SECUENCIA TRATAMIENTO HORMONAL CMM

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2 SECUENCIA TRATAMIENTO HORMONAL CMM

3 ELECCIÓN DE IA + INH CDK COMO PRIMERA LINEA

6 PALOMA2/MONALEESA2 SUBGRUPOS

7 APLICABLE A TODAS LAS PACIENTES? EXISTEN OTRAS OPCIONES EN PRIMERA LINEA?

8 TIENE CABIDA FULVESTRANT EN ESTE LIO?

9 Opciones de HT: Fulvestrant Fulvestrant 28 OH 7 HO (CH 2 ) 9 SO(CH 2 ) 3 CF 2 CF 3 Mecanismo de acción de Fulvestrant (No-agonista) 29 Fulvestrant + ER Attenuated Reduced dimerisation AF1 AF1 + AF2 nuclear INACTIVElocalisation of inactive ER to ERE ACCELERATED RECEPTOR DEGRADATION F F F F F ERE RNA POL II No coactivator recruitment NO TRANSCRIPCION (no división cel tumoral) HT: Hormonoterapia Nicholson RI, Johnston SR. Endocrine therapy-current benefits and limitations. Breast Cancer Res Treat. 2005;93 Suppl 1:S3-10. Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr-Relat Cancer 2000; 7: 17 28

10 Faslodex (fulvestrant) receives EU approval for use in 1st-line hormone receptor-positive advanced breast cancer on 26th July DATOS CLÍNICOS 4.1 Indicaciones terapéuticas Faslodex está indicado para el tratamiento de mujeres posmenopáusicas con cáncer de mama localmente avanzado o metastásico y con receptor de estrógeno positivo: no tratadas previamente con terapia endocrina, o cuya enfermedad ha recidivado durante o después del tratamiento adyuvante antiestrogénico, o bien cuya enfermedad ha progresado a un tratamiento antiestrogénico

11 FALCON: Phase III study design Postmenopausal women Locally advanced or metastatic breast cancer ER+ and / or PgR+ HER2- Endocrine therapy-naïve Randomised, double-blind, parallel-group, international, multicentre study Follow-up for disease progression and survival Fulvestrant 500 mg (500 mg IM on Days 0, 14 and 28, then every 28 days) + placebo to anastrozole 1:1 OS b Anastrozole 1 mg (daily PO) + placebo to fulvestrant Randomisation 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 (log-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 Primary endpoint: PFS a Secondary endpoints EDoCB HRQoL (FACT-B total and TOI) Safety ORR CBR DoR, EDoR DoCB, 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, Functional Assessment of Cancer Therapy Breast; TOI, Trial Outcome Index 60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet Dec 17;388(10063):

12 Proportion of patients alive and progression free FALCON: Primary endpoint, PFS Fulvestrant (n=230) Anastrozole (n=232) HR (95% CI 0.637, 0.999); p= Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months 0.0 Number of patients at risk: Fulvestrant 230 Anastrozole A circle represents a censored observation Time (months) Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet Dec 17;388(10063):

13 FALCON: Forest plot for PFS by patient subgroup All patients Breast cancer type Locally advanced Metastatic Prior chemotherapy Yes No Geographic region US and Canada Non-US or Canada Asia Non-Asia Measurable disease Measurable Non-measurable ER+ and PgR+ at baseline Yes No Prior systemic estrogen containing HRT Yes No Bisphosphonate use at baseline Yes No Visceral disease Yes No Number of patients with Fulvestrant Anastrozole event HR (95% CI) 143 / 230 (62.2%) 166 / 232 (71.6%) 11 / 28 (39.3%) 14 / 32 (43.8%) 132 / 202 (65.3%) 152 / 200 (76.0%) 31 / 36 (86.1%) 33 / 43 (76.7%) 112 / 194 (57.7%) 133 / 189 (70.4%) 16 / 25 (64.0%) 19 / 24 (79.2%) 127 / 205 (62.0%) 147 / 208 (70.7%) 19 / 34 (55.9%) 22 / 33 (66.7%) 124 / 196 (63.3%) 144 / 199 (72.4%) 124 / 193 (64.2%) 19 / 37 (51.4%) 103 / 175 (58.9%) 40 / 55 (72.7%) 3 / 3 (100.0%) 3 / 5 (60.0%) 140 / 227 (61.7%) 163 / 227 (71.8%) 44 / 61 (72.1%) 99 / 169 (58.6%) 92 / 135 (68.1%) 51 / 95 (53.7%) 143 / 196 (73.0%) 23 / 36 (63.9%) 127 / 179 (70.9%) 39 / 53 (73.6%) 53 / 62 (85.5%) 113 / 170 (66.5%) 87 / 119 (73.1%) 79 / 113 (69.9%) (0.637, 0.999) (0.360, 1.731) (0.621, 0.991) (0.659, 1.771) (0.585, 0.967) (0.338, 1.304) (0.640, 1.029) (0.438, 1.501) (0.622, 1.005) (0.599, 0.971) (0.534, 1.818) (0.561, 0.944) (0.669, 1.621) NC (0.622, 0.977) (0.455, 1.032) (0.626, 1.073) (0.740, 1.331) (0.419, 0.837) Global interaction test p=0.106 NC, not calculable HR (95% CI) 60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet Dec 17;388(10063):

14 Proportion of patients alive and progression-free Adaptado de: 60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet Dec 17;388(10063): Proportion of patients alive and progression-free FALCON: PFS in patients with or without visceral disease Without visceral disease Fulvestrant (n=95) 1.0 Anastrozole (n=113) With visceral disease Fulvestrant (n=135 Anastrozole (n= HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Time (months) Post hoc interaction test p<0.01 A circle represents a censored observation HR 0.99 (95% CI 0.74, 1.33) Median PFS Fulvestrant: 13.8 months Anastrozole: 15.9 months Time (months)

15 One size does not fit all Patient selection for the most appropriate therapy Numerous factors should be considered, such as: Disease free interval following adjuvant treatment Age Co-morbidities The extent of disease spread Tumour evolution Treatment decisions therefore need to be driven by patient and tumour characteristics

Mecanismos de resistencia a HT Mecanismos de resistencia a Inhibidores de Aromatasa ER pathway Loss of ER expression ESR1 mutation, amplification or translocation Aberrant expression or mutation of

16 Mecanismos de resistencia a HT Mecanismos de resistencia a Inhibidores de Aromatasa ER pathway Loss of ER expression ESR1 mutation, amplification or translocation Aberrant expression or mutation of ER co-regulators Apoptosis and senescence Mutation of TP53 Amplification of MDM2 BCL-2 and survivin Telomerase Tumour microenvironment ECM: fibronectin, collagen Cellular components: TAM (M1, M2), CAF, MSC, MDSC, T H 2cell, B cell, dendritic cell, NK cell, cytotoxic T cell, osteoclast, osteoblast and platelet Al resistance Growth factor receptor pathway HER2, IGF1R and EGFR overexpression, mutation or amplification Secondary messengers PI3K pathway (e.g. mutations in PI3KCA, PTEN and AKT1) MAPK pathway Cell cycle machinery Loss of Rb, p16 and p18 Amplification of CCND1 EMT and CSC Notch, Hedgehog, WNT and TWIST 1 Tumour dormancy 37. Ma et al Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer.2015 May;15(5):261-75

17 =0.0002

18 Which group of patients are at risk for mutation? Turner. ASCO 2016

19 What is the prevalence of mutation?

20 ESR1 mutations seem to be associated with resistance to AIs Biomarker Clinical studies Findings (mutant/amplified/loss vs wildtype) ESR1 PALOMA-3 PALOMA-3: no difference between mut vs wt SoFEA SoFEA: treatment less effective in mut vs wt BOLERO-2 BOLERO-2: improved OS and PFS in wt vs mut* Schiavon et al Schiavon et al: ESR1 mutations predict resistance to subsequent AI therapy** *no statistical analysis carried out; **small sample size (n=45); mut = mutant; wt = wildtype [PALOMA-3] Turner N, presented at ASCO 2016 (abstract 512); [SoFEA] Fribbens et al. J Clin Oncol 2016; 34: ; [BOLERO-2] Chandarlapaty, presented at SABCS 2015 (abstract S2-07); Schiavon et al. Sci Transl Med 2015;7 Not all medications used in these studies are approved/marketed for use in Spain

Pronostic of ESR1 mutation and OS Mutation N Median OS (m) HR WT 385 32.1 1.4 (1.2-1.65) MT 156 20.7 1.

22 Pronostic of ESR1 mutation and OS Mutation N Median OS (m) HR WT ( ) MT ( ) D538G ( ) Y537S ( ) Chandarlapaty S et al. SABCS 2015

23 Impact of ESR1 Mutation on EXE tratment Chandarlapaty S et al. SABCS 2015

24 Impact of ESR1 mutation on EVE treatment Chandarlapaty S et al. SABCS 2015

25 COMPROMETEMOS TRATAMIENTOS POSTERIORES? 25

27 Di Leo A et al. J Clin Oncol 2010; 28: Key inclusion / exclusion criteria Postmenopausal women with ER+ MBC or LABC Patients who experienced relapse during or within 1 year of completion of adjuvant endocrine therapy Previous treatment with either an anti-oestrogen or an aromatase inhibitor as a first-line therapy for metastatic breast cancer if relapse occurred after more than 1 year from completion of adjuvant endocrine therapy Previous treatment with either an anti-oestrogen or an aromatase inhibitor as a first-line therapy if patients had de novo advanced disease Measurable disease as per RECIST, or without measurable disease but with bone lesions with a lytic or mixed component ER, oestrogen receptor; MBC, metastatic breast cancer; LABC, locally advanced breast cancer; RECIST, Response Evaluation Criteria In Solid Tumors

28 BOLERO-2: Prior Therapies Were Balanced Between Treatment Arms Therapy Everolimus + Exemestane (N = 485), % Placebo + Exemestane (N = 239), % Sensitivity to prior hormonal therapy Last treatment: LET/ ANA Last treatment Adjuvant Metastatic Prior tamoxifen Prior fulvestrant Prior chemotherapy for metastatic BC Number of prior therapies: Abbreviations: ANA, anastrozole; LET, letrozole. Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):

29 BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent in All Subgroups by Local and Central Review (2/2) All Median PFS, mo Local Central N HR EVE + EXEPBO + EXE N Number of organs involved Prior chemotherapy No Yes Prior chemotherapy for metastatic disease No Yes Prior use of hormonal therapy other than NSAI No Yes Sensitivity to prior hormonal therapy No Yes Last therapy setting Neo/adjuvant/prevention 137 Advanced/metastatic Median PFS, mo HR EVE + EXEPBO + EXE Hazard Ratio and 95% CI Favors EVE + EXE Favors PBO + EXE Hazard Ratio and 95% CI Favors EVE + EXE Favors PBO + EXE Subgroup analysis of PFS by local investigator review (red) and central review (blue). Subgroup categories in black font indicate prespecified analyses. Subgroup categories in green indicate retrospective analyses. *Does not include patients who received neoadjuvant therapy. Yardley D, et al. Adv Ther. 2013;30: Train of Trainers organized by AstraZeneca

31 Demographics and Baseline Characteristics PALOMA-3 Characteristic a Relapsed after 24 months of adjuvant endocrine therapy or had clinical benefit to prior therapy in the advanced setting; b Any prior endocrine therapy anytime before study entry; GnRH = gonatotropin-releasing hormone. Palbociclib + Fulvestrant (n=347) Placebo + Fulvestrant (n=174) Median age (range), years (range) 57 (30 88) 56 (29 80) Receptor status, % ER+ PR ER+ PR ECOG performance status, % Menopausal status, a % Pre-/peri Post Visceral metastases, b % Number of disease sites, % Characteristic Palbociclib + Fulvestrant (n=347) Placebo + Fulvestrant (n=174) Documented sensitivity to prior hormonal therapy, a % Yes No Prior aromatase inhibitor +/- GnRH, b % Prior tamoxifen +/- GnRH, b % Disease stage at study entry, % Recurrent locally advanced Metastatic Prior chemotherapy in metastatic setting, % Prior lines of therapy in metastatic setting, % Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med Jul 16;373(3):

34 Palbociclib and Fulvestrant Front-Line: PARSIFAL Design Postmenopausal MBC ER+/HER2 AI sensitive first-line ET R 1:1 Fulvestrant HD (500 mg) + palbociclib (3w/4) N=304 (152 per treatment arm) Letrozole + palbociclib (3w/4) PD Stratification factors: Primary Objective: Visceral disease 1-year PFS Rates Adjuvant AI Odds Ratio: 70% vs. 85% PD, progressive disease; R, randomisation. Llombart, et al. ASCO Train of Trainers organized by AstraZeneca

35 FULVESTRANT, SEGUNDA LINEA Y MÁS ALLÁ

36 SECUENCIA TRATAMIENTO HORMONAL CMM

Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M;

37 PALOMA-3 : FUL+Palbociclib. 61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med Jul 16;373(3):

38 Primary Endpoint: PFS (Updated Analysis) 62. P Presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS); December 6 10, 2016; San Antonio, TX, USA Confidential and Proprietary to AstraZeneca. Not for Distribution.

39 PALOMA-3 : FUL+Palbociclib 61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone- Receptor-Positive Advanced Breast Cancer. N Engl J Med Jul 16;373(3):

40 Enferme MONARCH-2

41 Enfermed MONARCH-2: Abemaciclib + fulvestrant tras PD a ttº endocrino CMM RH+/HER2-, Aleatorización 2:1 Resistente a ttº endocrino: - Recaída en neoadyuvancia o dentro del primer año ady - Progresión a HT No QT, < 1 línea HT, ECOG PS 0/1 (N = 669) Abemaciclib 150 mg BID (cont) + Fulvestrant 500 mg Placebo BID (cont) + Fulvestrant 500 mg Sledge et al. JCO 2017 Jun 3. doi: /JCO [Epub ahead of print]

42 Enfermedad MONARCH-2: PFS Sledge et al. JCO 2017 Jun 3. doi: /JCO

43 Enfermed MONARCH-2: ORR Presentado por Sledge en ASCO 2017, abstract 1000

44 SECUENCIA TRATAMIENTO HORMONAL CMM

45 EN CONCLUSIÓN

46 First line therapy: ET alone or ET + CDK4/6 or Chemotherapy Disease activity - Short DFI - visceral disease burden - Symptoms Probability to respond to ET - Resistance Type (I⁰/II⁰) - Intrinsic Subtype - Biomarkers? Single Agent Endocrine Therapy Chemotherapy CDK4/6 inhibitors + Endocrine Therapy? Low Risk Intermediate Risk High Risk Single agent ET * ET + CDK4/6 Chemo (ET + CDK4/6) (Single agent ET) (Chemo) ET + CDK4/6 Visceral/non-visceral? *ESR1 Mutation and choice of ET

47 La opción de fulvestrant en monoterapia en primera linea podría considerarse en pacientes: - Sin exposición previa a tratamiento hormonal - Recidiva con ILE corto. - Pacientes de bajo riesgo o con afectación no visceral Es preciso disponer de los resultados de los estudios en marcha para considerar la opción de fulvestrant en combinación en primera linea. Constituye la opción preferente en monoterapia o en combinación tras progresión a una pauta que incluya un IA,

Endocrine Therapy 2017: Is There a Better Single Agent and when Should we Use it?

Endocrine Therapy 2017: Is There a Better Single Agent and when Should we Use it? ET1 ET2 ET3 Targeted agent 1 Targeted agent 2 Hope S. Rugo, MD Director, Breast Oncology and Clinical Trials Education