1 Dr. Adrián Agustín NervoAvances en Cancer de Mama Metastásico RH+ Her2- Dr. Adrián Agustín Nervo

2 Avances en Cancer de Mama MetastásicoRH+ Her2- 5

3 Tratamiento sistémico del CMM Factores pronósticos y predictivos Subtipos molecularesEl subtipo molecular se relaciona con la sobrevida desde el diagnóstico de Kennecke y col, J Clin Oncol 2010; 28: 3271

4 Cancer de Mama RH+ 75% de los cáncer de mama son hormonodependientes ( RH +) La terapia hormonal es el standard of care para estas pacientes. Importantes desarrollos en los últimos años han ofrecido tratamiento promisorios y mejor calidad vida para estas pacientes ( RH+ Her2-)

5 Recomendaciones para HR+/HER2–Cancer de Mama avanzado HR+/HER2– Crisis visceral SI NO Considerar QT HT Quimioterapia No beneficio clínico luego de 3 regimenes consecutivos de HT Progresion o toxicidad inaceptable . 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V ; 2. Osborne CK, et al. Annu Rev Med. 2011;62:

6 Terapia endócrina inicial en mujeres posmenopáusicas con CMM RH+AI son el SOC del tratamiento inicial de mujeres postmenopáusicas con CMM RH+ HER2- IA:mayor eficacia vs tamoxifeno HD Fulvestrant mayor eficacia comparado con anastrozol : FIRST: 23.4 vs HR:0.66 (FASE II). Beneficios marginales de la terapia combinada para el tratatmiento inicial: FACT y SWOG S0226: HR:0.80 P: 0.007 Combination Strategy FACT: FUL + ANA vs ANA6 55.1 vs 55.0 33.6 vs 31.8 10.8 vs 10.2 — SWOG S0226: ANA + FUL vs ANA7 15.5 vs 13.5

7 CMM RH+ Her2- 2º línea de TratamientoTreatments CBR (%) ORR (%) TTP (mo) PFS (mo) FUL vs ANA1 43.5 vs 40.9 19.2 vs 16.5 5.5 vs 4.1 — EFECT: FUL vs EXE2 32.2 vs 31.5 7.4 vs 6.7 3.7 vs 3.7 CONFIRM: FUL 500 mg vs FUL 250 mg3 45.6 vs 39.6 9.1 vs 10.2 6.5 vs 5.5 SoFeA: FUL + ANA vs FUL vs EXE4 7.4 vs 6.9 vs 3.6 4.4 vs 4.8 vs 3.4 1. Robertson JFR, et al. Cancer. 2003;98(2): ; 2. Chia S, et al. J Clin Oncol. 2008;26(10): ; 3. Di Leo A, et al. J Clin Oncol. 2010;28(30): ; 4. Johnston S, et al. EBCC, 2012; abstract LBA2.

8 Cancer de Mama Metastásico RH+ Her2- Respuesta a la HT40 % 30 % 25 % 15 % 4 línea 1 línea 2 línea 3 línea

9 Cancer de mama Avanzado HR+/HER2–La progresión de enfermedad es un desafío frecuente: Resistencia primaria, innata o de novo a la exposición inicial a la hormonoterapia Resistencia adquirida o secundaria, manifiesta a lo largo del tiempo luego de respuesta inicial al tratamiento hormonal 1. Bachelot T, et al. Breast Cancer Res Treat. 2010;100(suppl 1)SABCS 2010:Abstract S1-6; 2. Osborne CK, et al. Ann Rev Med. 2011;62:233–247

10 Cancer de mama Avanzado HR+/HER2–

11 Cancer de mama Avanzado HR+/HER2–

12 BOLERO-2: Phase III Study of Exemestane ± Everolimus in Patients with ABC Progressing After NSAIsPMW with HR+, HER2– ABC refractory to LET or ANA, defined as Recurrence during or within 12 months after end of adjuvant treatment, or Progression during or within 1 month after end of treatment for advanced disease Everolimus 10 mg/day + Exemestane 25 mg/day (n = 485) Primary endpoint: PFS Secondary endpoints: OS, ORR, CBR, safety, QoL, bone markers Placebo + Exemestane 25 mg/day (n = 239) Stratification Sensitivity to prior hormonal therapy Presence of visceral disease No crossover 25. Baselga J, et al. N Engl J Med. 2012;366: 12

13 Probability of Event (%)BOLERO-2: PFS 100 Median PFS, Mos EVE + EXE: 7.82 PBO + EXE: 3.19 Hazard ratio: 0.45 (95% CI: ; log-rank P < .0001) Censoring times EVE + EXE (n/N = 310/485) PBO + EXE (n/N = 200/239) 80 60 Probability of Event (%) 40 20 CI, confidence interval; EVE, everolimus; EXE, exemestane; PBO, placebo. 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120 Wk Patients at Risk, n EVE + EXE 485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 PBO + EXE 239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 28. Piccart-Gebhart M, et al. ASCO Abstract 559. 25. Baselga J, et al. N Engl J Med. 2012;366:

14 BOLERO-2 : análisis final de OS (39-meses)Piccart M, et al. Presented at EBCC-9; March 2014; Glasgow, Scotland. Abstract 1LBA.

15 SABCS 2014 RH+ Her2-

16 Cancer de mama metastásico

17 Terapia Hormonal y sus potenciales nuevos amigosInhibidores PI3k Inhibidores cDK4-6 Inhibidores mTOR

18 Ciclinas-CDK 4/6 como TargetActiva la Invasión y diseminación Sistémica

19 Control del Ciclo CelularPROTEÍNAS CLAVE: Quinasas dependientes de ciclina o Cdk Ciclinas Punto de control 1: Cdk 4/6 + Ciclina G1 Quinasa de inicio Comienza fase S Duplicación ADN BIOLOGIA  CELULAR  Y  MOLECULAR  DE  ROBERTIS De Robertis , Eduardo D. P. / Hib , Jose

20 Control del Ciclo CelularPunto de control 2: Cdk1 + ciclina mitótica Factor promotor de Mitosis Mitosis PROTEÍNAS CLAVE: Quinasas dependientes de ciclina o Cdk Ciclinas BIOLOGIA  CELULAR  Y  MOLECULAR  DE  ROBERTIS De Robertis , Eduardo D. P. / Hib , Jose

21 Regulación del Checkpoint G1/S en Cancer de MamaPl3K/Akt STATs MAPKs ER/PR/AR Wnt/β-catenin NF-κB D-type cyclins regulated in response to mitogenic stimuli, including activation of RTKs and steroid hormone receptors1 p16 p21 p53 CDK4/6 Cyclin D CDK 4/6 inhibitors Active tumour suppressor G2 S M G1 G0 RB E2F R Cyclin D1 is amplified in 15%–20% of breast cancers2,3 Human ER+ breast cancer cell lines (including those with HER2 amplification) sensitive to G0/G1 arrest4 E2F Mitogenic signals converge at the level of cyclin D1 upregulation and CDK4/6 association, localization, and kinase activity. CDK4/6 phosphorylates and inactivates RB tumor suppressor proteins, leading to dissociation of E2F transcription factors and transcriptional regulation of genes important for G1/S transition and cell cycle progression through the restriction point. Phosphorylation of the Rb protein early in G1 by CDK4 or CDK6 is central to the regulation of the G1 to S transition and cellular commitment to division Aberrations of the G1S checkpoint are involved in the pathogenesis of many human cancers Gene transcription P P P RB P Inactive Lange, et al. Endocr Rel Cancer. 2011;18:C19-C24; 1. Caldon CE, et al. J Cell Biochem. 2006;97: ; 2. Buckley MF, et al. Oncogene. 1993;8: ; 3. Dickson C, et al. Cancer Lett. 1995;90:43-50; 4. Finn RS, et al. Breast Cancer Res. 2009;11:R77. 21

22 Palbociclib (PD0332991) CDK (cyclin partner) IC50 (µM)Oral, highly selective inhibitor of CDK4/6 Prevents cell-cycle progression from G1 to S phase In vitro activity in Rb-positive tumour cell lines and primary tumours Low nanomolar concentrations block Rb phosphorylation, inducing G1 arrest in sensitive cell lines CDK (cyclin partner) IC50 (µM) CDK4 (cyclin D1) 0.011 CDK4 (cyclin D3) 0.009 CDK6 (cyclin D2) 0.015 CDK2 (cyclin A) >5 CDK1 (cyclin B) CDK5 (p25) PD 1. Fry DW, et al. Mol Cancer Ther. 2004;3: ; 2. Menu E, et al. Cancer Res. 2008;68: ; 3. Sutherland RL, Musgrove EA. Breast Cancer Res. 2009;11: Palbociclib (PD ) is an investigational compound 22

23 Lancet Oncology. E-pub December 16, 2014.The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study Finn RS, Crown JP, Lang I, Boer K, Bondarenko IM, Kulyk SO, Ettl J, Patel R, Pinter T, Schmidt M, Shparyk Y, Thummala AR, Voytko NL, Fowst C, Huang X, Kim ST, Randolph S, Slamon DJ. Lancet Oncology. E-pub December 16, 2014.

24 PALOMA-1 (TRIO-18): Randomised Phase II Trial1:1 Part 1: All Comers ER+, HER2– BC R A N D O M I S T PD mg QDa + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Part 2: Biomarker-Positive N = 99 ER+, HER2– BC with CCND1 amp and/or loss of p16 Postmenopausal women, first line ER+/HER2–, RECIST measureable or bone only Primary endpoint: PFS (powered for 50% improvement; 9 >13.5 months Analyses presented: IMPAKT 2012, SABCS 2012, AACR 2014 (final) Publication embargo in place for results presentation 1. Clinicaltrials.gov; NCT Finn RS, et al SABCS; December 4-8, 2012; San Antonio, TX. Abstract S1-6. aSchedule 3/1

25 Patient Baseline CharacteristicsPALOMA-1/TRIO-18: Patient Baseline Characteristics Combined Cohort 1 Cohort 2 Characteristic PAL + LET (n=84) LET (n=81) (n=34) (n=32) PAL +LET (n=50) (n=49) Median (IQR) age, years 63 (54–71) 64 (56–70) 66 (56–72) (57–70) 62 (54–70) (56–71) ECOG PS, n (%) 1 46 (55) 38 (45) 45 (56) 36 (44) 23 (68) 11 (32) 20 (63) 12 (38) 23 (46) 27 (54) 25 (51) 24 (49) Disease stage, n (%) III IV 2 (2) 82 (98) 1 (1) 80 (99) 2 (6) 32 (94) 32 (100) 50 (100) 1 (2) 48 (98) Disease site,* n (%) Visceral Bone Other (non-visceral) 37 (44) 17 (20) 30 (36) 43 (53) 12 (15) 26 (32) 10 (29) 7 (21) 17 (50) 11 (34) 6 (19) 15 (47) 10 (20) 13 (26) 32 (65) 6 (12) 11 (23) ECOG PS=Eastern Cooperative Oncology Group performance status; IQR=interquartile range; LET=letrozole; PAL=palbociclib. *Based on CRF data. All data were available for all patients. Finn et al. Lancet Oncol. E-pub Dec 16, 2014

26 PALOMA-1/TRIO-18: PFS (ITT Population)100 90 Palbociclib plus letrozole Letrozole 80 70 60 Progression-free survival, % 50 40 30 20 10 HR (95% CI 0.319–0.748; one-sided P=0.0004) 4 8 12 16 20 24 28 32 36 40 Number at risk Time, months Palbociclib plus letrozole 84 67 60 47 36 28 21 13 8 5 1 Letrozole 81 48 36 28 19 14 6 3 3 1 Finn et al. Lancet Oncol. E-pub Dec 16, 2014

27 PALOMA-1/TRIO-18: PFS (Cohorts)Palbociclib plus letrozole Letrozole 100 100 90 90 80 80 70 70 60 60 Progression-free survival, % 50 50 40 40 30 30 20 20 10 10 HR (95% CI 0.156–0.572; one-sided P=0.0001) HR (95% CI 0.303–0.853; one-sided P=0.0046) 4 8 12 16 20 24 28 32 36 40 4 8 12 16 20 24 28 32 36 40 Time, months Time, months Number at risk Palbociclib plus letrozole 34 26 23 18 15 13 11 8 8 5 1 50 41 37 29 21 15 10 5 Letrozole 32 15 10 8 5 4 4 3 3 1 49 33 26 20 14 10 2 Finn et al. Lancet Oncol. E-pub Dec 16, 2014

28 PALOMA-1/TRIO-18: Forest Plot for PFSPAL + LET LET Hazard ratio (95% CI) Interaction P value* Patients Events Patients Events All patients (intention-to-treat population) 84 41 81 59 0.488 (0.319–0.748) Cohort 1 34 15 32 25 0.299 (0.156–0.572) 0.14 2 50 26 49 34 0.508 (0.303–0.853) Age group (years) <65 years 47 24 42 35 0.315 (0.184–0.539) 0.34 ≥65 years 37 17 39 24 0.505 (0.269–0.948) Baseline ECOG performance status 46 21 45 31 0.434 (0.246–0.766) 0.78 1 38 20 36 28 0.398 (0.220–0.721) Disease site Visceral 37 21 43 34 0.547 (0.317–0.944) Bone Only 17 5 12 7 0.294 (0.092–0.945) 0.44 Other 30 15 26 18 0.402 (0.200–0.808) Previous chemotherapy Yes 34 17 37 24 0.479 (0.255–0.898) 0.75 No 50 24 44 35 0.397 (0.234–0.671) Previous antihormonal therapy Yes 27 12 28 19 0.460 (0.222–0.956) 0.88 No 57 29 53 40 0.397 (0.244–0.646) Previous systemic therapy Yes 40 20 44 28 0.539 (0.302–0.962) 0.36 No 44 21 37 31 0.341 (0.194–0.599) Time from end of adjuvant treatment to disease recurrence ≤12 months (including de-novo presentation) 59 31 51 39 0.418 (0.259–0.674) 0.95 >12 months 25 10 30 20 0.399 (0.185–0.858) 0.34 ≤12 months (excluding de-novo presentation) 15 7 14 5 0.765 (0.232–2.523) 0.062 0.125 0.250 0.500 1.000 2.000 4.000 Adju. Trt.=adjuvant treatment; Dis. Recur.=disease recurrence; ECOG PS=Eastern Cooperative Oncology Group performance status; LET=letrozole; PAL=palbociclib. *Two-sided P value. Favours palbociclib plus letrozole Favours letrozole Finn et al. Lancet Oncol. E-pub Dec 16, 2014

29 PALOMA-1/TRIO-18: Overall Survival (ITT Population)100 Palbociclib plus letrozole Letrozole 90 80 70 60 Overall survival, % 50 40 30 20 10 HR (95% CI 0.492–1.345; two-sided P=0.42) 4 8 12 16 20 24 28 32 36 40 44 Time, months Number at risk Palbociclib plus letrozole 84 80 78 73 68 65 47 35 22 17 7 2 Letrozole 81 76 74 67 64 59 37 23 14 12 5 1 With only 30 events in the palbociclib plus letrozole arm and 31 events in the control arm, the study was not powered to demonstrate an overall survival advantage; initial data suggest there is no detrimental effect on OS by adding palbociclib A follow-up overall survival analysis will be performed after the accrual of additional events Finn et al. Lancet Oncol. E-pub Dec 16, 2014

30 PALOMA-1/TRIO-18: All-Causality AEs Occurring in ≥10% of Patients (Safety Population)Adverse event, % PAL + LET (n=83) LET (n=77) All grades Grade 3/4 Any adverse event 99 76 84 21 Neutropenia 75 54 5 1 Leukopenia 43 19 3 Fatigue 41 23 Anemia 35 6 Nausea 25 2 13 Arthralgia 16 Alopecia 22 n/a Diarrhea 20 4 10 Hot flush 12 Thrombocytopenia 17 Decreased appetite 7 Dyspnea 8 Nasopharyngitis Back pain 11 LET=letrozole; n/a=not applicable; PAL=palbociclib. One (1%) grade 5 event occurred in the PAL + LET group (from disease progression); none occurred in the LET group. No cases of febrile neutropenia were reported Finn et al. Lancet Oncol. E-pub Dec 16, 2014

31 PALOMA-1 The combination of palbociclib and letrozole compared with letrozole alone showed statistically significant improvement in median PFS in patients with ER+/HER2– breast cancer at final analysis (AACR, 2014) The combination is generally well tolerated, with uncomplicated neutropenia as the most frequent adverse event A confirmatory phase 3 study (PALOMA-2) is fully enrolled and ongoing FDA February 2015

32 Palbociclib en HR+/HER2– BC: estudios fase IIIMetastatic Breast Cancer Post-Neoadjuvant Study 1008 (PALOMA-2) 1023 (PALOMA-3) PEARL PENELOPE Setting Endocrine sensitive Endocrine resistant High risk Menopausal status Postmenopausal Premenopausal + postmenopausal No. of patients 650 521 348 800 Treatment Palbociclib + letrozole vs placebo + letrozole Palbociclib + fulvestrant vs placebo + fulvestrant Palbociclib + exemestane vs capecitabine Palbociclib vs placebo Primary endpoint PFS iDFS FFPV, first patient first visit; iDFS, invasive disease-free survival; PFS, progression-free survival. Clinicaltrials.gov.Paloma 2: NCT , Paloma 3: NCT ; Pearl: NCT Penelope: NCT

33 Vía PI3k/AKT/mTOR como TargetActiva la Invasión y diseminación Sistémica

34 Inhibidores PI3k: pectilisibActivacion PI3K en cáncer de mama

35 Inhibidores PI3k: pectilisib

36 Inhibidores PI3k: pectilisib

37 Inhibidores PI3k: pectilisib

38 Inhibidores PI3k: pectilisib

39 CONCLUSIONES

40 Combinacion de Targets y Antiestrógenos en CMM RH+P EGFR HER2 E Aromatase Inhibitor Nonsteroidal AIs Anastrozole Letrozole Steroidal AIs Exemestane Inhibidores PI3k pectilisib TKI E RAS PI3K PTEN ER Downregulator Fulvestrant RAF ER E mTOR Inhibitors Everolimus AKT AI, aromatase inhibitor; E, estrogen; ER, estrogen receptor; HR, hormone receptor; mTOR, mammalian target of rapamycin; TKI, tyrosine kinase inhibitor. MEK MAPK mTOR Selective Estrogen Receptor Modulators Tamoxifen Toremifene CDK 4/6 Inhibitor PALBOCICLIB Cell Cycle ER target gene transcription ER E ER E HDAC Inhibitor Entinostat Transcription Silencing

41 Evolución Tratamiento en Cancer de Mama RH+ Her2-Que hubo de nuevo en San Antonio ?? Anti Cdk4/6 Palbociclib (2015) Letrozole (1997) Fulvestrant (2002) Toremifene (1997) Everolimus + exemestane (2012) Inhibidores PI3k Tamoxifen (1977) Anastrozole (1995) 1936 1975 1980 1985 1990 1995 2000 2005 2010 2015 Nada que cambie el SOC de tratamiento actual Palbociclib SABCS 2013 – FDA 2015

42 MUCHAS GRACIAS!