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Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: overall survival from the phase II ‘first’ study
Dr. Robertson
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Prof. Dr. Santiago R. BellaAdjunto de Medicina Jefe de OncologíaClínica Reina Fabiola
Supervivencia Global (OS) del estudio Fase II randomizado “FIRST”Anastrazol vs. Fulvestrant 500 mgs primera línea. Robertson J.
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Fulvestrant 500 mg versus anastrozole como primera línea de tratamiento para cáncer de mama
avanzado :
Supervivencia Global (OS) del estudio Fase II randomizado “FIRST”
John F. R. Robertson, Antonio Llombart-Cussac, David Feltl, Jhon
Dewar, Marek Jasiówka, Nicola Hewson, Yuri Rukazenkov, Matthew J. Ellis
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Esquema de la presentación
• Antecedentes
• Resumen del reporte inicial y análisis de
seguimiento
• Análisis de supervivencia
• Conclusión
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Fulvestrant: Mecanismo de Acción
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Antecedentes: Fulvestrant 250 mgs
Segunda Línea ETEstudio 0025: TTP
Segunda Línea ETEstudios 0020 and 0021:TTP
Robertson et al. Cancer 2003Howell et al. J Clin Oncol 2004
HR=1.1895% CI (0.98, 1.44)
p=0.09
0.0
0.2
0.4
0.6
0.8
1.0
0 100 200 300 400 500 600 700 800
Tiempo (días)
HR=0.95 95% CI (0.82, 1.10)
p=0.48
0 6 12 18 24 30 36
Tiempo (meses)
Fulvestrant 250 mg)
Anastrozole 1 mg (n=423)
Fulvestrant 250 mg (n=313)
Tamoxifeno 20 mg (n=274)
0.0
0.2
0.4
0.6
0.8
1.0
6
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Fulvestrant (250) vs. Fulvestrant (250) / Anastrazole
1ra. Línea
Bergh et al. JCO 2012 Mehta RS et al. N Engl J Med 2012
FACT SWOG
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Racional del empleo de 500 mgs
Br Ca Res 2013
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Antecedentes CONFIRM: fulvestrant 500 mg vs 250 mg
Di Leo et al. J Clin Oncol 2010Di Leo et al. J Natl Cancer Inst 2014
0 4 8 12 16 20 24 28 32 36 40
1.0
0.8
0.6
0.4
0.2
0.0
Fulvestrant 500 mg (n=362)
Fulvestrant 250 mg (n=374)
HR=0.80 95% CI (0.68, 0.94)
p=0.006
Tiempo (meses)
Anáisis final: 75% datos maduros
0.1
0.0
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80
Tiempo (meses)
Pro
po
rtio
n o
f p
ati
en
ts a
liv
e
HR=0.81 95% CI (0.69, 0.96) Nominal p=0.016
Segunda Línea ET
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FIRST: Diseño del estudio
Anastrozole (1 mg p.o. díaFulvestrant 500 mgi.m.días 0, 14, y 28 y luego cada 28 días)
Randomización 1:1, abierto, pacientes postmenopáusicas con cáncer de mama
avanzado ER+ (n=200)
TTP
Progresión Progresión
TTP
Robertson et al. J Clin Oncol 2009Robertson et al. Breast Cancer Res Treat 2012
OS OS
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Número de pacientes (%)
Fulvestrant 500 mgn=102
Anastrozole 1 mgn=103
Edad Media 66 años 68 años
Estadio
Localmente avanzado 19 (18.6) 18 (17.5)
Metastásicos 83 (81.4) 85 (82.5)
Enfermedad Medible 89 (87.3) 93 (90.3)
Tratamiento endócrino previo
No 73 (71.6) 80 (77.7)
Adyvuvancia endrócrina finalizada >12 meses previos a la inclusión
28 (27.5) 23 (22.3)
Quimioterapia adyuvante previa 29 (28.4) 25 (24.3)
Quimio y endócrinoterapia adyuvantes previas 19 (18.6) 13 (12.6)
11
Robertson et al. J Clin Oncol 2009
Características de los pacientes
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Localizaciones metastásicas
Fulvestrant Anastrazole
Sitios Metastásicos
Osea (única localización): 10 (9.8) 8 (7.8)Partes Blandas: 2 (2.0 )
0Cualquier loc. visceral: 48 (47.1) 58 (56.3)Hepáticas: 15 (14.7)
14 (13.6)Pulmonar: 30 (29.4)
42 (40.8)
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TBC
Fulvestrant 500 mg% (total with CB/n)
Anastrozole 1 mg% (total with CB/n)
Odds ratio(95% CI) p-value
(95% CI)
72.5%(74/102)
67.0% (69/103)
1.30(0.72, 2.38)
0.386 5.6%(-7.8%, 15.8%)
Robertson et al. J Clin Oncol 2009
Objetivo Primaria: Tasa de Beneficio Clínico (BC: RC + RP + EE > 24 semanas)
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Objetivo Primaria: Tasa de Beneficio Clínico (BC: RC + RP + EE > 24 semanas)
TBC
Fulvestrant 500 mg% (total with CB/n)
Anastrozole 1 mg% (total with CB/n)
Odds ratio(95% CI) p-value
(95% CI)
72.5%(74/102)
67.0% (69/103)
1.30(0.72, 2.38)
0.386 5.6%(-7.8%, 15.8%)
Robertson et al. J Clin Oncol 2009
Fulvestrant 500 mg fue al menos tan efectivo como anastrazole para el objetivo primario: TBC
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Fulvestrant 500 mgn=102
Anastrozole 1 mgn=103
Median (months) 23.4 13.1
0 6 12 18 24 30 36 42 480.0
0.2
0.4
0.6
0.8
1.0
Tiempo (meses)
Fulvestrant 500 mgAnastrozole 1 mg
HR=0.6695% CI (0.47, 0.92)
p=0.01
Robertson et al. Breast Cancer Res Treat 2012
TTP
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Comparación del TTP de estudios Fase III de terapia hormonal de primera línea
Bonneterre et al.
Cancer 2001
(n=1021)
Mouridsen et al.
J Clin Oncol 2001
(n=916)
Paridaens et al.
J Clin Oncol 2008
(n=371)
Ana Let Exe
TTP (meses) 8.5 9.4 9.9
16
FIRST
(n=205)
Ana F500
13.1 23.4
Tam Tam Tam
7.0 6.0 5.8
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Toxicidad
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FIRST: OS
• OS no fue definida inicialmente como un objetivo primario.
• Enmienda febrero 2011
• Análisis planificado con 65% de madurez (133 eventos)
• Seguimiento medio
Fulvestrant: 49.6 meses
Anastrozole: 42.5 meses
• 66.8% madurez (137 eventos)
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OS
Número de Pacientes (%)
Fulvestrant 500 mgn=102
Anastrozole 1 mgn=103
Estado
Vivos 23 (22.5) 10 (9.7)
Desconocidos 0 0
Perdidos de sguimiento 0 0
Fallecidos 63 (61.8) 74 (71.8)
No participaron del análisis 16 (15.7) 19 (18.4)
Negativa del paciente 6 (5.9) 9 (8.7)
Negativa del centro 10 (9.8) 10 (9.7)
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Fulvestrant 500 mgn=102
Anastrozole 1 mgn=103
OS (meses) 54.1 48.4
OS
0 6 12 18 24 30 36 42 1080.0
0.2
0.4
0.6
0.8
1.0
Tiempo (meses)
Fulvestrant 500 mgAnastrozole 1 mg
HR=0.7095% CI (0.50, 0.98)
p=0.041
48 54 60 66 72 78 84 90 96 102
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Análisis de subgrupo
HR (log-rank test; fulvestrant 500 mg vs anastrozole) y 95% CIs
0.25 0.50 1.0 2.00
Fulvestrant 500 mg
Eventos (%)
Anastrozole
Todos los pacientes 63/102 (61.8) 74/103 (71.8)
<65 años 29/45 (64.4) 29/40 (72.5)>65 años 34/57 (59.6) 45/63 (71.4)
ER+ y PgR+ divergentes 49/78 (62.8) 56/78 (71.8)Ambos ER+ y PgR+ 14/24 (58.3) 18/25 (72.0)
Sin compromiso visceral 29/54 (53.7) 26/45 (57.8)Con compromiso visceral 34/48 (70.8) 48/58 (82.8)
QT previa 20/29 (69.0) 17/25 (68.0)Sin QT previa 43/73 (58.9) 57/78 (73.1)
Con enfermedad medible 52/89 (58.4) 67/93 (72.0)
Con HT previa 19/29 (65.5) 15/23 (65.2)
Sin enfermedad medible 11/13 (84.6) 7/10 (70.0)NC
Sin HT previa 44/73 (60.3) 59/80 (73.8)
fulvestrant 500 mg anastrozole
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Número de pacientes (%)
Fulvestrant 500 mgn=101
Anastrozole 1 mgn=103
SAE (categoría)
Cualquier SAE 24 (23.8) 22 (21.4)
Cualquier SAE (sin fallecimiento) 21 (20.8) 18 (17.5)
Cualquier SAE (fallecimiento) 3 (3.0) 5 (4.9)
SAE con relación de causalidad 2 (2.0) 0
Seguridad
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23
Comparación de OS de estudios Fase III de terapia hormonal de primera línea
Nabholtz et al.
Eur J Cancer 2003
(n=1021)
Mouridsen et al.
J Clin Oncol 2003
(n=916)
Paridaens et al.
J Clin Oncol 2008
(n=371)
Ana Let Exe
OS (meses) 39.2 34 37.2
23
FIRST
(n=205)
Ana F500
48.4 54.1
Tam Tam Tam
40.1 30 43.3
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Fulvestrant 500 mgN=102 n (%)
Anastrozole 1 mgN=103 n (%)
Received any subsequent systemic therapy 64 (62.7) 69 (67.0)
Category of subsequent therapy
Chemotherapy 25 (39.1) 13 (18.8)
Endocrine therapy 34 (53.1) 50 (72.5)
Novel targeted therapy 2 (3.1) 1 (1.4)
Unknown / other 3 (4.7) 5 (7.2)
Best response to subsequent systemic therapy
Complete response 0 2 (2.9)
Partial response 15 (23.4) 13 (18.8)
ORR 15 (23.4) 15 (21.7)
Stable disease ≥24 weeks 13 (20.3) 17 (24.6)
CBR 28 (43.8) 32 (46.4)
Stable disease <24 weeks 16 (25.0) 19 (27.5)
Progressive disease 6 (9.4) 12 (17.4)
Not evaluable 14 (21.9) 6 (8.7)
Best response to first subsequent systemic breast cancer therapy (full analysis set)
Adapted from: Robertson JFR et al. The Breast 2011; 20 (Suppl 4): abstract S46
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OS media: 54.1 meses
OS significativamente mejor (incremento 5.7 meses) comparado con anastrozole
Beneficio consistente en diversos subgrupos
No hubo hallazgos de seguridad remarcables
Segundo estudio randomizado que encuentra beneficio en OS con fulvestrant
CONFIRM (Phase III) vs fulvestrant 250 mg (segunda línea)
FIRST (Phase II) vs anastrozole (primera línea)
25
Conclusiones (OS)
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Fase III: FALCON
Progresión
Fulvestrant 500 mg+ placebo
Supervivencia
Mujeres Postmenopáusicas con cáncer de mama avanzado o locamente avanzado, ER+ / o PgR+, sin tratamiento hormonal
previo
Progresión
Supervivencia
Anastrozole+ placebo
Randomización 1:1 (n=450)
26
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Algoritmo terapéutico para cáncer de mama avanzado receptor hormonal positivo (postmenopáusicas – HER 2 negtivas)
Ciruelos E et al, The Breast 2014
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Algoritmo terapéutico para cáncer de mama avanzado receptor hormonal positivo (postmenopáusicas – HER 2 negtivas)
Ciruelos E et al, The Breast 2014
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Gracias!
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