Câncer de Mama Metastático Quimioterapia Patrícia Schorn.
Transcript of Câncer de Mama Metastático Quimioterapia Patrícia Schorn.
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Câncer de Mama MetastáticoQuimioterapia
Patrícia Schorn
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Índice
• Ixabepilona• Eribulina• Bevacizumab – E2100, AVADO, RIBBON-
1,RIBBON -2, German• CALGB 40502• Manutenção até progressão
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IXABEPILONA
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Ixabepilona - epotilona B estabilizadoras de microtúbulos
resistência aos taxanos
• ativa em CMM em estudos fase II
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Objetivo primário: sobrevida globalObjetivo secundádio: sobrevida livre de progressão, resposta
Randomized phase III trial of Ixabepilone plus Capecitabine versus Capecitabine in patientes with metastatic breast cancer previously treated with and anthracicline and a taxane
Ixabepilona 40 mg/m² q3s+
Capecitabina 2g/m2/d/14dq3s
Capecitabina 2g/m2/d/14dq3s
1221 pacientes CMM previamente tratados com
antraciclinas / taxanos
Desenho estudo
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PFS OS
RESULTADOS
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Performance Status – faz diferença?
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Recidiva precoce – faz diferença?
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• Ixabepilona (Ixempra®, BMS) é ativa no tratamento do câncer de mama metastático após exposição/resistência a antraciclinas e taxanos ;
• A associação de ixabepilona e capecitabina é superior a capecitabina isolada com benefício em PFS;
• O benefício é mantido em pacientes com performance status reduzido (70-80) e em pacientes com recidiva precoce (<12 meses após A/T)
Take home message
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ERIBULINA
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EMBRACE: Eribulin monotherapy versus treatment of physician’s choice in patients whit metastatic breast cancer – a phase 3 open-label randomised study
Eribulina
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Eribulina - inibidor de microtúbulos inibe a fase de crescimento dos microtúbulos forma agregados de tubulina
EMBRACE: Eribulin monotherapy versus treatment of physician’s choice in patients whit metastatic breast cancer – a phase 3 open-label randomised study
CMM/ recorrência local esquemas de QT prêvia (A,T)
(762)
Eribulina 1,4 mg/m2 D1 e D8 q3s (n=508)
Tratamento de escolha do médico (NVB, GZ,X, Tax, A, outros, HT)
(n=254)
Desfecho Primário: sobrevida Global
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EMBRACE: Eribulin monotherapy versus treatment of physician’s choice in patients whit metastatic breast cancer – a phase 3 open-label randomised study
OSP>0,001
PFSP>0,0001
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Take home message
• A eribulina (Halaven®, Eisai Co.) apresenta benefício em PFS e OS em mulheres com câncer de mama metastático extensamente tratadas;
• 5% de suspensão de tratamento por neuropatia periférica ( 35% de incidência);
• Aprovado para tratamento de câncer de mama metastático com 2 esquemas prévios incluindo antraciclina e taxano .
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Bevacizumab
• E 2100• AVADO primeira linha
• RIBBON-1• GERMAN
• RIBBON-2 segunda linha
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Miiler at al. N Engl J Med 2007; O’Shaughnessy et al. SABCS 2010
E2100 incluiu 232 pacientes com CMTN (32%)1,2
•Objetivo primário: PFS –Outros objetivos: ORR, OS, qualidade de vida, segurança
Paclitaxel +/- Bevacizumab in Metastatic Breast Cancer (E2100)
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Robert at al. ASCO 2009; O’Shaughnessy et al. SABCS 2010
AVADO
n-52
n-53
n-58
- Objetivo primário: PFS
AVADO incluiu 279 pacientes com CMTN (23%)
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Mayer IA, et al. SABCS 2011. Abstract PD09-06.
RIBBON-1
n-87
n-50
n-96
n-46Escolha investigador
incluiu 110 pacientes com CMTN (15%)
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5,36,2 6,5
4,26,1
10
6,18,1
E2100 AVADO RIBBON-1Tax/Ac
RIBBON-1Capecitabina
QT
QT + B
0,49(0,34-0,70)
0,68(0,46-0,99)
0,78(0,53-1,15)
0,72(0,49-1,06)
HR (IC 95%)
Bevacizumab x PFS
12
0
2
4
6
8
10
Med
iana
PFS
(MES
ES)
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German Oncology Practice Study (First-Line):Open-Label, Single-Arm ‘Real-World’ Study
• Multicentre non-interventional study
• Endpoints: safety and efficacy
• 818 154 patients had TNBC 664 patients had positive or unknown ER, PgR and/or HER2 status
• TNBC group (younger, a short disease-free interval, lung metastases, extensivelytreated with anthracycline and taxane therapy, a high tumour grade
1. Schneeweiss et al. EMCC 2011
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German Oncology Practice Study:Efficacy in TNBC and Non-TNBC Subgroups
1. Schneeweiss et al. EMCC 2011
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•Bevacizumab em primeira:
- Tratamento efetivo para pacientes com câncer de mama metastático - TN - Rotina oncológica confirmada pelos dados descritos
- Média PFS of 8.0 months
Take Home Message
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RIBBON-2 trial design
HER2-negativeLR/mBC, one priorLine of CT, no priorAnti-VEGF therapy
(n=684)
Taxane or gemcitabine or capecitabine or vinorelbine
RBEV + CT
PLA + CT
Treat to disease
progression;crossover
after progression permitted
}Investigator,s
choice ofchemotherapy
•Taxane (paclitaxel 90mg/m² d1, 8, 15 q4w or paclitaxel 175 mg/m²,nab- paclitaxel 260mg/m², or docetaxel 75-100 mg/m² q3w)• Gemcitabine ( 1250 mg/m² d1, 8 q3w)• Cabine ( 1000 mg/m² bid d1-14 q3w)• Vinorelbine ( 30 mg/m² d1, 8, 15 q3w)• BEV or PLA (15mg/Kg q3w or 10 mg/kg q2w, depending on CT regimen)
Breast Cancer Res Treat , 22 february 2012
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RIBBON-2
Breast Cancer Res Treat , 22 february 2012
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Breast Cancer Res Treat , 22 february 2012
RIBBON-2
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RIBBON-2
Breast Cancer Res Treat , 22 february 2012
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RIBBON-2: Conclusions
• Bevacizumab combinado com quimioterapia em segunda linha determina benefício de sobrevida livre de progressão e taxa de resposta
- PFS: HR0,49 (median 6.0 vs 2,7 months)- ORR: 41% vs 18%
• Tendência de beneficio em sobrevida global - OS: HR 0,624 (median 17.9 vs 12.6 months), p= 0,0534;
• Dados sugerem que em pacientes com câncer de mama metastático TN que não receberam Bevacizumab em primeira linha, a droga é uma opção
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Take Home Message
28
• Bevacizumabe combinado com Paclitaxel semanal duplica a taxa de resposta e TLP sem aumento da sobrevida global.
• O impacto em pacientes com CMTN é semelhante.• Na segunda linha, o uso de Bevacizumab apresenta impacto
semelhante ao da primeira linha. • Bevacizumabe continua aprovado para o tratamento de CMM
em combinação com Paclitaxel semanal no Brasil e com Paclitaxel e Capecitabina na Europa (EMA).
• NCCN manteve a sua recomendação.
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BEVACIZUMAB, IXABEPILONA E NAB-PACLITAXEL
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CALGB 40502: Bevacizumab Plus Nab-Pac, Ixabepilone, or Pac in Untreated MBC
Stratified by receipt of adjuvant taxanes and HR status
Disease progression†
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)
Treatment-naive patients with locally recurrent or metastatic breast cancer
(N = 799)
Note: All chemotherapy given for 3 wks on, 1 wk off.*†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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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: Survival Not Improved vs Paclitaxel
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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: 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.
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P < .0001
P = .004
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
Any Hematologic Nonhematologic
Nab-Paclitaxel vs Ixabepilone in MBC:
Worse Toxicities vs Paclitaxel
PaclitaxelNab-paclitaxel
Ixabepilone
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Take Home Message
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• Paclitaxel apresenta benefício de PFS em relação a Ixabepilona e nab-paclitaxel (não significativo)
• Não há impacto em sobrevida global
• Maior interrupção do tratamento para Ixabepilona e nab-paclitaxel
• Menor toxicidade para paclitaxel em comparaçào a Ixabepilona e nab-paclitaxel
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QUIMIOTERAPIA DE MANUTENÇAO
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Phase III Study: Maintenance vs Obs in MBC with Response to First-line Pac/Gem
Stratified by visceral disease, prior adjuvant taxane, response (CR/PR vs SD), HR status
Maintenance Paclitaxel and Gemcitabine*until progression
(n = 116)
Observationuntil progression
(n = 115)
Patients withMBC and CR, PR, or SD
to 6 cycles first-linepaclitaxel/gemcitabine*
(N = 231)
*Paclitaxel 175 mg/m2 on Day 1 and gemcitabine 1250 mg/m2 on Days, 1, 8 q3w
Primary endpoint: PFS from randomization Secondary endpoints: OS, toxicity, QOL, DOR
Im Y-H, et al. ASCO 2012. Abstract 1003.
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Maintenance vs Observation in MBC With Response to First-line Pac/Gem: Results
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.
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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
Im Y-H, et al. ASCO 2012. Abstract 1003.
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Take Home Message
41
• Quimioterapia de mautenção com Paclitaxel e Gemcitabina em pacientes com resposta apresenta benefício de PFS e OS
• Boa tolerância, toxicidade aceitável
• Adequada seleção de pacientes
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Obrigada