Sequenciamento hormonal na doença
metastática na mulher pós-menopáusica
.
Sergio D Simon
Hospital Israelita Albert Einstein
Centro Paulista de Oncologia (CPO)
Câncer de Mama RH+/HER2 avançado
Tratamento após progressão em primeira linha
Progressão em
tratamento
adjuvante em
adjuvância/doença
metastática
•
Quimioterapia
Resistência
Endócrina
•
Fulvestranto 500 mg
Apenas para
pacientes com
necessidade de
rápido controle
•
Everolimo + exemestano
NCCN
1
ABC-1
2
Atualização do ABC2
3
Recomenda 3 tratamentos
endócrinos consecutivos antes
de encaminhar a paciente para
quimioterapia
Sem consenso após IA
inicial. Opções incluem:
•Tamoxifeno
•Outro IA
•Fulvestranto
•Acetato de Megestrol
Primeira linha recomendada é IA ou
TAM, dependendo do tipo e duração
da adjuvância. Fulvestranto é
também uma opção.
†
*Guidelines refer to postmenopausal HR+ advanced breast cancer, and recommend endocrine therapy for patients who are not in visceral crisis. †The decision to treat must take into account the relevant toxicities associated with this combination and should be made on a case-by-case basis.
NÃO
SIM
Inibidor da
Aromatase
OPÇÕES DE HORMONIOTERAPIA
EM PRIMEIRA LINHA
Estudo FIRST
Robertson JFR et al. J Clin Oncol 2009; 27: 4530-4535
Desfecho primário
Taxa de benefício clínico
Desfechos secundários
Tempo até a progressão
Taxa de resposta objetiva
Duração da resposta
Duração do benefício clínico
Segurança
Desfechos exploratórios
Melhor resposta para a terapia
subsequente
Resultado clínico subsequente em
participantes da pesquisa que
demonstrarem alterações nos
marcadores tumorais séricos
Randomização (1:1), Fase II, aberto, de
primeira linha, RH+, pós-menopausa com
câncer de mama avançado (N=205), sem
tratamento prévio
Fulvestranto 500 mg
(500 mg i.m. nos Dias 0, 14 e
28 e a cada 28 dias a partir de
então)
N=102
Anastrozol 1 mg
(1 mg p.o. diariamente)
N=103
Progressão
Progressão
Acompanhamento
Acompanhamento
Tempo até a progressão
(conjunto de análise completo)
0
0,0
0,2
0,4
0,6
0,8
1,0
102
74
65
52
45
34
20
6
103
69
55
39
30
21
8
2
Participantes da pesquisa em risco:
Tempo (meses)
6
12
18
24
30
36
48
Proporção de
participantes da
pesquisa vivos e
livres de
progressão
HR = 0,66; 95% IC: 0,47, 0,92;
p=0,01
Fulvestranto 500 mg
Anastrozol 1 mg
Anastrozol 1 mg
Fulvestranto 500 mg
Após o primeiro corte dados primário, a progressão foi determinada por parecer do investigador
42
0
0
FALCON: Ongoing Confirmatory Phase 3 Study of
Fulvestrant in First-Line MBC
Phase 3 randomized, double-blind, parallel-group study
•
Primary endpoint: PFS
•
Secondary endpoints: OS, ORR, DOR, CBR
*Estimated enrollment.
ELIGIBILITY CRITERIA
• Postmenopausal women with
ER+ and/or PR+ ABC
• No prior ET for advanced
disease
• ≥1 lesion suitable for repeated
assessment
1
:1
R
A
N
D
O
M
IZ
A
T
IO
N
Fulvestrant 500 mg
+
Anastrozole placebo PO, QD
Anastrozole 1 mg PO, QD
+
Fulvestrant placebo
N=450*
FALCON: KEY INCLUSION / EXCLUSION CRITERIA
Postmenopausal women with histologically confirmed ER+ and / or PgR+,
HER2- locally advanced or metastatic breast cancer
WHO performance status 0–2
≥1 measurable and / or non-measurable lesion(s)
Key exclusion criteria:
Prior endocrine treatment for breast cancer
Systemic estrogen-containing hormone-replacement therapy use
≤6 months prior to randomisation
Presence of life-threatening metastatic visceral disease
Prior systemic treatment for breast cancer except one line of
chemotherapy, radiotherapy completed ≤28 days prior to
randomisation (except radiotherapy for control of bone pain)
FALCON: BASELINE PATIENT CHARACTERISTICS
Fulvestrant (N=230)
Anastrozole (N=232)
Median age, years (range)
64.0 (38–87)
62.0 (36–90)
Race, n (%)
White
175
(76.1)
174
(75.0)
Any prior chemotherapy, n (%)
79
(34.3)
81
(34.9)
Advanced disease
36
(15.7)
43
(18.5)
Adjuvant / neoadjuvant
35 / 11
(15.2 / 4.8)
27 / 16
(11.6 / 6.9)
WHO performance status, n (%)
0 / 1 / 2
117 / 106 / 7
(50.9 / 46.1 / 3.0)
115 / 105 / 12
(49.6 / 45.3 / 5.2)
Receptor status, n (%)
ER+ / PgR+
175
(76.1)
179
(77.2)
ER+ / PgR-
44
(19.1)
43
(18.5)
ER+ / PgR unknown
10
(4.3)
7
(3.0)
ER- / PgR+
1
(0.4)
3
(1.3)
ER- / PgR-
0
0
Overall disease classification, n (%)
Locally advanced disease
28
(12.2)
32
(13.8)
Metastatic disease
202
(87.8)
200
(86.2)
Visceral disease, n (%)
135
(58.7)
119
(51.3)
Measurable disease, n (%)
193
(83.9)
196
(84.5)
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
P
ro
p
o
rt
io
n
o
f
p
a
ti
e
n
ts
a
li
v
e
a
n
d
p
ro
g
re
ss
io
n
f
re
e
Time (months)
0.9
1.0
0.7
0.8
0.5
0.6
0.3
0.4
0.1
0.0
0
3
6
9
12
15
18
21
24
27
30
33
36
39
0.2
Fulvestrant (n=230)
Anastrozole (n=232)
FALCON: FOREST PLOT FOR PFS BY PATIENT
SUBGROUP
Global interaction test p=0.106 NC, not calculable
All patients Breast cancer type
Locally advanced Metastatic Prior chemotherapy Yes No Geographic region US and Canada Non-US or Canada Asia Non-Asia Measurable disease Measurable Non-measurable ER+ and PgR+ at baseline
Yes No
Prior systemic estrogen containing HRT Yes
No
Bisphosphonate use at baseline Yes No Visceral disease Yes No 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 event Fulvestrant Anastrozole 0.25 0.5 1 1.5 2 HR (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) NC 0.779 (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)
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 months Anastrozole: 13.8 months P ro p o rt io n o f p a ti e n ts a li v e a n d p ro g re ss io n -f re e Time (months) 0.9 1.0 0.7 0.8 0.5 0.6 0.3 0.4 0.1 0.0 0.2 P ro p o rt io n o f p a ti e n ts a li v e a n d p ro g re ss io n -f re e 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 months Anastrozole: 15.9 months Fulvestrant (n=135) Anastrozole (n=119) Fulvestrant (n=95) Anastrozole (n=113)
FALCON: OS (31% MATURITY)
Median follow up 25.0 months
A circle represents a censored observation
0 6 21 Time (months) Fulvestrant (N=230) Anastrozole (N=232) 3 9 12 15 18 24 27 30 33 36 39 0.9 1.0 0.7 0.8 0.6 0.5 0.4 0.3 0.2 0.1 0.0 P ro p o rt io n o f p a ti e n ts a li v e
HR 0.88 (95% CI 0.63, 1.22); p=0.428
Number of patients at risk: Fulvestrant Anastrozole 230 232 221 223 208 213 200 197 188 186 180 175 168 164 153 155 129 122 92 94 57 61 31 37 17 18 0 0
FALCON: SECONDARY ENDPOINTS
aIn patients with measurable disease at baseline
Endpoint
Fulvestrant (N=230)
Anastrozole (N=232)
ORR
a46.1%
(89 / 193)
44.9%
(88 / 196)
Odds ratio (95% CI)
1.07 (0.72, 1.61);
p=0.729
CBR
78.3%
(180 / 230)
74.1%
(172 / 232)
Odds ratio (95% CI)
1.25 (0.82, 1.93);
p=0.305
Median DoR
20.0 months
13.2 months
-Median DoCB
22.1 months
19.1 months
-EDoR
11.4 months
7.5 months
Ratio (95% CI)
1.52 (1.23, 1.89);
p<0.001
EDoCB
21.9 months
17.5 months
Ratio (95% CI)
1.26 (1.13, 1.39);
p<0.001
Median time to
deterioration in
FACT-B total score
13.8 months
11.1 months
HR (95% CI)
0.84 (0.66, 1.07);
p=0.159
FALCON: AEs IN ANY CATEGORY
(SAFETY ANALYSIS POPULATION)
AE category
Number (%) of patients
Fulvestrant (N=228)
Anastrozole (N=232)
SAEs
30
(13.2)
31
(13.4)
Considered related to
treatment
4
(1.8)
3
(1.3)
Discontinuations due to AEs
16
(7.0)
11
(4.7)
AEs Grade 3 or worse
51
(22.4)
41
(17.7)
Deaths due to AEs
6
(2.6)
7
(3.0)
Considered related to
FALCON: CONCLUSIONS
The Phase III FALCON study met its primary endpoint
Statistically significant improvement in PFS for fulvestrant vs. anastrozole
The primary analysis was supported by secondary efficacy endpoints
Treatment effects were largely consistent across pre-specified patient
subgroups, with the largest treatment effect seen in patients without visceral
disease
The AE profile was generally consistent with known profiles
Overall, HRQoL was maintained and was similar in both treatment groups
These results are consistent with data from the FIRST study and confirm
that fulvestrant is more efficacious than anastrozole in postmenopausal
women with hormone receptor-positive locally advanced or metastatic
breast cancer who have not received prior endocrine therapy
Molecular Targets in Advanced Breast Cancer
HR+ HER2 neg
1-5
PI3K AKT ER GRB2 P P P P ER CoA ER CoA AP-1 P CoA TFsEREs AP-1/SP-1 TFs-REs
SOS Shc Rb E2F E2F
Gene transcription
Cyclin D CDK4/6 P P P P P Cyclin D CDK4/6 P P mTORGrowth factor
receptor (eg, EGFR)
Ras Raf MAPK Src
Aromatase inhibitors
MEKEstradiol
p21 p16 G1 S G2 M p53 Cell cycleEstrogen receptor
downregulator
Paloma1: Progression-free Survival
PFS
20.2 months
10.2 months
PALOMA-2: Phase III Study Design in Postmenopausal Patients
with ER+, HER2– Advanced Breast Cancer
•
Phase III, randomized, double-blind trial at 186 centers in 17 countries
•
Treatment continued until objective disease progression, unacceptable toxicity, or withdrawal of consent. Crossover
was not allowed
•
Palbociclib/placebo dose reductions were allowed per protocol. Letrozole dose reductions were not permitted
aRandomization stratified by disease site (visceral/non-visceral), disease-free interval, and prior (neo)adjuvant hormonal therapy.
ECOG PS, Eastern Cooperative Oncology Group Performance Status; ER+, estrogen receptor-positive; HER2–, human epidermal growth factor receptor 2-negative; NSAI, non-steroidal aromatase inhibitor; QD, once a day; RECIST, Response Evaluation Criteria In Solid Tumors
b3 weeks on/1 week off of a 4-week cycle
Placebo
(3/1 schedule)
+ letrozole
(2.5 mg QD)
Palbociclib
(125 mg QD, 3/1 schedule
b)
+ letrozole
(2.5 mg QD)
• Postmenopausal
• ER+, HER2– advanced breast cancer
• No prior systemic treatment for advanced disease
• Prior (neo)adjuvant treatment with anastrozole or
letrozole was allowed if the disease free interval was ≥12
months from completion of therapy
• Measurable disease according to RECIST v1.1 or
bone-only disease
• ECOG PS 0–2
• Adequate organ function
• No advanced, symptomatic visceral spread at risk of
short-term life-threatening complications
R
A
N
D
O
M
IZ
A
T
IO
N
N=666
a2:1
PALOMA-2: Demographics and
Baseline Characteristics (ITT
Population)
aVisceral disease was defined as: any lung (including pleura) and/or liver involvement
bTime since completion of (neo)adjuvant therapy and onset of recurrence; percentage calculated based on number of patients who received (neo)adjuvant therapy
Patients who progressed while receiving or ≤12 months from completion of prior anastrozole or letrozole were excluded
Palbociclib + letrozole
(N=444)
Placebo + letrozole
(N=222)
Age, n (%) Median (range) 62 (30–89) 61 (28–88) <65 years 263 (59.2) 141 (63.5) ≥65 years 181 (40.8) 81 (36.5) Race, n (%) White 344 (77.5) 172 (77.5) Asian 65 (14.6) 30 (13.5) Black 8 (1.8) 3 (1.4) Other 27 (6.1) 17 (7.7) ECOG PS, n (%) 0 257 (57.9) 102 (45.9) 1 178 (40.1) 117 (52.7) 2 9 (2.0) 3 (1.4) Disease site, n (%) Viscerala 214 (48.2) 110 (49.5) Non-visceral 230 (51.8) 112 (50.5) Bone-only 103 (23.2) 48 (21.6)No. of disease sites
1 138 (31.1) 66 (29.7)
2 117 (26.4) 52 (23.4)
3 112 (25.2) 61 (27.5)
≥4 77 (17.3) 43 (19.4)
Disease-free interval,bn (%)
Newly metastatic disease 167 (37.6) 81 (36.5)
≤12 months 99 (22.3) 48 (21.6)
PALOMA-2: Demographics and
Baseline Characteristics (ITT
Population)
a“Other” was an option for the site to select on the clinical report form if none of the other available options were applicable; “data missing” means that the site did not complete that field because the information was not available.
Palbociclib + letrozole (N=444)
Placebo + letrozole (N=222) Disease stage at initial
diagnosis, n (%) I 51 (11.5) 30 (13.5) II 137 (30.9) 68 (30.6) III 72 (16.2) 39 (17.6) IV 138 (31.1) 72 (32.4) Unknown 36 (8.1) 12 (5.4)
Other or data missinga 10 (2.3) 1 (0.5)
Recurrence type, n (%) Locoregional 2 (0.5) 2 (0.9) Loca 6 (1.4) 3 (1.4) Regional 3 (0.7) 1 (0.5) Distant 294 (66.2) 145 (65.3) Newly diasgnosed 139 (31.3) 71 (32.0)
Prior neoadjuvant therapy, n (%)
Chemotherapy 213 (48.0) 109 (49.1)
Neoadjuvant 54 (12.2) 32 (14.4)
Adjuvant 180 (40.5) 89 (40.1)
Adjuvant hormonal therapyb 249 (56.1) 126 (56.8)
Tamoxifen 209 (47.1) 98 (44.1) Anastrozole 56 (12.6) 29 (13.1) Letrozole 36 (8.1) 16 (7.2) Exemestant 30 (6.8) 13 (5.9) Goserelin 5 (1.1) 6 (2.7) Toremifene 7 (1.6) 1 (0.5) Other 3 (0.7) 4 (1.8)
PALOMA 2 PFS Subgroup Analysis
(ITT, Investigator Assessment)
Subgroup n (%) Hazard Ratio (95% CI)
All randomized patients 666 (100) 0.576 (0.463–0.718) Age <65 y ≥65 y 404 (60.7) 262 (39.3) 0.567 (0.434–0.740) 0.571 (0.386–0.843) Race White Asian 516 (77.5) 95 (14.3) 0.576 (0.450–0.739) 0.484 (0.269–0.871) Site of metastatic
disease VisceralNonvisceral
324 (48.6) 342 (51.4)
0.633 (0.472–0.849) 0.502 (0.360–0.699) Prior hormonal therapy Yes
No
375 (56.3) 291 (43.7)
0.528 (0.400–0.698) 0.628 (0.439–0.897) Disease-free interval De novo metastases≤12 months
>12 months 248 (37.2) 147 (22.1) 271 (40.7) 0.674 (0.457–0.993) 0.501 (0.329–0.761) 0.516 (0.365–0.731) Region North AmericaEurope
Asia/Pacific 267 (40.1) 307 (46.1) 92 (13.8) 0.605 (0.431–0.849) 0.571 (0.410–0.796) 0.486 (0.270–0.872) ECOG performance status 01/2 359 (53.9) 307 (46.1) 0.646 (0.466–0.896) 0.531 (0.393–0.718) Bone-only disease at baseline YesNo 151 (22.7) 515 (77.3) 0.363 (0.221–0.594) 0.654 (0.512–0.837) Measurable disease Yes
No
509 (76.4) 157 (23.6)
0.663 (0.517–0.849) 0.350 (0.215–0.568) Prior chemotherapy Yes
No
322 (48.3) 344 (51.7)
0.533 (0.395–0.720) 0.611 (0.443–0.842) Most recent therapy Aromatase inhibitor
Antiestrogen
135 (20.3) 229 (34.4)
0.549 (0.341–0.883) 0.558 (0.390–0.799) Number of disease sites 1
≥2 204 (30.6) 462 (69.4) 0.511 (0.339–0.770) 0.606 (0.467–0.787) 0.00 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 In favor of PAL+LET In favor of PCB+LET
Let + Palb = 24.8 m
Let
= 14.5 m
Let + Palb = 30.5 m
Let
= 19.35 m
OPÇÕES DE HORMONIOTERAPIA
EM SEGUNDA LINHA
Molecular Targets in Advanced Breast
Cancer HR+ HER2 neg
1-5
PI3K AKT ER GRB2 P P P P ER CoA ER CoA AP-1 P CoA TFs
EREs AP-1/SP-1 TFs-REs
SOS Shc Rb E2F E2F
Gene transcription
Cyclin D CDK4/6 P P P P P Cyclin D CDK4/6 P P mTORGrowth factor
receptor (eg,
EGFR)
Ras Raf MAPK SrcAromatase inhibitors
MEKEstradiol
p21 p16 G1 S G2 M p53 Cell cycleEstrogen receptor
downregulator
BOLERO-2: Phase III dtudy of Exemestane ±
Everolimus in patients with ABC progressing
after NSAIs
•
Stratification
1.
Sensitivity to prior endocrine therapy
2.
Presence of visceral disease
•
No crossover
Everolimus 10 mg/day
+
Exemestane 25 mg/day
(n = 485)
Placebo +
Exemestane 25 mg/day
(n = 239)
Primary endpoint
PFS
Secondary endpoints
OS, ORR, CBR, safety,
QOL, bone markers
N = 724
PMW with HR+, HER2–
ABC refractory to LET or
ANA, defined as
•
Recurrence during or
within 12 months after
end of adjuvant
treatment, or
•
Progression during or
within 1 month after end
of treatment for advanced
disease
Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival. .
EVE+EXE PBO+EXE
Number of patients still at risk
485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0 239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0
Log-rank P value: < .0001
0
20
40
60
80
100
Time, wk 0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102108114120P
ro
b
ab
ili
ty
(
%
)
o
f
E
ve
n
t
HR = 0.45 (95% CI = 0.38, 0.54)
Everolimus + Exemestane: 7.8 mo
Placebo + Exemestane: 3.2 mo
Local Assessment
0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 485 239 427 179 359 114 292 76 239 56 211 39 166 31 140 27 108 16 77 13 62 9 48 6 32 4 21 1 18 0 11 0 10 0 5 0 0 00
20
40
60
80
100
P
ro
b
ab
ili
ty
(
%
)
o
f
E
ve
n
t
Time, wkHR = 0.38 (95% CI = 0.31, 0.48)
Everolimus + Exemestane: 11.0 mo
Placebo + Exemestane: 4.1 mo
Log-rank P value: < .0001
EVE+EXE PBO+EXENumber of patients still at risk
Central Assessment
BOLERO-2: PFS at 18 Months / Median FUP
55% reduction in the risk of
progression or death
(local analysis)
62% reduction in the risk of
progression or death
(central analysis)
(independent blind radiology committee)
33
Abstract LBA502 <br /><br /> A Double Blind Phase 3 Trial of Fulvestrant With or Without Palbociclib in Pre- and Post-menopausal Women With Hormone Receptor-positive, HER2-negative Advanced Breast Cancer That Progressed on Prior Endocrine Therapy<br />(PALOMA3 Study)
Câncer de Mama RH+/HER2 avançado
Tratamento após progressão em primeira linha
Progressão em
tratamento
adjuvante em
adjuvância/doença
metastática
•
Quimioterapia
Resistência
Endócrina
•
Fulvestranto 500 mg
Apenas para
pacientes com
necessidade de
rápido controle
•
Everolimo + exemestano
NCCN
1
ABC-1
2
Atualização do ABC2
3
Recomenda 3 tratamentos
endócrinos consecutivos antes
de encaminhar a paciente para
quimioterapia
Sem consenso após IA
inicial. Opções incluem:
•Tamoxifeno
•Outro IA
•Fulvestranto
•Acetato de Megestrol
Primeira linha recomentada é IA ou
TAM, dependendo do tipo e duração
da adjuvância. Fulvestranto é
também uma opção.
†
*Guidelines refer to postmenopausal HR+ advanced breast cancer, and recommend endocrine therapy for patients who are not in visceral crisis. †The decision to treat must take into account the relevant toxicities associated with this combination and should be made on a case-by-case basis.