(0.47–0.86)
Avastin + paclitaxel better
Paclitaxelbetter
0.2 0.5 1 2 5
*IRF assessmentGray et al. JCO 2009
0.2 0.5 1 2 5
10
E2100: PFS-Benefit in allen Subgruppena
Pat
ient
s, %
22%
50%
Investigator assessment
IRF assessment
aPatients with measurable disease at baselineKlencke et al. ASCO 2008 11
Pat
ient
s, %
23%
Paclitaxel Avastin + paclitaxel
48%
p<0.0001
Paclitaxel Avastin + paclitaxel
p<0.0001
E2100: Response Ratea
0.8
0.6
0.4
0.2
0.0
1.0
543630 6048420 18 24126
0.8
0.6
0.4
0.2
543630 60484218 24126
*Post-hoc
HR=0.869 (95% CI 0.722–1.046)
Log-rank p=0.1374
Avastin + paclitaxel (n=368): median 26.5 months
Paclitaxel (n=354): median 24.8 months
OS
est
imat
e
Months
Avastin SmPC 2009; Cameron EJC Suppl 2008; Roche data on file 2007 12
E2100: Overall Survival
p=0.017*
74.0%
81.4%
. . . but OS is not statistically significant
• Subsequent therapies may dilute any benefit obtained in the 1st-line setting
– patients typically receive multiple therapies for mBC
• Post-trial use of experimental compound in control arm patients might mask an overall survival benefit
• In E2100
– data on subsequent therapies after first progression were not collected
– Avastin was commercially available in the USA at the time the results were presented (ASCO 2005)
K.Miller, Bevacizumab Investigator Meeting, Chicago
Selected grade 3/4 adverse eventsa, %
Paclitaxel (n=348)
Avastin + 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 0.3
Infection with grade 3/4 neutropenia 1.1 0.3 2.8 0
Hypertension 1.4 0 15.4 0.6
Arterial thromboembolic events†b 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†c 0 0 1.9 0.3aIncludes NCI AdEERS mandatory collection in the Avastin + paclitaxel arm only, which does not allow a valid comparison between the two armsbTwo additional patients died from myocardial infarction in the Avastin + paclitaxel armcOne additional patient died in the paclitaxel arm
Roche data on file 2007; Miles EJC Suppl 2008 14
E2100: Safety
E2100: Conclusio
• Avastin 1st line in Kombination mit Paclitaxel:
– Verdoppelung des progressionsfreien Überlebens (11,3 vs. 5,8 Monate)
– Verdoppelung der Ansprechrate (50% vs. 22%)
– Ausgezeichnete Verträglichkeit
– 1 year survival signifikant verlängert (81,2 vs. 73,4%), median OS nicht. (Primärer Studienendpunkt war PFS!)
• Xeloda (1000 mg/m2 bid d1–14)
• Taxane (docetaxel 75–100 mg/m2 or nab-paclitaxel 260 mg/m2 q3w)
• Anthracycline-based chemotherapy • AC (doxorubicin 50–60 mg/m2, cyclophosphamide 500–600 mg/m2)
• EC (epirubicin 90–100 mg/m2, cyclophosphamide 500–600 mg/m2)
• FAC (5-FU 500 mg/m2, doxorubicin 50 mg/m2, cyclophosphamide 500 mg/m2)
• FEC (5-FU 500 mg/m2, epirubicin 90–100 mg/m2, cyclophosphamide 500 mg/m2)
• Avastin or placebo (15 mg/kg q3w)
Investigator’s choice of
chemotherapy
Xeloda or taxane/
anthracycline
Treat to disease
progression
RA
ND
OM
ISE
2:1
Xeloda + Avastin
Xeloda + placebo
Taxane/anthra + Avastin
Taxane/anthra + placebo
Robert et al. ASCO 2009
RIBBON-1: Studiendesign
Previously untreated LR/mBCN=1237
Stratification factors:
• Disease-freeinterval
• Previous adjuvant chemotherapy
• No. of metastatic sites
• Xeloda, taxane or anthracycline
RIBBON-1: Studien-Endpunkte
•Primary endpoint:– PFS (investigator assessed)
•Secondary endpoints:– Overall survival and 1-year overall survival rate
– ORR
– PFS (assessed by Independent Review Committee)
– Safety (NCI CTCAE v3.0; incidence of selected AEs*, serious AEs, AEs leading to treatment discontinuation and clinical cardiotoxicity)
*Any grade GI perforation, RPLSGrade ≥2 arterial thromboembolic events, left ventricular systolic dysfunctionGrade ≥3 venous thromboembolic events, hypertension, bleeding, proteinuria, sensory neuropathy, wound dehiscence, neutropenia, febrile neutropenia
Robert et al. ASCO 2009
RIBBON-1: Statistical Design
– Two independently powered cohorts
– Statistical and sample size assumptions:
Hazard ratio
Median PFS (months) Power Sample size
Xeloda 0.75 6 8 80% 600
Taxane + anthracycline
0.70 7 10 90% 300/300
Robert et al. ASCO 2009
RIBBON-1: Baseline Characteristics
Xeloda Taxane Anthracycline
Placebo(n=206)
Avastin (n=409)
Placebo(n=104)
Avastin(n=203)
Placebo(n=103)
Avastin (n=212)
Mean age, years 57 57 55 57 54 54
(range) (23–88) (28–91) (29–85) (32–88) (34–78) (28–81)
≥65 years, % 26 24 19 26 13 18
ECOG PS 0, % 53 53 57 58 50 47
HR positive, % 74 77 80 74 74 79
Triple negative, % 25 22 19 26 25 20
DFI ≤12 months, % 22 27 24 22 57 52
Adjuvant chemotherapy, % 76 70 71 69 22 22
Taxane 41 39 30 30 0 1
Anthracycline 69 60 61 60 0 1
≥3 metastatic sites, % 45 43 45 47 45 43
Measurable disease, % 79 80 82 79 89 87
DFI = disease-free intervalRobert et al. ASCO 2009; Roche data on file 2009
Robert et al. ASCO 2009
5.78.6
aStratified analysis
PF
S e
stim
ate
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30
Months
IRC assessment
Median, months 6.2 9.8
HR (95% CI) 0.68 (0.54–0.86)
p=0.0011
Investigator assessment
Median, months 5.7 8.6
HR (95% CI) 0.69 (0.56–0.84)
p=0.0002
Placebo + Xeloda
(n=206)
Avastin + Xeloda
(n=409)
RIBBON-1: PFSa Avastin + Xeloda
Baseline risk factor n
Median, months
HRFavours Avastin
+ Xeloda
Favours placebo +
XelodaAvastin +
XelodaPlacebo +
XelodaAge, years <65
≥65462153
8.69.1
4.76.2
0.670.69
Disease-free interval, months
≤12>12
154461
8.38.7
6.94.4
0.810.63
Metastatic sites, n <3 ≥3
345270
10.26.6
6.44.2
0.630.74
Prior adjuvant chemotherapy
YesNo
444171
8.39.2
4.46.7
0.640.80
Prior taxane therapy YesNo
245370
8.78.3
4.26.1
0.620.72
Visceral disease YesNo
423192
8.110.6
4.46.2
0.720.58
Hormone receptor status
PositiveNegative
458143
9.26.1
6.24.2
0.690.70
Triple negative YesNoUnknown
137462 16
6.19.2
12.4
4.26.13.9
0.720.680.35
5210.50.2
Unstratified analyses
Dieras et al. ECCO-ESMO 2009; Roche data on file 2009
RIBBON-1: PFS Subgruppen (Xeloda Kohorte)
RIBBON-1: ORR (Avastin + Xelodaa)
Placebo + Xeloda (n=161)
Avastin + Xeloda (n=325)
Patients, %
p=0.0097
aPatients with measurable disease at baseline
23.6
35.4
Robert et al. ASCO 2009
OR
R,
%
Number at risk:Avastin 409 398 386 374 357 328 265 192 135 87 59 27 14 6 2 1 0Placebo 206 198 188 178 165 148 124 95 60 44 28 10 5 2 0 0 0
Placebo + Xeloda(n=206)
Avastin + Xeloda(n=409)
Events, n (%) 72 (35.0) 122 (29.8)
Median, months 21.2 29.0HR (95% CI) 0.85 (0.63–1.14)
p=0.27
1-year rate, % 74 81
p=0.076
Pro
por
tion
aliv
e
1.0
0.8
0.6
0.4
0.2
00 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32
Months
Robert et al. ASCO 2009; Roche data on file 2009
Avastin at progression, % 69 52
RIBBON-1: Overall Survival (Xeloda Kohorte)
PF
S e
stim
ate
1.0
0.8
0.6
0.4
0.2
00 6 12 18 24 30
8.09.2
Months
aStratified analysis
Robert et al. ASCO 2009
IRC assessment
Median, months 8.3 10.7
HR (95% CI) 0.77 (0.60–0.99)
p=0.040
Placebo + tax/anthra(n=207)
Avastin + tax/anthra(n=415)
Investigator assessment
Median, months 8.0 9.2
HR (95% CI) 0.64 (0.52–0.80)
p<0.0001
RIBBON-1: PFSa (Avastin + Taxane/Anthrazykline)
RIBBON-1: PFS Subgruppen (Taxane/Anthrazykline)
Baseline risk factor n
Median, months
HRFavours Avastin +
tax/anthraFavours placebo
+ tax/anthraAvastin + tax/anthra
Placebo + tax/anthra
Age, years <65≥65
498124
9.110.1
7.98.5
0.630.83
Disease-free interval, months
≤12>12
239383
8.69.6
6.48.2
0.620.69
Metastatic sites, n <3 ≥3
341281
10.38.5
8.56.8
0.650.64
Prior adjuvant chemotherapy
YesNo
283339
9.29.2
7.98.0
0.670.64
Prior taxane therapy YesNo
94528
9.19.2
6.78.2
0.650.66
Visceral disease YesNo
438184
8.610.8
6.98.7
0.680.63
Hormone receptor status PositiveNegative
459142
10.36.5
8.26.2
0.610.78
Triple negative YesNoUnknown
142459 21
6.510.312.1
6.28.26.7
0.780.610.52
5210.50.2
Unstratified analyses
Dieras et al. ECCO-ESMO 2009; Roche data on file 2009
RIBBON-1: ORR (Avastin + Taxane/Anthrazyklinea)
p=0.0054
aPatients with measurable disease at baseline
37.9
51.3
Robert et al. ASCO 2009
OR
R,
%
Placebo + tax/anthra (n=177)
Avastin + tax/anthra (n=345)
Number at risk:Avastin 415 404 392 380 356 328 317 291 232 169 109 54 31 12 8 1 0Placebo 207 201 197 192 185 176 165 148 127 88 56 25 16 8 5 1 0
Pro
por
tion
aliv
e
1.0
0.8
0.6
0.4
0.2
0
Robert et al. ASCO 2009; Roche data on file 2009
RIBBON-1: Overall Survival (Taxane/Anthrazykline)
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32Months
Placebo + tax/anthra(n=207)
Avastin + tax/anthra(n=415)
Events, n (%) 73 (35.3) 141 (34.0)
Median, months 23.8 25.2
HR (95% CI) 1.03 (0.77–1.38)
p=0.83
1-year rate, % 81 83
p=0.44
Avastin at progression, % 55 50
Xeloda Taxane Anthracycline
Selected grade ≥3 AEs, %Placebo (n=201)
Avastina
(n=404)Placebo (n=102)
Avastina (n=203)
Placebo (n=100)
Avastina (n=210)
Bleeding 0.5 0.2 0 5.4 0 0
Febrile neutropenia 0 0 2.0 7.9 5.0 3.8
GI perforation 0 0 1.0 2.0 0 0
Hypertension 1.0 9.4 2.0 8.9 0 10.0
LV systolic dysfunction 0.5 1.0 0 2.0 0 2.9b
Neutropenia 1.0 1.2 4.9 9.4 4.0 4.3
Proteinuria 0 2.2 0 3.4 0 1.9
Sensory neuropathy 0.5 3.0 8.8 8.4 0 0.5
Venous thromboembolism 3.5 4.8 4.9 2.0 1.0 2.9
AE leading to deathc 2.5 1.5 3.0 2.5 3.0 1.4
RIBBON-1: Safety
a15 mg/kg q3w; bGrade 3 or 4 events: clinical CHF (grade 3=1, grade 4=1); non-specific symptoms (n=1); measurement error (n=2); progressive disease (n=1); LV = left ventricularRobert et al. ASCO 2009
cExcluding AEs related to mBC progression
RIBBON-1: Conclusio
• RIBBON-1 ist die dritte positive Phase III Studie zu first-line Avastin plus Standard-Chemotherapie:
– Avastin plus Taxane, incl. nab-Paclitaxel
– Avastin plus nicht-taxanhältige Chemotherapie, incl. Xeloda oder Anthrazykline
• In allen drei Studien (E2100, AVADO und RIBBON-1), konnte Avastin das PFS und die ORR mit allen Chemotherapieregimen signifikant erhöhen
• Das Nebenwirkungsprofil war mit dem früherer Phase III-Studien konsistent (insbes. keine kardiale Toxizität von Avastin in Kombination mit Anthrazyklinen)
Avastin: Essentielle Komponente der First-LineTherapie des LR/mBC
•In drei Phase III Studien im first-line Setting wurde, unabhängig vom Chemotherapie-Partner:
– Der primäre Endpunkt (signifikante Verlängerung des PFS durch Avastin + Chemotherapie gegenüber Chemotherapie alleine) erreicht1–3
– Die Ansprechraten signifikant erhöht
– Ein konsistenter Benefit aller Patientenssubgruppen demonstriert
– Gute Verträglichkeit mit geringen Auswirkungen auf das Safety-Profil der Chemotherapie gezeigt
1Miller et al. NEJM 2007; 2Miles et al. ASCO 2008; 3Robert et al. ASCO 2009
•ZUSAMMENFASSUNG
•LEVEL 1-Evidenz in MBC
•(3 positive Phase III Studien)
Drei positive randomisierte Phase III Studien:Konsistenter Benefit von First-Line Avastin in mBC•E21001,2: open-label Phase III Studie
– Avastin + Paclitaxel verdoppelte PFS und ORR in mBC-Patientinnen, was zur Zulassung in diesem Setting führte
•AVADO3,4: doppelblinde, Plazebo-kontrollierte, Phase III Studie
•RIBBON-15: doppelblinde, Plazebo-kontrollierte, Phase III Studie
– Avastin + Standard-Chemotherapie (Taxane, Anthrazyklin-basierte Kombination oder Xeloda) mit signifikanter Verbesserung von PFS und ORR
– Der Benefit durch Avastin wird um viele Chemotherapie-Schemata im first-line Setting erweitert.
1Miller et al. NEJM 2007; 2Gray et al. JCO 2009; 3Miles et al. ASCO 2008; 4Avastin SmPC 2009; 5Robert et al. ASCO 2009
RIBBON-12
E21001 Xeloda Taxane/ anthracycline
Placebo controlled No Yes
ChemotherapyWeekly
paclitaxelXeloda
3-weekly docetaxel/nab-paclitaxel or
AC/FAC/EC/FEC
Avastin dose 10 mg/kg
q2w15 mg/kg q3w
Primary endpoint PFS (inv) PFS (inv)
IRF reviewRetrospectiv
eProspective
1Miller et al. NEJM 2007; 2Robert et al. ASCO 2009
Positive Phase III Studien: Designs
RIBBON-12
E21001 XelodaTaxane/
anthracycline
N 673 615 622
ER and PgR negative
35% 24% 24%
≥3 metastatic sites
45% 44% 45%
Measurable disease
73% 80% 84%
Adjuvant chemotherapy
65% 72% 45%
Adjuvant taxane
16% 40% 15%
ER = oestrogen receptor; PgR = progesterone receptor1Miller et al. NEJM 2007; 2Robert et al. ASCO 2009
Positive Phase III Studien: Patientenpopulationen
RIBBON-14
E21001,2a XelodaTaxane/
anthracycline
Pacl Avastin + pacl
Placebo + Xeloda
Avastin + Xeloda
Placebo + t/a
Avastin + t/a
ORR, % 22 50 24 35 38 51
p<0.0001 p=0.0097 p=0.0054
Median PFS, months
5.8 11.3 5.7 8.6 8.0 9.2
HR 0.48
p<0.0001
0.69
p=0.0002
0.64
p<0.0001
aIRF assessment; bPFS censored for non-protocol therapy before disease progression; c15 mg/kg q3w; dExploratory p value
1Klencke et al. ASCO 2008; 2Gray et al. JCO 2009; 3Avastin SmPC 2009; 4Robert et al. ASCO 2009
Positive Phase III Studien: PFS und ORR
RIBBON-14
E21001 XelodaTaxane/
anthracycline
Pacl Avastin pacl
Placebo + Xeloda
Avastin + Xeloda
Placebo + t/a
Avastin + t/a
Median OS, months
24.8 26.5 21.2 29.0 23.8 25.2
HR 0.87
p=0.14
0.85
p=0.27
1.03
p=0.83
1-year OS rate, %b
74 81 74 81 83 81
p=0.017 p=0.076 p=0.44
a15 mg/kg q3w; bExploratory p value1Cameron EJC Suppl 2008; 2Avastin SmPC 2009; 3Roche data on file 2009; 4Robert et al. ASCO 2009
Positive Phase III Studien: OS (sek. Endpunkt)
RIBBON-12b
E21001,2a Xeloda Taxane/ anthracycline
HR
Median, months
HR
Median, months
HR
Median, months
PacAvastin+ pac
Pla + Xeloda
Avastin + Xeloda
Pla + t/a
Avastin + t/a
Overalln=722 n=615 n=622
0.54 5.8 11.3 0.67 5.7 8.6 0.66 8.0 9.2
Age ≥65 years
n=167 n=153 n=124
0.69 7.4 10.4 0.69 6.2 9.1 0.83 8.5 10.1
Triple negative
n=232 n=137 n=142
0.49 5.3 10.6 0.72 4.2 6.1 0.78 6.2 6.5
Adjuvant taxane
n=142 n=245 n=94
0.33 5.8 13.1 0.62 4.2 8.7 0.65 6.7 9.1
aUnstratified analyses; bStratified analyses1Cameron EJC Suppl 2008; 2Roche data on file 2009 37
Drei positive Phase III Studien: PFS-Subgruppen
Bevacizumab in combination with chemotherapy- data from the general oncology practice (ATHENA)
Avastin plus taxane-based chemotherapy safety study (ATHENA, MO19391): study design
• Primary endpoint: safety
– secondary endpoints: TTP, OS, safety in patients with CNS metastases
Previously untreated HER2-negative LR or
mBC (n=2,027)
Avastin (10mg/kg q2w or 15mg/kg q3w)
+taxane-based
chemotherapy*
Treat to disease progression
*Taxane use according to routine practice or, if taxanes contraindicated, alternative chemotherapy allowed at physician’s discretion Anthracyclines were not permittedSmith, et al. SABCS 2008
Avastin plus taxane-based chemotherapy safety study (ATHENA): eligibility
• Inclusion criteria
– age 18 years
– histologically/cytologically confirmed, HER2-negative, LR or mBC
– ECOG PS 0–2
• Exclusion criteria
– previous chemotherapy for LR or mBC
– concomitant hormonal therapy for LR or mBC
– increased risk of haemorrhage
– non-healing wound, active peptic ulcer or bone fracture
– uncontrolled hypertension
– history of fistula
– major surgery within 28 days prior to initiation of study therapy
Smith, et al. SABCS 2008
Athena: chemotherapy regimens
Smith, et al. SABCS 2008
*Paclitaxel + Xeloda, Gemcitabine, Carboplatin, Doxorubicin, Epirubicin, Vinorelbine
**Docetaxel + Xeloda, Gemcitabine, Carboplatin, 5-FU, Cisplatin, Doxorubicin, Cyclophosphamid, Epirubicin, Vinorelbine
MO19391 (Athena): Efficacy
Smith, et al. SABCS 2008
median TTP = 9.5 Monate
ATHENA (MO19391): Conclusio
Avastin Summary of Product Characteristics (SmPC); 2. Miller, et al. NEJM 2007; 3. Miles, et al. ASCO 2008;
Smith, et al. SABCS 2008
– Mit >2000 Pat ist ATHENA die größte Studie mit Avastin + Chemo in 1st line lr/mBC
– 75% der Patienten erhielten eine taxan-basierte Chemotherapie mit Avastin
– Safety Daten sind mit denen von AVADO und E2100 konsistent (geringer Impact auf Safety-Profil der Chemo
– TTP ist mit PFS-Daten der Phase III Studien (E2100 und AVADO) konsistent
– Bestätigung der Safety und Wirksamkeit von Avastin in Kombination mit Chemotherapie in MBC im „real world clinical setting“