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SECUENCIA TRATAMIENTO HORMONAL CMM
ELECCIÓN DE IA + INH CDK COMO PRIMERA LINEA
PALOMA2/MONALEESA2 SUBGRUPOS
¿APLICABLE A TODAS LAS PACIENTES?¿EXISTEN OTRAS OPCIONES EN PRIMERA LINEA?
¿TIENE CABIDA FULVESTRANT EN ESTE LIO?
Opciones de HT: Fulvestrant
Fulvestrant28
Mecanismo de acción de Fulvestrant (No-agonista)29
HO (CH2)9SO(CH2)3CF2
CF3
7
OH
Fulvestrant
AF1
ER+Attenuated
dimerisationReduced nuclear
localisation of inactiveER to ERE
ERE RNAPOL II
NOTRANSCRIPCION(no división cel tumoral)
No coactivatorrecruitment
AF1 + AF2INACTIVE
F F FF
F
ACCELERATED RECEPTOR
DEGRADATION
Nicholson RI, Johnston SR. Endocrine therapy-current benefits and limitations. Breast Cancer Res Treat. 2005;93 Suppl 1:S3-10.
Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr-Relat Cancer 2000; 7: 17–28
HT: Hormonoterapia
4. DATOS CLÍNICOS
4.1 Indicaciones terapéuticas
Faslodex está indicado para el tratamiento de mujeres
posmenopáusicas con cáncer de mama localmente
avanzado o metastásico y con receptor de estrógeno positivo:
• no tratadas previamente con terapia endocrina, o
• cuya enfermedad ha recidivado durante o después del
tratamiento adyuvante antiestrogénico, o bien
cuya enfermedad ha progresado a un tratamiento
antiestrogénico.
http://ec.europa.eu/health/documents/community-register/html/h269.htm
http://ec.europa.eu/health/documents/community-register/html/h269.htm
http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/08/WC500232800.pdf
Faslodex (fulvestrant) receives EU approval for use in 1st-line hormone receptor-positive advanced breast cancer on 26th July 2017
FALCON: Phase III study design
• Randomised, double-blind, parallel-group, international, multicentre study
• Follow-up for disease progression and survival
• Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)
• Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic disease
• Subgroup analysis of PFS for pre-defined baseline covariates
aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis at the time of PFS analysis EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy – Breast; TOI, Trial Outcome Index
• Postmenopausal women• Locally advanced or
metastatic breast cancer• ER+ and / or PgR+• HER2-• Endocrine therapy-naïve
Fulvestrant 500 mg(500 mg IM on Days 0, 14 and 28, then
every 28 days)
+ placebo to anastrozole
Anastrozole 1 mg (daily PO)
+ placebo to fulvestrant
Primary endpoint: PFSa
Secondary endpoints1:1 • OSb
• ORR
• CBR
• DoR, EDoR
• DoCB,
EDoCB
• HRQoL
(FACT-B
total and
TOI)
• Safety
60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005
FALCON: Primary endpoint, PFS
A circle represents a censored observation
HR 0.797 (95% CI 0.637, 0.999); p=0.0486
Median PFS
Fulvestrant: 16.6 months
Anastrozole: 13.8 months
Number of patients at
risk:Fulvestrant
Anastrozole
230
232
187
194
171
162
150
139
124
120
110
102
96
84
81
60
63
45
44
31
24
22
11
10
2
0
0
0
Pro
port
ion o
f patients
aliv
e a
nd
pro
gre
ssio
n fre
e
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.00 3 6 9 12 15 18 21 24 27 30 3633 39
0.2
Fulvestrant (n=230)
Anastrozole (n=232)
60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005
FALCON: Forest plot for PFS by patient subgroup
Global interaction test p=0.106
NC, not calculable
All patientsBreast cancer type
Locally advancedMetastatic
Prior chemotherapy YesNo
Geographic regionUS and CanadaNon-US or CanadaAsiaNon-Asia
Measurable diseaseMeasurableNon-measurable
ER+ and PgR+ at baselineYesNo
Prior systemic estrogen containing HRTYesNo
Bisphosphonate use at baselineYesNo
Visceral diseaseYesNo
143 / 230 (62.2%)
11 / 28 (39.3%)132 / 202 (65.3%)
31 / 36 (86.1%)112 / 194 (57.7%)
16 / 25 (64.0%)127 / 205 (62.0%)
19 / 34 (55.9%)124 / 196 (63.3%)
124 / 193 (64.2%)19 / 37 (51.4%)
103 / 175 (58.9%)40 / 55 (72.7%)
3 / 3 (100.0%)140 / 227 (61.7%)
44 / 61 (72.1%)99 / 169 (58.6%)
92 / 135 (68.1%)51 / 95 (53.7%)
166 / 232 (71.6%)
14 / 32 (43.8%)152 / 200 (76.0%)
33 / 43 (76.7%)133 / 189 (70.4%)
19 / 24 (79.2%)147 / 208 (70.7%)
22 / 33 (66.7%)144 / 199 (72.4%)
143 / 196 (73.0%)23 / 36 (63.9%)
127 / 179 (70.9%)39 / 53 (73.6%)
3 / 5 (60.0%)163 / 227 (71.8%)
53 / 62 (85.5%)113 / 170 (66.5%)
87 / 119 (73.1%)79 / 113 (69.9%)
Number of patients with eventFulvestrant Anastrozole
0.25 0.5 1 1.5 2HR (95% CI)
0.797 (0.637, 0.999)
0.790 (0.360, 1.731) 0.784 (0.621, 0.991)
1.081 (0.659, 1.771) 0.752 (0.585, 0.967)
0.664 (0.338, 1.304) 0.811 (0.640, 1.029)0.811 (0.438, 1.501)0.791 (0.622, 1.005)
0.763 (0.599, 0.971) 0.985 (0.534, 1.818)
0.728 (0.561, 0.944) 1.041 (0.669, 1.621)
NC0.779 (0.622, 0.977)
0.685 (0.455, 1.032)0.820 (0.626, 1.073)
0.993 (0.740, 1.331) 0.592 (0.419, 0.837)
HR (95% CI)
60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005
FALCON: PFS in patients with or without visceral disease
Post hoc interaction test p<0.01
A circle represents a censored observation
Without visceral disease With visceral disease
HR 0.59 (95% CI 0.42, 0.84)
Median PFS Fulvestrant: 22.3 monthsAnastrozole: 13.8 monthsP
roport
ion o
f patients
aliv
e a
nd p
rogre
ssio
n-f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.0
0.2P
roport
ion o
f patients
aliv
e a
nd p
rogre
ssio
n-f
ree
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.0
0 5 10 15 20 25 30 35 40
0.2
0 5 10 15 20 25 30 35 40
HR 0.99 (95% CI 0.74, 1.33)
Median PFS Fulvestrant: 13.8 monthsAnastrozole: 15.9 months
Fulvestrant (n=135)
Anastrozole (n=119)
Fulvestrant (n=95)
Anastrozole (n=113)
Adaptado de:60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005
One size does not fit allPatient selection for the most appropriate therapy
• Numerous factors should be considered, such as:
• Disease free interval following adjuvant treatment
• Age
• Co-morbidities
• The extent of disease spread
• Tumour evolution
• Treatment decisions therefore need to be driven by patient and tumour characteristics
Mecanismos de resistencia a HT
37. Ma et al Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer.2015 May;15(5):261-75
Mecanismos de resistencia a Inhibidores de Aromatasa
Al resistance
ER pathway• Loss of ER
expression• ESR1 mutation, amplificationor translocation• Aberrant
expressionor mutation of ER co-regulators
Apoptosis and senescence•Mutation of TP53•Amplification of MDM2•↑BCL-2 and survivin•↑Telomerase
Cell cycle machinery• Loss of Rb, p16 and p18• Amplification of CCND1
Tumourmicroenvironment
• ECM: fibronectin, collagen
• Cellular components: TAM
(M1, M2), CAF, MSC, MDSC,TH2cell, B cell,
dendritic cell, NK cell, cytotoxic T cell, osteoclast, osteoblast and platelet
Growth factor receptor pathway
HER2, IGF1R and EGFR overexpression, mutation oramplification
Secondary messengers• PI3K pathway (e.g. mutationsin PI3KCA, PTEN and AKT1)• MAPK pathway
EMT and CSC• Notch, Hedgehog, WNT and TWIST1
• Tumour dormancy
=0.0002
Which group of patients are at risk for mutation?
Turner. ASCO 2016
What is the prevalence of mutation?
ESR1 mutations seem to be associated with resistance to AIs
SoFEA SoFEA: treatment less effective in mut vs wt
PALOMA-3: no difference between mut vs wtPALOMA-3
BOLERO-2 BOLERO-2: improved OS and PFS in wt vs mut*
Schiavon et al Schiavon et al: ESR1 mutations predict resistance to subsequent AI therapy**
*no statistical analysis carried out; **small sample size (n=45); mut = mutant; wt = wildtype[PALOMA-3] Turner N, presented at ASCO 2016 (abstract 512); [SoFEA] Fribbens et al. J Clin Oncol 2016; 34:2961–2968; [BOLERO-2] Chandarlapaty, presented at SABCS 2015 (abstract S2-07); Schiavon et al. Sci Transl Med 2015;7
Biomarker Clinical studies Findings (mutant/amplified/loss vs wildtype)
ESR1
Not all medications used in these studies are approved/marketed for use in Spain
Chandarlapaty S et al. SABCS 2015
Pronostic of ESR1 mutation and OS
Mutation N Median OS (m) HR
WT 385 32.1 1.4 (1.2-1.65)
MT 156 20.7 1.25 (1.02-1.54)
D538G 83 26.0 2.31 (1.34-3.97)
Y537S 42 20.0 1.77 (1.31-2-39)
Impact of ESR1 Mutation on EXE tratment
Chandarlapaty S et al. SABCS 2015
Impact of ESR1 mutation on EVE treatment
Chandarlapaty S et al. SABCS 2015
¿COMPROMETEMOS TRATAMIENTOS POSTERIORES?
25
▪ Postmenopausal women with ER+ MBC or LABC
▪ Patients who experienced relapse during or within 1 year of completion of adjuvant endocrine therapy
▪ Previous treatment with either an anti-oestrogen or an aromatase inhibitor as a first-line therapy for metastatic breast cancer if relapse occurred after more than 1 year from completion of adjuvant endocrine therapy
▪ Previous treatment with either an anti-oestrogen or an aromatase inhibitor as a first-line therapy if patients had de novo advanced disease
▪ Measurable disease as per RECIST, or without measurable disease but with bone lesions with a lytic or mixed component
▪ ER, oestrogen receptor; MBC, metastatic breast cancer; LABC, locally advanced breast cancer; RECIST, Response Evaluation Criteria In Solid Tumors
Key inclusion / exclusion criteria
Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600
BOLERO-2: Prior Therapies Were Balanced
Between Treatment Arms
Therapy
Everolimus +
Exemestane
(N = 485), %
Placebo +
Exemestane
(N = 239), %
Sensitivity to prior hormonal therapy 84 84
Last treatment: LET/ ANA 74 75
Last treatment
Adjuvant 21 15
Metastatic 79 85
Prior tamoxifen 47 49
Prior fulvestrant 17 16
Prior chemotherapy for metastatic BC 26 26
Number of prior therapies: ≥ 3 54 53
Abbreviations: ANA, anastrozole; LET, letrozole.
Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):520-529.28
Subgroup analysis of PFS by local investigator review (red) and central review (blue).
Subgroup categories in black font indicate prespecified analyses. Subgroup categories in green indicate retrospective analyses.
*Does not include patients who received neoadjuvant therapy.
Yardley D, et al. Adv Ther. 2013;30:870-884.
BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent in All Subgroups by Local and Central Review (2/2)
0.40 10.91 4.14
0.37 11.04 4.14
114
610
Sensitivity to prior hormonal therapy
No
Yes
0.55 6.83 2.83
0.43 8.05 3.94
0 0.20.40.60.8 1 1.21.4Hazard Ratio and 95% CI
0.38 11.00 4.10
0.24 19.52 6.51
0.53 8.28 4.17
0.35 8.48 2.83
0.44 10.58 5.55
0.35 11.27 4.07
0.35 13.83 4.21
0.42 7.13 2.83
724
219
232
271
231
493
538
186
N
All
Number of organs involved
1
2
Prior chemotherapy
No
Yes
Prior chemotherapy
for metastatic disease
No
Yes
Median PFS, mo
HR EVE + EXEPBO + EXE
0.45 7.8 3.2
0.40 11.50 4.37
0.52 6.70 3.45
0.41 6.93 2.56
0.53 6.97 3.45
0.41 8.18 3.19
0.46 8.31 4.07
0.38 6.11 2.69
Favors EVE + EXE Favors PBO + EXE
≥ 3
Local Central N
Median PFS, mo
HR EVE + EXEPBO + EXE
0 0.20.40.60.8 1 1.21.4Hazard Ratio and 95% CI
Favors EVE + EXE Favors PBO + EXE
Last therapy setting
Neo/adjuvant/prevention
Advanced/metastatic
0.32 15.24 4.21
0.40 10.84 4.11
0.39 11.50 4.07
0.47 6.93 2.96
0.46 9.95 4.21
0.32 12.02 3.32
326
398
Prior use of hormonal therapy
other than NSAI
No
Yes
0.52 7.00 4.11
0.39 8.11 2.76
538
186
137
587
Train of Trainers organized by AstraZeneca
Demographics and Baseline Characteristics PALOMA-3
aRelapsed after 24 months of adjuvant endocrine therapy or had clinical benefit to prior therapy in the advanced setting; bAny prior endocrine therapy anytime before study entry;
GnRH = gonatotropin-releasing hormone.
Characteristic Palbociclib + Fulvestrant
(n=347)
Placebo + Fulvestrant
(n=174)
Documented sensitivity to prior hormonal therapy,a %
Yes 79 78
No 21 22
Prior aromatase inhibitor +/- GnRH,b %
85 87
Prior tamoxifen +/-GnRH,b %
61 60
Disease stage at study entry, %
Recurrent locally advanced
14 14
Metastatic 85 84
Prior chemotherapy in metastatic setting, %
31 36
Prior lines of therapy in metastatic setting, %
0 24 26
1 38 40
2 26 25
≥3 12 9
Characteristic Palbociclib + Fulvestrant
(n=347)
Placebo + Fulvestrant
(n=174)Median age (range), years (range)
57 (30−88) 56 (29−80)
Receptor status, %
ER+ PR+ 69 64
ER+ PR– 26 28
ECOG performance status, %
0 60 66
1 40 34
Menopausal status,a %
Pre-/peri- 21 21
Post- 79 79
Visceral metastases,b %
59 60
Number of disease sites, %
1 32 35
2 29 29
3 39 36
61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19.
N=304(152 per treatment arm)
Fulvestrant HD (500 mg) + palbociclib (3w/4)
Letrozole + palbociclib (3w/4)
PD1:1
Stratification factors:
• Visceral disease
• Adjuvant AI
Postmenopausal MBC ER+/HER2–AI sensitivefirst-line ET
PD, progressive disease; R, randomisation. Llombart, et al. ASCO 2015.
Palbociclib and Fulvestrant Front-Line: PARSIFAL Design
R
Primary Objective:
• 1-year PFS Rates
• Odds Ratio: 70% vs. 85%
Train of Trainers organized by AstraZeneca
FULVESTRANT, SEGUNDA LINEA Y MÁS ALLÁ…
SECUENCIA TRATAMIENTO HORMONAL CMM
PALOMA-3 : FUL+Palbociclib.
61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19.
Primary Endpoint: PFS (Updated Analysis)
62. P4-22-06 Presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS); December 6–10, 2016; San Antonio, TX, USA
Confidential and Proprietary to AstraZeneca. Not for Distribution.
39
61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19.
PALOMA-3 : FUL+Palbociclib
• MONARCH-2
Enferme
• MONARCH-2: Abemaciclib + fulvestrant tras PD a ttº endocrino
Enfermed
Abemaciclib 150 mg BID
(cont) + Fulvestrant 500 mg
Placebo BID (cont) +
Fulvestrant 500 mg
CMM RH+/HER2-,
Resistente a ttº
endocrino:
- Recaída en
neoadyuvancia o
dentro del primer año
ady
- Progresión a HT
No QT, < 1 línea HT,
ECOG PS 0/1
(N = 669)
Aleatorización 2:1
Sledge et al. JCO 2017 Jun 3.
doi: 10.1200/JCO.2017.73.7585. [Epub ahead of print]
• MONARCH-2: PFS
Enfermedad
Sledge et al. JCO 2017 Jun 3. doi: 10.1200/JCO.2017.73.7585.
• MONARCH-2: ORR
Enfermed
Presentado por Sledge en ASCO 2017, abstract 1000
SECUENCIA TRATAMIENTO HORMONAL CMM
EN CONCLUSIÓN…
Single AgentEndocrine Therapy
Chemotherapy
Disease activity
- Short DFI- visceral disease burden- Symptoms
Probability to respond to ET
- Resistance Type (I⁰/II⁰)- Intrinsic Subtype- Biomarkers ?
CDK4/6 inhibitors + Endocrine Therapy ?
“Low Risk” “Intermediate Risk” “High Risk”
Single agent ET * ET + CDK4/6 Chemo
(ET + CDK4/6) (Single agent ET) ET + CDK4/6(Chemo)
First line therapy: ET alone or ET + CDK4/6 or Chemotherapy
Visceral/non-visceral?
*ESR1 Mutation and choice of ET
La opción de fulvestrant en monoterapia en primera linea podría
considerarse en pacientes:
- Sin exposición previa a tratamiento hormonal
- Recidiva con ILE corto.
- Pacientes de bajo riesgo o con afectación no visceral
Es preciso disponer de los resultados de los estudios en marcha
para considerar la opción de fulvestrant en combinación en
primera linea.
Constituye la opción preferente en monoterapia o en
combinación tras progresión a una pauta que incluya un IA,