Câncer de Mama Metastático Quimioterapia Patrícia Schorn

Índice Ixabepilona Eribulina Bevacizumab – E2100, AVADO, RIBBON-1,RIBBON -2, German CALGB 40502 Manutenção até progressão

IXABEPILONA

Ixabepilona - epotilona B estabilizadoras de microtúbulos resistência aos taxanos ativa em CMM em estudos fase II

1221 pacientes CMM previamente tratados com antraciclinas / taxanos Randomized phase III trial of Ixabepilone plus Capecitabine versus Capecitabine in patientes with metastatic breast cancer previously treated with and anthracicline and a taxane Desenho estudo Ixabepilona 40 mg/m² q3s + Capecitabina 2g/m2/d/14d q3s 1221 pacientes CMM previamente tratados com antraciclinas / taxanos Capecitabina 2g/m2/d/14d q3s Objetivo primário: sobrevida global Objetivo secundádio: sobrevida livre de progressão, resposta

RESULTADOS PFS OS

Performance Status – faz diferença?

Recidiva precoce – faz diferença?

Take home message 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)

ERIBULINA

EMBRACE: Eribulin monotherapy versus treatment of physician’s choice in patients whit metastatic breast cancer – a phase 3 open-label randomised study Eribulina

CMM/ recorrência local esquemas de QT prêvia (A,T) EMBRACE: Eribulin monotherapy versus treatment of physician’s choice in patients whit metastatic breast cancer – a phase 3 open-label randomised study Eribulina - inibidor de microtúbulos inibe a fase de crescimento dos microtúbulos forma agregados de tubulina Eribulina 1,4 mg/m2 D1 e D8 q3s (n=508) CMM/ recorrência local esquemas de QT prêvia (A,T) (762) Tratamento de escolha do médico (NVB, GZ,X, Tax, A, outros, HT) (n=254) Desfecho Primário: sobrevida Global

EMBRACE: Eribulin monotherapy versus treatment of physician’s choice in patients whit metastatic breast cancer – a phase 3 open-label randomised study OS P>0,001 PFS P>0,0001

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 .

Bevacizumab E 2100 AVADO primeira linha RIBBON-1 GERMAN RIBBON-2 segunda linha

E2100 incluiu 232 pacientes com CMTN (32%)1,2 Paclitaxel +/- Bevacizumab in Metastatic Breast Cancer (E2100) •Objetivo primário: PFS –Outros objetivos: ORR, OS, qualidade de vida, segurança MBC, metastatic breast cancer; TTP, time to progression.   William J. Gradishar, MD, FACP: My take-home message would be that healthcare professionals should be familiar with mTOR inhibitors because they are likely going to be using them in clinical practice. Practitioners should be familiar with the associated toxicities of mTOR inhibitors so they can manage and educate their patients. As we have discussed, there is a biologic rationale to use mTOR inhibitors in the hormone setting, a biologic rationale for combining them with chemotherapy, and a biologic rationale for combining them with HER2-targeted therapies. Kathy D. Miller, MD: I agree that there is a biologic rationale for combining mTOR inhibitors with many of the agents commonly used in clinical practice, but there is also real potential for toxicity. It is likely that we will see reports from other studies looking at mTOR inhibitors in combination with a variety of different therapies—these should really be done in the context of a clinical trial, both for safety and to identify patients who will benefit most, so that we can use these agents responsibly. E2100 incluiu 232 pacientes com CMTN (32%)1,2 Miiler at al. N Engl J Med 2007; O’Shaughnessy et al. SABCS 2010

AVADO incluiu 279 pacientes com CMTN (23%) MBC, metastatic breast cancer; TTP, time to progression.   William J. Gradishar, MD, FACP: My take-home message would be that healthcare professionals should be familiar with mTOR inhibitors because they are likely going to be using them in clinical practice. Practitioners should be familiar with the associated toxicities of mTOR inhibitors so they can manage and educate their patients. As we have discussed, there is a biologic rationale to use mTOR inhibitors in the hormone setting, a biologic rationale for combining them with chemotherapy, and a biologic rationale for combining them with HER2-targeted therapies. Kathy D. Miller, MD: I agree that there is a biologic rationale for combining mTOR inhibitors with many of the agents commonly used in clinical practice, but there is also real potential for toxicity. It is likely that we will see reports from other studies looking at mTOR inhibitors in combination with a variety of different therapies—these should really be done in the context of a clinical trial, both for safety and to identify patients who will benefit most, so that we can use these agents responsibly. - Objetivo primário: PFS AVADO incluiu 279 pacientes com CMTN (23%) Robert at al. ASCO 2009; O’Shaughnessy et al. SABCS 2010

incluiu 110 pacientes com CMTN (15%) RIBBON-1 n-87 n-50 n-96 n-46 Escolha investigador MBC, metastatic breast cancer; TTP, time to progression.   William J. Gradishar, MD, FACP: My take-home message would be that healthcare professionals should be familiar with mTOR inhibitors because they are likely going to be using them in clinical practice. Practitioners should be familiar with the associated toxicities of mTOR inhibitors so they can manage and educate their patients. As we have discussed, there is a biologic rationale to use mTOR inhibitors in the hormone setting, a biologic rationale for combining them with chemotherapy, and a biologic rationale for combining them with HER2-targeted therapies. Kathy D. Miller, MD: I agree that there is a biologic rationale for combining mTOR inhibitors with many of the agents commonly used in clinical practice, but there is also real potential for toxicity. It is likely that we will see reports from other studies looking at mTOR inhibitors in combination with a variety of different therapies—these should really be done in the context of a clinical trial, both for safety and to identify patients who will benefit most, so that we can use these agents responsibly. incluiu 110 pacientes com CMTN (15%) Mayer IA, et al. SABCS 2011. Abstract PD09-06.

Bevacizumab x PFS HR (IC 95%) 10 Mediana PFS (MESES) QT 8,1 6,5 QT + B 12 0,49 (0,34-0,70) 0,68 (0,46-0,99) 0,78 (0,53-1,15) 0,72 (0,49-1,06) 10 10 8 Mediana PFS (MESES) QT 6 8,1 6,5 QT + B 4 6,2 6,1 6,1 5,3 4,2 2 E2100 AVADO RIBBON-1 Tax/Ac RIBBON-1 Capecitabina

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, extensively treated with anthracycline and taxane therapy, a high tumour grade 1. Schneeweiss et al. EMCC 2011

German Oncology Practice Study: Efficacy in TNBC and Non-TNBC Subgroups 1. Schneeweiss et al. EMCC 2011

Take Home Message 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

Taxane or gemcitabine or capecitabine RIBBON-2 trial design Investigator,s choice of chemotherapy } Treat to disease progression; crossover after progression permitted HER2-negative LR/mBC, one prior Line of CT, no prior Anti-VEGF therapy (n=684) Taxane or gemcitabine or capecitabine or vinorelbine BEV + CT R PLA + CT 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

RIBBON-2 Breast Cancer Res Treat , 22 february 2012

RIBBON-2 Breast Cancer Res Treat , 22 february 2012

RIBBON-2 Breast Cancer Res Treat , 22 february 2012

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

FOR INTERNAL USE ONLY: It remains the responsibility of the individual markets to ensure that all promotional, educational and internal materials that are produced using the branding elements and templates provided are approved by local affiliate, medical, legal and regulatory functions Take Home Message 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. 28

BEVACIZUMAB, IXABEPILONA E NAB-PACLITAXEL

Stratified by receipt of adjuvant taxanes and HR status 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) Treatment-naive patients with locally recurrent or metastatic breast cancer (N = 799) 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) 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.

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.

Proportion Progression Free Nab-Paclitaxel vs Ixabepilone in MBC: Survival Not Improved vs Paclitaxel PFS OS 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 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 1 0.8 0.8 Paclitaxel Nab-paclitaxel Ixabepilone 0.6 0.6 Proportion Progression Free Proportion Alive 0.4 0.4 Paclitaxel Nab-paclitaxel Ixabepilone 0.2 0.2 10 20 30 10 20 30 Mos Mos Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

Nab-Paclitaxel vs Ixabepilone in MBC: More Discontinuation vs Paclitaxel 60 Paclitaxel Nab-paclitaxel Ixabepilone 50 40 30 Discontinued (%) 20 10 1 2 3 4 5 Cycle number 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.

Grade ≥ 3 Adverse Event (%) Nab-Paclitaxel vs Ixabepilone in MBC: Worse Toxicities vs Paclitaxel P < .0001 90 Nab-paclitaxel 79 80 P = .005 Paclitaxel Ixabepilone 70 P = .004 59 60 60 55 56 51 50 44 Grade ≥ 3 Adverse Event (%) 40 30 21 20 12 10 Any Hematologic Nonhematologic Rugo HS, et al. ASCO 2012. Abstract CRA1002. Used with permission.

FOR INTERNAL USE ONLY: It remains the responsibility of the individual markets to ensure that all promotional, educational and internal materials that are produced using the branding elements and templates provided are approved by local affiliate, medical, legal and regulatory functions Take Home Message 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 35

QUIMIOTERAPIA DE MANUTENÇAO

Primary endpoint: PFS from randomization 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) Patients with MBC and CR, PR, or SD to 6 cycles first-line paclitaxel/gemcitabine* (N = 231) Observation until progression (n = 115) *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.

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.

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.

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.

FOR INTERNAL USE ONLY: It remains the responsibility of the individual markets to ensure that all promotional, educational and internal materials that are produced using the branding elements and templates provided are approved by local affiliate, medical, legal and regulatory functions Take Home Message 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 41

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