Tratamento hormonal da doença metastática

Transcrição

1 Tratamento hormonal da doença metastática Daniele Assad, MD, MSc Oncologia clínica Hospital Sírio Libanês- Brasília

2 Conflitos de interesses De acordo com a Resolução 1931/2009 do Conselho Federal de Medicina e com a RDC 96/2008 da ANVISA, declaro que: Aulas como speaker das industrias: Roche, Pfizer, Astrazenica

3 Can Molecular Profiles Help Define Endocrine Sensitivity? Luminal subtype can guide decision towards adjuvant chemotherapy Luminal subtype does not guide the choice of endocrine therapy

4 Prognostic Value of Intrinsic Subtypes in Hormone Receptor- Positive metastatic Breast Cancer Treated with Letrozole With or Without Lapatinib HER2-negative disease treated with placebo Unsupervised clustering heatmap of the 821 samples and the PAM50 genes JAMA Oncology October 2016 Volume 2, Number 10

5 Casos Clínicos Caso 1 Paciente pós menopausa, 48 anos, CDI de mama 4 linfonodos positivos: QT adjuvante: AC/paclitaxel Tamoxifen adjuvante por 2 anos seguido de anastrozol adjuvante por 5 anos Sem doença por 3 anos Agora com 59 anos, com dor lombar. Caso 2 Paciente 60 anos, pós menopausa, CDI de mama IIIC, luminal B HER2- Ki 67 40% QT neo AC- taxol- cirurgia+ RT Letrozol adjuvante por 1 ano com progressão de doença óssea e linfonodal O que fazer? CO: lesões ósseas. Biópsia confirmou doença metastática com mesmo perfil do primário IHQ: ER+ PR+ HER2- O que fazer?

6 Sumário Estudos de hormonioterapia em 1ª linha Estudos de hormonioterapia em 2ª linha Inibidores CDK4/6 Inibidores de mtor Mecanismos de resistência endócrina

7 Milestones in the treatment of HR+ ABC Tamoxifen Exemestane Everolimus + exemestane CDK 4/6 i + letrozole Letrozole Toremifene Anastrozole Fulvestrant Fulvestrant + anastrozole Ana + trastuzumab Let + Lapatinib

8 1ª Linha Bonneterre 2001 (Combined ) Mouridsen 2007 (PO25) Paridaens 2008 Robertson 2009 (FIRST) Mehta 2012 (SWOG 0226) Bergh 2012 (FACT) Tam Ana Let Ta m Exe Tam Ful Ana Ful+Ana Ana Ful+Ana Ana N= CBR% Not done Not done Median TTP (PFS) 5.8 (PFS) (PFS) 13.5 (PFS) hazard ratio = % CI: 1.00-NR; p = hazard ratio = 0.72 p <.0001 Log-rank p =.121 (p=0.028 using Wilcoxon test) hazard ratio = % CI: ; p =.01 p = hazard ratio = % CI: 0.81 to 1.20, p = 0.91 HR+ %

9 Falcon: PHASE III Study Design Postmenopausal women Locally advanced or metastatic breast câncer ER+ and/or PgR+ HER2- Endocrine therapy-naïve 1:1 Fulvestrant 500 mg (500 mg IM on Days 0, 14 and 28, then every 28 days) + placebo to anastrozole Anastrozole 1 mg (daily PO) + placebo to fulvestrant Primary endpoint: PFS a Secondy endpoints OS b DoCB, EDoCB ORR HRQoL (FACT-B CBR toal and TOI) DoR, EDoR Safety Randomised, double-blind, parallel-group, international, multicentre study Follow-up for disease progression and survival Randomization of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (long-rank test) Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic disease Subgroup analysis of PFS for pre-defined baseline covariates a Assessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; b Interim analysis at the time of PFS analysis EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, FunctionalAssessment of Cancer Therapy-Breast; TOI, Trial Outcome Index

10 The FALCON study - patients Fulvestrant (n=230) Anastrozole (n=232) Median age (years) Previous chemotherapy for early stage disease Previous chemotherapy for advanced disease 20% 18.5% 15.7% 18.5% ER-positive; PR-positive 76.1% 77.2% ER-positive only 19.1% 18.5% Visceral disease 58.7% 51.3% Ellis, ESMO 2016

11 PFS 16.6 months x 13.8 months

12 The FALCON Study - OS Fulvestrant (N=230) Anastrozole (N=232) Proportion of patients alive % maturity Median follow-up 25.0 months Number of patients at risk: HR 0.88 (95% CI 0.63, 1.22); p= Time (months) Fulvestrant Anastrozole

13 The FALCON Study with versus without visceral disease Proportion of patients alive and progression-free Without visceral disease HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Time (months) Fulvestrant (n=95) Anastrozole (n=113) Proportion of patients alive and progression-free With visceral disease 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) Time (months) Note: The PFS estimates for Anastrozole are > 12 months regardless of visceral disease Visceral disease is not an indication for first-line chemotherapy

14 Fulvestrant in the first-line setting? FALCON cohort does not reflect the majority of ER-positive stage IV patients in our clinics Patients in FALCON were all naïve to endocrine therapy De novo stage 4 disease (represents approx. 5-10% new diagnoses)

15 2ª Linha Buzdar 1998 Dombernowsky 1998 Kaufmann 2000 Rose 2003 Chia 2008 Johnston 2012 Di Leo -Confirm 2012 Ana Meg Let 2.5 mg Meg EXE Meg Let Ana Ful Exe Ful Ful + Ana Exe Ful 500 Ful 250 N= CBR Not availa ble TTP months Significance Hazard ratio = 0.94; p =.49 (0.76, 97.5% Ci, 1.16) p = 0.07 p = p = p = 0.98 p = 0.56 Hazard ratio = 0.80; 95% CI, 0.68 to 0.94 p = Known HR+ 26% 42% 68% 49% 98% 100% 100% 100%

16 PRIMARY ENDOCRINE RESISTANCE is defined as: Relapse while on the first 2 years of adjuvant ET, or PD within first 6 months of 1st line ET for MBC, while on ET. SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as: Relapse while on adjuvant ET but after the first 2 years, or Relapse within 12 months of completing adjuvant ET, or PD 6 months after initiating ET for MBC, while on ET.

17 Crosstalk das vias de sinalização JNCI J Natl Cancer Inst (2015) 107(10): djv212

18 PALOMA-2 and MONALEESA-2: Study Design PALOMA-2* MONALEESA-2** Postmenopausal ER+, HER2- advanced breast cancer No prior treatment for advanced disease Patients who are AI-resistant are excluded N = 666 2:1 Palbociclib 1:1 Ribociclib + + letrozole letrozole Randomization Placebo + letrozole Postmenopausal ER+, HER2- advanced breast cancer First-line Patients who are AI-resistant are excluded N = 668 Randomization Placebo + letrozole AI, aromatase inhibitor *Finn RS, et al. N Engl J Med. 2016; 375(20): **Hortobagyi GN, et al. N Engl J Med 2016; 375(18):

19 PALOMA-2 and MONALEESA-2: Progression-Free Survival (PFS) Analysis PALOMA-2* MONALEESA-2** *Finn RS, et al. N Engl J Med 2016; 375(20): **Hortobagyi GN, et al. N Engl J med 2016; 375(18): LET, letrozole; PAL, palbociclib; PBO, placebo

20 PALOMA3 Study Design HR+, HER2 ABC Pre- or post-menopausal Progressed on prior endocrine therapy: 2:1 Randomization N=521* n=347 Palbociclib (125 mg QD; 3 wks on/1 wk off) + Fulvestrant (500 mg IM q4w) On or within 12 mo adjuvant Stratification: On therapy for ABC 1 prior chemotherapy regimen for advanced cancer Visceral metastases Sensitivity to prior hormonal therapy Pre-/peri- vs Postmenopausal n=174 Placebo (3 wks on/ 1wk off) + Fulvestrant (500 mg IM q4w) Pre- and peri-menopausal women received concurrent ovarian function suppression with goserelin 1. Post-menopausal patients must have progressed on prior aromatase inhibitor therapy. HER2=human epidermal growth factor receptor 2; HR=hormone receptor; IM=intramuscular; q4w=once every 4 weeks; ABC=advanced breast cancer; QD=once daily. *Number of patients randomized; administered on Days 1 and 15 of Cycle 1. Clinicaltrials.gov NCT NCCN Guidelines: Breast Cancer Version Turner et al, ASCO 2015

21 PFS: ITT population Lancet Oncol; 17:

22 Hormonioterapia isolada x combinação com inibidores CDK4/6 Estudo Falcon- pacientes virgens de tratamento com HT x Paloma 2- incluiu também pacientes que receberam HT adjuvante (mais de 12 meses) SLP no Falcon: grupo fulvestranto 16,6 meses x 13,8 meses anastrozol SLP no Paloma 2: grupo letrozol+palbociclib 24,8 meses x 14,5 meses letrozol Aumento de toxicidades no Paloma 2- eventos adversos grau 3: combinação 76% x 24% letrozol Necessidade de monitorização laboratorial na combinação Seleção de pacientes: Falcon denovo Paloma-2 de novo e recorrência tardia (+ de 12 meses após término da adj) Paloma-3 recorrência precoce

23 BOLERO-2: Exemestano±Everolimus em pacientes refratárias a IA Não esteroidais Fase III; N = 724 Câncer de Mama Avançado HR+ HER2- Pós Menopausa refratário a Anstrozol ou Letrozol Recorrência durante ou em até 12m após término de HT adjuvante ou PD durante ou em até 1m após término de HT paliativo Everolimus 10 mg/d + Exemestano 25 mg/d (n = 485) Placebo + Exemestano 25 mg/d (n = 239) Endpoint primário: PFS Endpoints secundários: OS, ORR, CBR, segurança, QoL, marcadores ósseos Baselga J, et al. N Engl J Med. 2012;366(6):

24 BOLERO-2: Endpoint primário, SLP (F/U 12.5 meses - avaliação central) Probability of Not Having an Event, % HR = 0.36 (95% CI = 0.28, 0.45) Log-rank P value: < Everolimus + Exemestane: 11.0 mo (E/N = 155/485) Placebo + Exemestane: 4.1 mo (E/N = 127/239) Time, wk Abbreviations: CI, confidence interval; E/N, patients with events/total patients; HR, hazard ratio; PFS, progression-free survival. Hortobagyi G, et al. SABCS 2011; abstract S3-7 (oral).

25 Defining Endocrine Sensitivity / Resistance with Adjuvant Treatment

26 Alterações genômicas- alvos moleculares para terapêutica The Lancet December 6, 2016

27 Resistência endócrina 187 tumores metastaticos ER+ 21% mutaçaoer LBD Jeselsohn, R. et al. Nat. Rev. Clin. Oncol. 12, (2015);

28 Structural diagram of the ERα protein encoded by the ESR1 gene Jeselsohn, R. et al. Nat. Rev. Clin. Oncol. 12, (2015);

29 Alterações genéticas nos tumores primários x metastáticos ERα LBD mutada- elevada atividade do receptor na ausência de ligação com hormônio Clin Cancer Res; 20(7) April 1, 2014 Nature Genetics Volume 45 / Number 12 /December 2013

30 Jeselsohn, R. et al. Nat. Rev. Clin. Oncol. 12, (2015)

31 Analysis of ESR1 mutation in circulating tumor DNA demonstrates evolution during therapy for metastatic breast cancer PFS on AI therapy after ctdna analysis for patients with ESR1 mutant and WT ctdna ESR1 mutations are rarely acquired during adjuvant AI and frequently during metastatic AI therapy (HR, 3.1; 95% CI, 1.9 to 23.1) Sci Transl Med Nov 11;7(313):313ra182.

32 Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant Nature Communications 13 May 2016

33 Impact of ESR1 mutation on sensitivity to endocrine therapies in SoFEA ESR1 MUT ESR1 WT Fribbens et al. J Clin Oncol June 2016

34 Impact of ESR1 mutation on sensitivity to palbociclib in PALOMA3 ESR1 MUT ESR1 WT Fribbens et al. J Clin Oncol June 2016

35 Prevalence of ESR1 Mutations in Cell-Free DNA and Outcomes inmetastatic Breast Cancer A Secondary Analysis of the BOLERO-2 Clinical Trial OS for WT vs MT SG: 20.7 x 30.2 months Overall Survival (OS) by mutation and Multivariate Analysis a JAMA Oncol. 2016;2(10):

36 Mecanismos de resistência endócrina e estratégias de tratamento Ativação do ER independente do ligante: down regulation do receptor Sinalização alternativa: terapia combinada Fatores de transcriçao Drug Discovery Today Volume 21, Number 7 July 2016

37 Take home messages Podemos identificar pacientes com câncer de mama metastático que não responderão à terapia endócrina? Mudanças adaptativas nas vias de sinalização podem dificultar a identificação dos drivers dominantes O que acontece na clínica? Mutação do ESR1? Ou vias de sinalização alternativas up- regulated? Quais seriam os fatores para definir sequencia ótima? Biomarcadores? Quem pode usar hormonioterapia isolada? Após uso de terapia combinada com mtor ou CDK4/6 os tumores adquirem biologia diferente? Qual impacto na terapêutica?

38 Take home messages Inibidores CD4/6 são ferramentas valiosas em combinação com hormonioterapia no câncer de mama avançado Ainda incerto se a combinação deve ser oferecida em primeira linha para a maioria das pacientes Hormonioterapia isolada ainda é uma opção especialmente em pacientes com doença hormôniosensível

39 Custo Droga Dose Custo Mensal US Dollar Tamoxifeno 20 mg/dia $120 Anastrozol 1mg/dia $450 Letrozol 2,5 mg/dia $550 Exemestano 25 mg/dia $600 Fulvestranto Ampola 500 mg $2 000 Everolimus 10 mg/dia $ Palbociclib 125 mg D1-21 /28 dias $ *Custo da administração fulvestranto não incluído

40 O Futuro: testes com biomarcadores Journal of Cellular Biochemistry 114: (2013)

41 Pós menopausa- ASCO J Clin Oncol Sept, 2016

42 Obrigada