recuperando una alternativa terapéutica€¦ · conflicting data swog0226 fact ¿por qué es más...
TRANSCRIPT
Fulvestrant: recuperando una alternativa
terapéutica
Dr. José Ángel García Sáenz
Estrogen Receptor & Anti-estrogen Therapy
Antiestrogen Therapy
LHRH agonists
Aromatase inhibitors
SERMs
SERDs
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
Meta-analysis of chemotherapy vs endocrine RX for MBC HR for overall mortality
Wilcken N. Cochrane Datbase Syst, 2011
For postmenopausal women, 1st line letrozole improves TTP
Mouridsen H. JCO 2003
Letrozole 9.4m
Tamoxifen 6.0m
Second-line setting after NS-AIs Low-Dose Fulvestrant = Exemestane
Chia S. JCO 2008
Johnston SR. Lancet Oncol 2013
EFECT SoFEA
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
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
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
¿cuál va ser la primera línea en CMM RE+?
Paloma 2
MonaLEEsa 2
FALCON
FLIPPER
Mehta. NEJM 2012
Bergh M. JCO 2012
Fulvestrant + AIs in 1st-line Conflicting data
SWOG0226 FACT
¿por qué es más apropiado FULVESTRANT,
y no EXEMESTANO en aquellas pacientes
previamente expuestas a NSAI?
Mechanisms of endocrine therapy resistence
Activation of signaling pathways
Alteration of survival and cell cycle pathways
ESR1 activation mutations
ESR1 mutations
Jeselsohn R. Nat Rev Clin Oncol. 2015
Toy. AACR 2016
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?
What is the prevalence of mutation?
Which group of patients are at risk for mutation?
Turner. ASCO 2016
Prognostic implication for mutation?
Augusto. ASCO 2016 Chandarlapaty. SABC 2015
Implication for AI or SERD monotherapy
(SOFEA)?
Turner. ASCO 2016
Implications for SERD monotherapy
(FERGI)?
Spoerke et al. Nat Comm 2016
Implications for CDK4inh efficacy?
Turner. ASCO 2016
¿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
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
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