22 atualização tratamento sistêmico
TRANSCRIPT
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HER2 negativo
Atualização TratamentoSistêmico
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Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
Manutenção (?)
Hormonioterapia Faslodex na primeira linha Everolimus Duplo bloqueio hormonal (?)
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Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
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CALGB 40502: Bevacizumab Plus Nab-Pac, Ixabepilone, or Pac in Untreated MBC
Treatment-naive patients with locally recurrent or
metastatic breast cancer(N = 799)
Paclitaxel 90 mg/m2/wk +Bevacizumab* 10 mg/kg q2w
(n = 283)
Nab-paclitaxel 150 mg/m2/wk +Bevacizumab* 10 mg/kg q2w
(n = 271)
Ixabepilone 16 mg/m2/wk +Bevacizumab* 10 mg/kg q2w
(n = 245)
Disease progression†Stratified by receipt of adjuvant taxanes and HR status
Note: All chemotherapy given for 3 wks on, 1 wk off.*Protocol amended in March 2011 (n = 669) to allow optional use of bevacizumab following ODAC recommendation that approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab.†Patients with SD or responding disease after 6 cycles could discontinue chemotherapy and continue bevacizumab alone.
Rugo HS, et al. ASCO 2012. Abstract CRA1002.
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Bevacizumab Plus Nab-Pac, Ixabepilone, or Paclitaxel in MBC: Interim Monitoring First interim PFS analysis (165 events)
– Ixabepilone vs paclitaxel crossed superiority futility boundary
– Accrual to ixabepilone arm closed July 2011
Second interim PFS analysis (236 events)
– Nab-paclitaxel vs paclitaxel crossed superiority futility boundary
– Study closed November 2011
Rugo HS, et al. ASCO 2012. Abstract CRA1002.
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Nab-Paclitaxel vs Ixabepilone in MBC: Survival Not Improved vs Paclitaxel
PFS OS
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
Comparison HR P Value 95% CI
Nab vs Pac 1.19 .12 0.96-1.49
Ixa vs Pac 1.53 < .0001 1.24-1.90
1
0.8
0.6
0.4
0.2
0Pro
po
rtio
n P
rog
ress
ion
Fre
e
0 10 20 30
PaclitaxelNab-paclitaxelIxabepilone
Mos
Comparison HR P Value 95% CI
Nab vs Pac 1.02 .92 0.75-1.38
Ixa vs Pac 1.28 .10 0.95-1.72
1
0.8
0.6
0.4
0.2
0
Pro
po
rtio
n A
live
0 10 20 30
PaclitaxelNab-paclitaxelIxabepilone
Mos
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Nab-Paclitaxel vs Ixabepilone in MBC: More Discontinuation vs Paclitaxel
45% dose reductions with nab-paclitaxel by cycle 3 compared with 15% for both ixabepilone and paclitaxel
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
Dis
con
tin
ued
(%
)
Cycle number1 2 3 4 5
60
50
40
30
20
10
0
PaclitaxelNab-paclitaxelIxabepilone
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Nab-Paclitaxel vs Ixabepilone in MBC: Worse Toxicities vs Paclitaxel
P < .0001
P = .004
P = .0002
P = .005
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
90
Gra
de
≥ 3
Ad
vers
e E
ven
t (%
)
80
70
60
50
40
30
20
10
0
79
5559
51
21
12
6056
44
Nab-paclitaxel (n = 258)Paclitaxel (n = 262)Ixabepilone (n 237)
Any Hematologic Nonhematologic
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Nab-Paclitaxel vs Ixabepilone vs Paclitaxel in MBC: Adverse EventsGrade 3/4 Adverse Event, % Nab-Paclitaxel
(n = 258)Paclitaxel(n = 262)
Ixabepilone(n = 237)
Leukopenia 17 (P = .0004) 7 3 (P = .042)
Neutropenia 47 (P = .0001) 18 7 (P = .0002)
Hypertension 7 8 11
Fatigue 16 (P = .010) 9 15 (P = .036)
Pain 10 (P = .010) 4 4
Neuropathy
Motor 10 (P = .0003) 2 6 (P = .021)
Sensory 25 (P = .012) 16 25 (P = .022)
• Grade 3 24 16 22
• Grade 4 1 < 1 3
Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.
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Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
Manutenção (?)
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Phase III Study: Maintenance vs Obs in MBC with Response to First-line Pac/Gem
Primary endpoint: PFS from randomization Secondary endpoints: OS, toxicity, QOL, DOR
Im Y-H, et al. ASCO 2012. Abstract 1003.
Maintenance Paclitaxel and Gemcitabine*until progression
(n = 116)Patients withMBC and CR, PR, or SD
to 6 cycles first-linepaclitaxel/gemcitabine*
(N = 231) Observationuntil progression
(n = 115)
*Paclitaxel 175 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Days, 1, 8 q3w
Stratified by visceral disease, prior adjuvant taxane, response (CR/PR vs SD), HR status
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Maintenance vs Observation in MBC With Response to First-line Pac/Gem: Results
Maintenance(n = 116)
Observation(n = 115)
HR (95% CI) P Value
Median PFS, mos 7.5 3.8 0.73 (0.55-0.96) .026
Median OS, mos 36.8 28.0 0.65 (0.42-0.99) .048
Dose delivery, % Paclitaxel Gemcitabine
94.786.6
95.991.7
Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.
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Maint vs Obs in MBC With Response to First-line Pac/Gem: Grade ≥ 3 AEs
Im Y-H, et al. ASCO 2012. Abstract 1003. Used with permission.
Grade 3/4 AE, n (%)
Cycles 1-6 Cycle 7 and Beyond
Maint(n = 116)
Obs(n = 115)
P ValueMaint
(n = 116)Obs
(n = 115)P Value
Neutropenia 80 (69.0) 78 (67.8) .57 71 (61.2) 1 (0.9) < .0001
Thrombocytopenia 0 1 (0.9) .50 1 (0.9) 0 .50
Anemia 3 (2.6) 6 (5.2) .33 1 (0.9) 0 .50
Azotemia 0 0 NS 5 (4.3) 0 .06
AST ↑ 0 0 NS 1 (0.9) 1 (0.9) .10
ALT ↑ 4 (3.4) 2 (1.7) .68 0 0 NS
Febrile neutropenia 0 3 (2.6) .12 0 0 NS
Diarrhea 0 2 (1.7) .25 1 (0.9) 1 (0.9) .10
Grade 3 neuropathy 4 (3.4) 1 (1.7) .68 4 (3.4) 2 (1.7) .68
Grade 2/3 neuropathy 32 (27.6) 39 (33.9) .30 49 (42.2) 18 (15.7) < .0001
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Maint vs Obs in MBC With Response to First-line Pac/Gem: Expert Perspectives Maintenance paclitaxel/gemcitabine in responding patients with MBC
substantially prolonged PFS vs observation
– 3.8 vs 7.5 mos (HR: 0.73; 95% CI: 0.55-0.96; P = .026)
OS significantly prolonged in maintenance arm
Maintenance therapy was tolerable and feasible
No negative effect on QoL with maintenance
Maintenance paclitaxel/gemcitabine after 6 cycles should be considered for selected patients
– Hormone receptor negative
– Visceral disease
– High tumor burden
– 50 yrs of age or younger
– Premenopausal
Im Y-H, et al. ASCO 2012. Abstract 1003.
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Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
Manutenção (?)
Hormonioterapia Faslodex na primeira linha Everolimus Duplo bloqueio hormonal (?)
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Clinical scenario
“Virgem” de Tratamento
Tamoxifen sensível (TAM sens.)
Tamoxifen resistente (TAM resist.)
IA resistente (IA resist.)
⌫
⌫
⌫
⌫
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‘Virgem’ Tratamento &Sensível ao TAM
Imagem do cristal de ESTRADIOL por microscopia de luz polarizada
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Opções
Tamoxifeno (TAM)
Inibidor da Aromatase (IA)
Fulvestranto (Fulv)
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Tamoxifenoversus
Inibidor da Aromatase
Imagem do cristal de TAMOXIFENO por microscopia de varredura
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Resposta Objetiva (%)
ANAST ANAST LETRO EXEMEST10
20
30
40
50
60
70
80
17
32.6
21
31.2
21.1
32.9 32
45.6
TAM IA
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ANAST ANAST LETRO EXEMEST10
20
30
40
50
60
70
80
45.6
55.5
3841.7
59.156.2
50
66.2
TAM IA
Benefício Clínico (%)
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ANAST ANAST LETRO EXEMEST0
2
4
6
8
10
12
5.6
8.2
6 5.8
11.1
8.2
9.49.9
TAM IA
Tempo até Progressão (meses)
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Time-to-Chemotherapy
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Tamoxifenoversus
Fulvestranto
Imagem do cristal de ESTRADIOL por microscopia de varredura
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Resposta Objetiva &Benefício Clínico (%)
RO BC10
20
30
40
50
60
70
80
31.6
62
33.9
54.3
TAM FULV
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TAP0
2
4
6
8
10
12
8.3
6.8
TAM FULV
Tempo até Progressão (meses)
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Clinical scenario
“Virgem” de Tratamento
Tamoxifen sensível (TAM sens.)
Tamoxifen resistente (TAM resist.)
IA resistente (IA resist.)
⌫
⌫
⌫
⌫
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Resistente ao TAM
Imagem do cristal de ESTRADIOL por microscopia de luz polarizada
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Opções
Inibidor da Aromatase (IA)
Fulvestranto (Fulv)
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Anastrozolversus
Fulvestranto
Imagem do cristal de ESTRONA por microscopia de luz polarizada
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TAM resistente
Estudo Americano
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Estudo Europeu
TAM resistente
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Fulvestranto dose
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Fulvestranto dose
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Fulvestranto dose
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Fulvestrant dose
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Fulvestranto dose
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CONFIRM loading and high dose
RR (%)
CB (%)
TTP* (m)
DOCB (m)
OS(m)
FULVESTRANT
250 mg 9.1% 39.6%
5.5 16.6 22.8
500 mg 10.2%
45.6%
6.5 13.9 22,8*HR=0.80; p=0.006
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CONFIRM loading and high dose
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FIRST 500 mg vs ANA 1 mg
RR (%)
CB (%)
TTP (m)
FULVESTRANT
14% 41.2%
23,4
ANASTROZOLE
8.8% 42% 13.1
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FIRST 500 mg vs ANA 1 mg
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Imagem do cristal de PROGESTERONA por microscopia de luz polarizada
Resistente aoIA não-esteroidal
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Opções
Exemestano
Exemestano + Everolimus
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Exemestanoversus
Fulvestranto
Imagem do cristal de Testosterona por microscopia de varredura
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RO BC0
10
20
30
40
50
60
70
6.7
32.2
7.4
31.5
EXEMEST FULV
Resposta Objetiva &Benefício Clínico (%)
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Exemestane & Fulvestrant3,7 months
Tempo até Progressão (meses)
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IA (non-steroidal) resistant
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IA (non-steroidal) resistant
Placebo PO dailyExemestane 25 mg PO daily (N=239)
Everolimus 10 mg PO dailyExemestane 25 mg PO daily
(N=485)Postmenopausal ER+, Her2-, unresectable locally advanced or metastatic breast cancer refractory to letrozole or anastrozole
R
N = 7242:1
(everolimus:placebo)
PFS
OSORR
Bone MarkersSafety
PK
Stratification:1. Sensitivity to prior hormonal therapy2. Presence of visceral disease
No cross-over
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IA (non-steroidal) resistant
RR (%)
CB (%)
TTP (m)
EXEMESTANE 0,4% - 4.1
EXE + Everolimus
9.0% - 10,6
BOLERO2 study
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IA (non-steroidal) resistant
Time (weeks)
HR = 0.36 (95% CI: 0.27–0.47)
EVE + EXE: 10.6 MonthsPBO + EXE: 4.1 Months
Log rank P value = 3.3 x 10 -15
0 126 18 24 30 36 48 6042 54 7266 78
80
60
40
20
100
0
Pro
babili
ty o
f Event
(%)
Everolimus + Exemestane (E/N=114/485)Placebo + Exemestane (E/N=104/239)
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IA (non-steroidal) resistant
P < 0.0001
P < 0.0001
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TAM
IA
FULV
IA
FULV
EXEM
FULV
BOLERO2
0 5 10 15 20 25
6
23,4
5
5
4
10
10Naive/TAM sens.
TAM resist.
AI resist.
500 mg
5