Atualização no Tratamento Infecções Fúngicas Pulmonares Miguel Aidé-UFF 2012.
22 atualização tratamento sistêmico
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Transcript of 22 atualização tratamento sistêmico
HER2 negativo
Atualização TratamentoSistêmico
Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
Manutenção (?)
Hormonioterapia Faslodex na primeira linha Everolimus Duplo bloqueio hormonal (?)
Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
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amended in March 2011 (n = 669) to allow optional use of bevacizumab following ODAC recommendation that approval be withdrawn for metastatic breast cancer; 98% of all patients received bevacizumab.†Patients with SD or responding disease after 6 cycles could discontinue chemotherapy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.
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.
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
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
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
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.
Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
Manutenção (?)
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
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.
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
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.
Tratamento da Doença Metastática QT Doença Metastática
Paclitaxel vs Nab-Paclitaxel vs Ixabepilona
Manutenção (?)
Hormonioterapia Faslodex na primeira linha Everolimus Duplo bloqueio hormonal (?)
Clinical scenario
“Virgem” de Tratamento
Tamoxifen sensível (TAM sens.)
Tamoxifen resistente (TAM resist.)
IA resistente (IA resist.)
⌫
⌫
⌫
⌫
‘Virgem’ Tratamento &Sensível ao TAM
Imagem do cristal de ESTRADIOL por microscopia de luz polarizada
Opções
Tamoxifeno (TAM)
Inibidor da Aromatase (IA)
Fulvestranto (Fulv)
Tamoxifenoversus
Inibidor da Aromatase
Imagem do cristal de TAMOXIFENO por microscopia de varredura
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
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 (%)
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)
Time-to-Chemotherapy
Tamoxifenoversus
Fulvestranto
Imagem do cristal de ESTRADIOL por microscopia de varredura
Resposta Objetiva &Benefício Clínico (%)
RO BC10
20
30
40
50
60
70
80
31.6
62
33.9
54.3
TAM FULV
TAP0
2
4
6
8
10
12
8.3
6.8
TAM FULV
Tempo até Progressão (meses)
Clinical scenario
“Virgem” de Tratamento
Tamoxifen sensível (TAM sens.)
Tamoxifen resistente (TAM resist.)
IA resistente (IA resist.)
⌫
⌫
⌫
⌫
Resistente ao TAM
Imagem do cristal de ESTRADIOL por microscopia de luz polarizada
Opções
Inibidor da Aromatase (IA)
Fulvestranto (Fulv)
Anastrozolversus
Fulvestranto
Imagem do cristal de ESTRONA por microscopia de luz polarizada
TAM resistente
Estudo Americano
Estudo Europeu
TAM resistente
Fulvestranto dose
Fulvestranto dose
Fulvestranto dose
Fulvestrant dose
Fulvestranto dose
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
CONFIRM loading and high dose
FIRST 500 mg vs ANA 1 mg
RR (%)
CB (%)
TTP (m)
FULVESTRANT
14% 41.2%
23,4
ANASTROZOLE
8.8% 42% 13.1
FIRST 500 mg vs ANA 1 mg
Imagem do cristal de PROGESTERONA por microscopia de luz polarizada
Resistente aoIA não-esteroidal
Opções
Exemestano
Exemestano + Everolimus
Exemestanoversus
Fulvestranto
Imagem do cristal de Testosterona por microscopia de varredura
RO BC0
10
20
30
40
50
60
70
6.7
32.2
7.4
31.5
EXEMEST FULV
Resposta Objetiva &Benefício Clínico (%)
Exemestane & Fulvestrant3,7 months
Tempo até Progressão (meses)
IA (non-steroidal) resistant
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
IA (non-steroidal) resistant
RR (%)
CB (%)
TTP (m)
EXEMESTANE 0,4% - 4.1
EXE + Everolimus
9.0% - 10,6
BOLERO2 study
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)
IA (non-steroidal) resistant
P < 0.0001
P < 0.0001
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