2378 Monarch Butterfly Monitoring in North America Es (1) Tala Pariposa
recuperando una alternativa terapéutica€¦ · Conflicting data SWOG0226 FACT ¿por qué es más...
Transcript of recuperando una alternativa terapéutica€¦ · Conflicting data SWOG0226 FACT ¿por qué es más...
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Fulvestrant: recuperando una alternativa
terapéutica
Dr. José Ángel García Sáenz
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Estrogen Receptor & Anti-estrogen Therapy
Antiestrogen Therapy
LHRH agonists
Aromatase inhibitors
SERMs
SERDs
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SERD Phase of development
Fulvestrant Approved
GDC-0810 Phase 1/2
GDC-0927 Phase 1
AZD9496 Phase 1
SERDs: Ongoing phase 1/2 trials
Estradiol OH
Fulvestrant OH
7
HO HO (CH2)9SO(CH2)3CF2CF3
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Meta-analysis of chemotherapy vs endocrine RX for MBC HR for overall mortality
Wilcken N. Cochrane Datbase Syst, 2011
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For postmenopausal women, 1st line letrozole improves TTP
Mouridsen H. JCO 2003
Letrozole 9.4m
Tamoxifen 6.0m
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Second-line setting after NS-AIs Low-Dose Fulvestrant = Exemestane
Chia S. JCO 2008
Johnston SR. Lancet Oncol 2013
EFECT SoFEA
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Fulvestrant 500 mg versus 250 mg improves PFS and OS CONFIRM Trial
Di Leo A. JCO 2010
Di Leo A. JNCI 2014
5.5m
6.5m
26.4 m
22.3 m
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Fulvestrant 500 ↑ TTP & OS vs Anastrozole in 1st-line
FIRST Trial
Robertson . Breast Cancer Res Treat 2012
Ellis M. JCO 2015
TTP: 23.4 vs 13.1 mo OS: 54.1 vs 48.4 mo
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1st Line: Fulvestrant 500 vs Anastrozol
FALCON
n= •Postmenopausal HR+/HER2- MBC •1st Line
Fulvestrant 500 plus placebo
Placebo plus Fulvestrant
1
1
PFS analisis: 306 events
OS analisis: 50% survival
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¿cuál va ser la primera línea en CMM RE+?
Paloma 2
MonaLEEsa 2
FALCON
FLIPPER
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Mehta. NEJM 2012
Bergh M. JCO 2012
Fulvestrant + AIs in 1st-line Conflicting data
SWOG0226 FACT
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¿por qué es más apropiado FULVESTRANT,
y no EXEMESTANO en aquellas pacientes
previamente expuestas a NSAI?
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Mechanisms of endocrine therapy resistence
Activation of signaling pathways
Alteration of survival and cell cycle pathways
ESR1 activation mutations
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ESR1 mutations
Jeselsohn R. Nat Rev Clin Oncol. 2015
Toy. AACR 2016
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Clinical significance of ESR1 mutations in Breast cancer
Chandarlapaty S. 2016 ASCO Annual Meeting
1. What is the clinical prevalence of mutation among patient subsets?
– Which group of patients are at risk for mutation?
2. What are the outcomes of patients with muts?
– Implication of mutation for overall survival?
– Implication of mutation for specific endocrine therapies?
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What is the prevalence of mutation?
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Which group of patients are at risk for mutation?
Turner. ASCO 2016
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Prognostic implication for mutation?
Augusto. ASCO 2016 Chandarlapaty. SABC 2015
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Implication for AI or SERD monotherapy
(SOFEA)?
Turner. ASCO 2016
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Implications for SERD monotherapy
(FERGI)?
Spoerke et al. Nat Comm 2016
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Implications for CDK4inh efficacy?
Turner. ASCO 2016
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¿Debe incorporarse el estudio de mutaciones
de ESR1 a la práctica asistencial?
¿Debe de abandonarse los IA como un
tratamiento estándar en 2L ?
¿Deben incorporarse
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2nd line Trials Cohorts
BELLE2 Fulvestrant +/- Buparlisib
SOLAR-1 Fulvestrant +/- Alpelisib
PALOMA-3 Fulvestrant +/- Palbociclib
PEARL Fulvestrant +Palbociclib vs XEL
Monarch-3 Fulvestrant +/- Abemaciclib
MANTA Fulvestrant +/- AZ dual mTOR-in
TAKEDA Fulvestrant +/- ML dual mTOR-in
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First line
Single agent
Combination therapy
Non-steroidal AIS
Anastrozole + Fulvestrant
Letrozole + Palbociclib
2nd line
Single agent
Combination therapy
Fulvestrant + Palbociclib
Exemestane + Everolimus
Fulvestrant
Fulvestrant
Letrozole + Ribociclib