Recommended management for ER Positive Advanced Breast Cancer Sandra Ximena Franco, MD Hematología Oncología Directora, Centro de Oncología/ Clínica de Seno Clínica del Country

Mexico City, Abril 19 2017

Molecular portraits of human breast tumors: Luminal Subtype

Perou CM et al, Nature 406:747,2000; Cancer Genome Atlas doi:10.1038/nature11412

The intrinsic subtype classification Luminal A Luminal B

Frequence 35-40% 25-30% ER expression +++ ++ PR expression +++ +

GATA3 expression +++ ++ Ki67 expression low (<14%) moderate(>14%) )PI3K mutations 43% 29%

GATA3 mutations 14% 15% HER2 amplification no 30%

Tp53 mutations 12% 29%

Prognosis according to molecular subtype

Genomic landscape varies among subtypes of breast cancer (N=510)

Network CGA: Comprehensive molecular portraits of human breast tumours. Nature 2012, 490:61–70. PI3CA 36%, TP53 37%, GATA3 11%, all others <10%

The tumor profile may evolve over time and in response to treatment

Reprinted from Arnedos, M. et al., Nat Rev Clin Oncol. 2015 Jul 21. doi: 10.1038/nrclinonc.2015.123. [Epub ahead of print]. Aurilio G, et al., EJC. 2014;50:277-289.

As tumors evolve, tumor profile in metastases does not necessary correlate to the one in primary tumor

Changes in ER status of ~20-33% and in HER2 of ~5-8% depending on the series

Oncogenesis

Cancer Residual disease Residual lethal disease

Treatment resistance

Treatment Recurrence

Changes in hormonal and HER-2 receptors in primary tumor and metastatic biopsies: A metanalysis

Aurilio G, et al., Acta Oncol. 2013;52:1649-1656; Aurilio G, et al., EJC. 2014;50:277-289.

48 articles (mostly retrospective studies) – ER (33 articles, 4200 patients) – PR (24 articles, 2739 patients) – HER2 (31 articles, 2987 patients)

Receptor Pooled Discordances (95% CI) Positive to Negative Negative to Positive

ER 20% (16-35) 24% 14% (P = 0.018) PR 33% (29-38) 46% 15% (P < 0.0001) HER2 8% (6-10) 13% 5% (P = 0.0004)

Conventional approach to ER-positive/HER2-negative MBC

HORMONES

response

CHEMOTHERAPY

3RD LINE CHEMO

2ND LINE CHEMO

no response

Bone, soft tissue disease Low burden visceral disease Long disease-free interval Hormonosensitive disease

Visceral crisis

High tumor burden Relevant symptoms

Need for a rapid response

Guías internacionales de tratamiento del cáncer de mama metastásico RH+/HER2- enfatizan el uso de terapia endocrina Recomendaciones ASCO1 Terapia endocrina en lugar de quimioterapia debe ser ofrecido como estándar de tratamiento de primera línea en pacientes con cáncer de mama metastásico, receptor hormonal positivo, excepto para la enfermedad que amenaza la vida o en la que hay dudas sobre la resistencia endocrina. • El mayor beneficio es menor toxicidad y mejor calidad de vida para las pacientes, asociado con terapia endocrina comparado con quimioterapia. (Beneficio potencial: alto). El daño potencial es que la enfermedad metastásica progrese rápidamente y pueda ser fatal si no hay respuesta; sin embargo, este riesgo es bajo (Riesgo potencial de daño: bajo) Recomendaciones ESMO/ABC2 2 Las guías de ESMO refuerzan el uso preferente de la terapia endocrina, inclusive en presencia de metástasis viscerales para el tratamiento del cáncer de mama RE +/HER2-. La quimioterapia debe ser reservada para los casos con enfermedad rápidamente progresiva o que se haya probado resistencia endocrina. Recomendaciones NCCN3 Mujeres con cáncer metastásico o recurrente, con tumores; caracterizado por ser RE y/o RP positivos son candidatas apropiadas para iniciar terapia endocrina.

Menor toxicidad Mejor calidad de vida

RH, receptor hormonal; RP, receptor de progesterona; RE, receptor de estrógenos; HER2, receptor 2 del factor de crecimiento epidérmico humano. 1. Partridge AH, et al. J Clin Oncol 2014;32:3307–3329; 2. Cardoso F, et al. The Breast 2014;23:489–502; 3. NCCN Guidelines: Breast Cancer. Version 3.2015.

Analysis Nº ER+/ HER2– First-Line Treatment for ABC Number of ET Lines Before First CT

QT TE 1a línea 2a línea ≥3a línea USA1 19,120 40% 60% 44% 12% 4%

Europa2 355 31% 69% 62% 7% 0% Brasil3 690 53% 47% - - -

UK 209 50% 50% - - -

How Are Physicians Treating ER+/HER2–?

• La evidencia de estos estudios sugiere que el uso de líneas TH múltiples es bajo y posiblemente subóptimo entre pacientes estadounidenses / europeos / brasileños con CMMA ER+ / HER2- • Una justificación puede ser la baja actividad mostrada por las terapias endocrinas clásicas en la progresión a IANE CMA, cáncer de mama avanzado; QT, quimioterapia; TE, Terapia endocrina; TH, Terapia hormonal; IANE, Inhibidor de aromatasa no esteroideo. 1. Swallow E, et al. Curr Med Res Opin 2014;30:1537–1545; 2. Andre F, et al. Curr Med Res Opin 2014;30:1007–1016. 3. Barrios CH, et al. Can Res. 2016;76, P06,-16,-04. 4. Kurosky S, et al. Presented at the International Society for Pharmacoeconomics and Outcomes Research 18th Annual European Congress, 2015; Milan, Italy (PCN352)

Análisis Nº ER+/ HER2– Tratamiento de primera línea para CMA Número de líneas de TE antes de la primera QT

QT TE 1a línea 2a línea ≥3a línea EUA1 19,120 40% 60% 44% 12% 4%

Europa2 355 31% 69% 62% 7% 0% Brasil3 690 53% 47% - - -

RU4 209 50% 50% - - -

How Are Physicians Treating ER+/HER2–?

• La evidencia de estos estudios sugiere que el uso de líneas TH múltiples es bajo y posiblemente subóptimo entre pacientes estadounidenses / europeos / brasileños con CMMA ER+ / HER2- • Una justificación puede ser la baja actividad mostrada por las terapias endocrinas clásicas en la progresión a IANE CMA, cáncer de mama avanzado; QT, quimioterapia; TE, Terapia endocrina; TH, Terapia hormonal; IANE, Inhibidor de aromatasa no esteroideo.

Front-line endocrine therapy is chosen for 60%–70% of ER+ ABC patients

Fewer than 1 out of 4 (25%) treated with front-line ET continue on a second endocrine option. 1. Swallow E, et al. Curr Med Res Opin 2014;30:1537–1545; 2. Andre F, et al. Curr Med Res Opin 2014;30:1007–1016. 3. Barrios CH, et al. Can Res. 2016;76, P06,-16,-04. 4. Kurosky S, et al. Presented at the International Society for Pharmacoeconomics and Outcomes Research 18th Annual European Congress, 2015; Milan, Italy (PCN352)

First line therapy

Efficacy of chemotherapy in TTP of disease

Response (%) Median TP (months) Overall Survival (Months) Paclitaxel1 34% 6.0 22.2

Doxorrubicina1 36% 5.9 20.1 Paclitaxel / doxorrubicina1 47% 8.0 22.4 Docetaxel/ capecitabina2

42% 6.1 14.5 Gemcitabina / paclitaxel3 40.8% 5.2 18.5

TP, Tiempo hasta la progresión. 1.Sledge G.W, et al. Journal of Clinical Oncology. 2003;21:588-592 .O’Shaugh essy et al. Clin Oncol. 2002; 20(12):2812-2823. 3. Biganzoli L, et al. European Oncological Disease, 2007;1(2):52-3

Exemestano1 Anastrozol2 Letrozol3 Núm. de pacientes 190 vs. 192 340 vs. 328 458 vs. 458

Tasa de respuesta % 45 vs. 30 33 vs. 33 32 vs. 21 Beneficio clínico % 57 vs. 49 56 vs. 56 50 vs. 38

TP (meses) 10 vs. 6 8 vs. 8 9 vs. 6 SG (meses) --- 40 vs. 40 34 vs. 30

1.Paridaens R, et al. 4th EBCC,2004. 2.Bonneterre J, et al. JCO 2000;18:3748-3757. 3. Mouridsen H, et al. JCO . 2003;21:2101-9

Inhibidores de aromatasa versus tamoxifeno como terapia hormonal de primera línea

TP, Tiempo hasta la progresión; SG, Sobrevida global

PFS and OS in recent phase III trials of first line hormonal therapy for ER-positive/HER2-negative ABC Estudio Experimental arm PFS (months) OS (months) Control arm PFS (months) OS (months) FACT1 Anastrozol + Fulvestrant 10.8 37.8 Anastrozol 10.2 38.2 SWOG2262 Anastrozol + Fulvestrant 15.0 47.7 Anastrozol 13.5 41.3 FIRST3 Fulvelstrant 23.4 54.1 Anastrozol 13 48.4 LEA4 Letrozol o fulvestrant +Bevacizumab 19.3 52.1 Letrozol o fulvestrant 14.4 51.8 CALGB 405035 Letrozol+ Bevacizumab 20.2 47.2 Letrozol 15.6 43.9 PALOMA 26 Letrozol +Palbociclib 24.8 ND Letrozol 14.5 ND FALCON7 Fulvestrant 16.6 ND Anastrozol 13.8 ND CMA, cáncer de mama avanzado; SLP, supervivencia libre de progresión; SG, sobrevida global; ND, no disponible.

1. Bergh J et al., J Clin Oncol 2012; 2. Mehta RS et al., NEJM 2012; 3. Robertson JFR et al., JCO 2012; 4. Martin M et al., JCO 2015; 5. Dickler M et al, JCO 2016; 6. Finn et al., ASCO 2015 ; 6. Finn R. S, et al. N Engl J Med 2016;375:1925-36. 7. Robertson, et al. Lancet . 2016; 388: 2997–3005

Combination anastrozole and fulvestrant in metastatic breast cancer

Mehta RS et al, N Engl J Med 367:435, 2012. Bergh J et al, J Clin Oncol 30:1919,2012

SWOG FACT

Mehta et al1 Bergh et al2

Patient characteristics: Prior adjuvant hormones Prior adjuvant chemotherapy

40% 33% 68%* 46%**

Median progression-free survival (anastrozol arm) 13.5 mo. 10.2 mo.

Fulvestrant plus anastrozol versus anastrozol: patient, treatment and tumor characteristics

1 N Engl J Med 2012;367:435; 2 J Clin Oncol 30:1919,2012

*70% relative increase **28% relative increase

CONFIRM Study: Overall Survival (final analysis at 75% of events)

0.1

0

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 4 8 12 16 20 24 28 32 36 40 44 48 52 56 60 64 68 72 76 80

Fulvestrant 500 mg

Fulvestrant 250 mg

362 333 288 254 227 202 178 163 141 123 114 98 81 64 47 30 26 15 8 1 0 500 mg 374 338 299 261 223 191 164 137 112 96 87 74 64 48 37 22 14 8 3 2 0 250 mg

Time (months)

Pro

po

rtio

n o

f p

ati

en

ts a

live

Patients at risk:

Tick marks indicate censored observations. Time to censoring was similar between the treatment arms

aNominal value, cannot be claimed as significant as no adjustments were made for multiplicity

Median TTD (months) Fulvestrant 500 mg 26.4 Fulvestrant 250 mg 22.3

HR = 0.81; 95% CI: 0.69, 0.96; p=0.016a

Di Leo A et al. Cancer Research 2012, 72 (24 Suppl. 3) ; Abs S1-4 Di Leo A, et al. 2012 CTRC-AACR SABCS; Dec 5, 2012; General Session 1. http://sabcs12.m2usa.com/sabcsdsv.html

Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: results from the FIRST study* (full analysis set)

0

0.0

0.2

0.4

0.6

0.8

1.0

102 74 65 52 45 34 20 6 103 69 55 39 30 21 8 2

Patients at risk: Time (months)

6 12 18 24 30 36 48

Proportion of patients alive and progression-free

HR = 0.66; 95% CI: 0.47, 0.92; p=0.01

Fulvestrant 500 mg Anastrozole 1 mg

Anastrozole 1 mg Fulvestrant 500 mg

42

0 0

Robertson JFR et al. Breast Cancer Res Treat 2012; 136(2): 503-11

*Fulvestrant is not approved in this population

Progression

Fulvestrant + placebo to Anastrozole Fulvestrant (500 mg/day i.m.) days 0, 14

& 28 then every 28 days + placebo to Anastrozole (1 mg/day p.o.)

Survival

Postmenopausal women with ER+ve and/or PgR+ve locally advanced or metastatic breast cancer not previously treated with any hormonal therapy

Progression

Survival

Anastrozole + placebo to Fulvestrant Anastrozole (1 mg/day p.o.)

+ placebo to Fulvestrant (500 mg/day i.m.) days 0, 14 & 28 then every 28 days

FALCON Study Design

PFS analysis at 306 progression events OS analysis at 50%

La indicación aprobada para Colombia de Faslodex es en mujeres posmenopáusicas con Ca de mama avanzado local o metastásico, RE+, que presentan una recidiva durante o después del tratamiento antiestrogénico adyuvante o bien una progresión de la enfermedad durante el tratamiento con un antiestrógeno.

FALCON: PRIMARY ENDPOINT PFS

A circle represents a censored observation

HR 0.797 (95% CI 0.637, 0.999); p=0.0486 Median PFS Fulvestrant: 16.6 months Anastrozole: 13.8 months Number of patients at risk: Fulvestrant Anastrozole 230 232 187 194 171 162 150 139 124 120 110 102 96 84 81 60 63 45 44 31 24 22 11 10 2 0 0 0

Proportio

n of patie

nts alive a

nd prog

ression fr

ee

Time (months)

0.9 1.0

0.7 0.8

0.5 0.6

0.3 0.4

0.1 0.0 0 3 6 9 12 15 18 21 24 27 30 36 33 39

0.2

Fulvestrant (n=230) Anastrozole (n=232)

FALCON: PFS IN PATIENTS WITH OR WITHOUT VISCERAL DISEASE

Post hoc interaction test p<0.01 A circle represents a censored observation

Without visceral disease With visceral disease

HR 0.59 (95% CI 0.42, 0.84) Median PFS Fulvestrant: 22.3 months Anastrozole: 13.8 months Proportio

n of patie

nts alive a

nd progre

ssion-free

Time (months)

0.9 1.0

0.7 0.8

0.5 0.6

0.3 0.4

0.1 0.0

0.2 Prop

ortion of

patients a

live and p

rogression

-free

Time (months)

0.9 1.0

0.7 0.8

0.5 0.6

0.3 0.4

0.1 0.0 0 5 10 15 20 25 30 35 40

0.2

0 5 10 15 20 25 30 35 40

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) Fulvestrant (n=95) Anastrozole (n=113)

Checkpoint G1/S REGULATION

Lange CA, Yee D. Endocr Relat Cancer 2011;18:C19–24 AR, receptor andrógeno; ER, receptor estrogénico; MAPK, proteínas kinasas activadas por mitógeno; NF-κB, factor nuclear kappa de cadena ligera potenciador de células B activadas; PI3K, kinasa fosfoinositido; PR, receptor de progsterona; R, punto de restricción; RB, retinoblastoma; STAT, activador de transcripción (todos por sus siglas en inglés)

RB

RB Trancripción de genes G2 S

M G1

G0

P P P

P

Inactivo

Supresor tumoral activo E2F

E2F R

CDK4/6 Ciclina D

Pl3K/Akt STATs MAPKs

(ER/PR/AR) Wnt/β-catenina NF-κB

p16

p21

p53

PALOMA-1 / TRIO-18: Diseño del estudio (NCT00721409)

Estudio fase II aleatorizado, abierto, con la participación de 50 centros en 12 países. Principales criterios de elegibilidad: enfermedad localmente recurrente, inoperable RE-positivo / HER2 negativo, postmenopáusicas, sin terapia previa para cáncer de mama avanzado, sin inhibidores CDK previos, sin letrozol en los últimos 12 meses, sin metástasis cerebrales previas/presentes, enfermedad medible (RECIST 1.0) o sólo e fer edad ósea, estado fu io al ECOG , fu ió edular ósea y re al ade uadas.

Palbociclib 125 mg/d† + Letrozol 2.5 mg/d

Letrozol 2.5 mg/d

Cáncer de mama avanzado RE+/HER2- 1:1

ALEATORIZACIÓN*

Palbociclib 125 mg/d† + Letrozol 2.5 mg/d

Letrozol 2.5 mg/d

Cáncer de mama avanzado RE+/HER2- con amplificación CCND1 y/o pérdida de p16 1:1

n=66 n=99

ALEATORIZACIÓN*

Cohorte 1 Cohorte 2

Finn, et al. Lancet Oncol. E-pub Dec 16, 2014.

PALOMA-1/TRIO 18: PFS (ITT Population): Combined Cohorts

HR, hazard ratio; LET, letrozole; PAL, palbociclib

Finn RS, et al. Lancet Oncol 2015;16:25–35

PAL + LET (N=84) LET (N=81) No. of events (%) 41 (49) 59 (73) Median PFS, months (95% CI) 20.2 (13.8−27.5) 10.2 (5.7−12.6) HR (95% CI) 0.488 (0.319−0.748) P value 0.0004

100

81 48 36 28 19 14 6 3 3 1 LET

90 80 70 60 50 40 30 20 10

0

PFS proba

bility (%)

0 4 8 12 16 20 24 28 32 36 40 Time (months) 84 67 60 47 36 28 21 13 8 5 1 PAL + LET No. of patients at risk

Palbociclib + letrozole Letrozole

25

Final OS Analysis: ITT Population • The addition of palbociclib led to a 3-month increase in OS

Data cutoff December 30, 2016 Median duration of follow-up 64.7 months (95% CI: 58.8–73.0) CI, confidence interval; HR, hazard ratio; ITT, intention-to-treat; LET, letrozole; OS, overall survival; PAL, palbociclib

Finn RS, et al. Presented at ASCO 2017 (Abstract 1001)

PAL + LET (n=84) LET (n=81) No. of patients at risk (%) 60 (71) 56 (69) Median (95% CI) OS, months 37.5 (31.4–47.8) 34.5 (27.4–42.6) HR (95% CI) 0.897 (0.623–1.294) P value 0.281

Time (months) 0 12 24 84

OS proba

bility (%)

0 20 40 60 80

100

No. of patients at risk

LET PAL + LET

36 48 60 72 84 81

73 67

63 52

– –

38 33

28 21

13 10

8 3

PAL + LET LET

PALOMA-2: Study Design (1008)1

1. clinicaltrials.gov NCT01740427; Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

Placebo (3/1 schedule) + letrozole (2.5 mg QD)

Palbociclib (125 mg QD, 3/1 scheduleb) + letrozole (2.5 mg QD) • Postmenopausal • ER+, HER2– advanced breast cancer • No prior treatment for advanced disease • AI-resistant patients excluded

RANDOM

IZATION

N=666a 2:1 Primary endpoint Investigator-assessed PFS Secondary endpoints Response, OS, safety, biomarkers, patient-reported outcomes Stratification factors –Disease site (visceral, non-visceral) –Disease-free interval (de novo metastatic; o, >12 mo) –Prior (neo)adjuvant hormonal therapy (yes, no)

• Statistical analysis designed to detect an increase in PFS with a true HR of 0.69 (representing a 31% improvement) with 347 events - 90% power with 1-sided α=0.025 Assumptions: Median PFS of placebo plus letrozole = 9 mos vs. palbociclib plus letrozole = 13 mos • Blinded independent central review of efficacy endpoints performed as supportive analysis aActual. AI=aromatase inhibitor; HER2=human epidermal growth factor receptor 2; OS=overall survival; PFS=progression-free survival; QD=once daily.

PALOMA-2: SLP evaluada por el investigador (Población IT) Prob

abilidad de

SLP (%)

Tiempo desde la aleatorización (meses) 0 3 6 9 12 15 18 21 24 27 30 33 444 395 360 328 295 263 238 154 69 29 10 2 222 171 148 131 116 98 81 54 22 12 4 2 PAL+LET PCB+LET

Número de pacientes en riesgo

Palbociclib + letrozol (n=444)

Placebo + letrozol (n=222) 0 10 20 30 40 50 60 70 80 90

100

PAL+LET (N=444) PCB+LET (N=222) Número de eventos, n (%) 194 (44) 137 (62)

Mediana de SLP (IC 95%) 24.8 (22.1–NR) 14.5 (12.9–17.1) CR (IC 95%); valor P en 1 cola 0.58 (0.46–0.72); P<0.000001

IT, Intención de tratar; LET, letrozol; NR, no alcanzada; PAL, palbociclib; PCB, placebo; SLP, supervivencia libre de progresión; CR, cociente de riesgo. Finn, et al. N Engl J Med 2016, 17;375(20): 1925–1936.

PALOMA-2: PFS Subgroup Analysis (ITT, Investigator Assessment)

aVisceral disease was defined as: any lung (including pleura) and/or liver involvement CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio; ITT, intention to treat; LET, letrozole; PAL, palbociclib; PCB, placebo; PFS, progression-free survival Finn RS, et al. N Engl J Med 2016 Nov 17;375(20): 1925–1936

Subgroup Palbociclib–Letrozole, n (%) Placebo–Letrozole, n (%) HR (95% CI) All randomized patients 444 (100) 222 (100) 0.58 (0.46–0.72) Age <65 years

years 263 (59.2) 181 (40.8) 141 (63.5) 81 (36.5) 0.57 (0.43–0.74) 0.57 (0.39–0.84) Race White Asian 344 (77.5) 65 (14.6) 172 (77.5) 30 (13.5) 0.58 (0.45–0.74) 0.48 (0.27–0.87) Site of metastatic disease Viscerala Non-visceral 214 (48.2) 230 (51.8) 110 (49.5) 112 (50.5) 0.63 (0.47–0.85) 0.50 (0.36–0.70) Prior hormonal therapy Yes No 249 (56.1) 195 (43.9) 126 (56.8) 96 (43.2) 0.53 (0.40–0.70) 0.63 (0.44–0.90) Disease-free interval Newly metastatic disease o ths >12 months

167 (37.6) 99 (22.3) 178 (40.1) 81 (36.5) 48 (21.6) 93 (41.9)

0.67 (0.46–0.99) 0.50 (0.33–0.76) 0.52 (0.37–0.73) Region North America Europe Asia/Pacific 168 (37.8) 212 (47.7) 64 (14.4)

99 (44.6) 95 (42.8) 28 (12.6) 0.61 (0.43–0.85) 0.57 (0.41–0.80) 0.49 (0.27–0.87) ECOG performance status 0 1/2 257 (57.9) 187 (42.1) 102 (45.9) 120 (54.1) 0.65 (0.47–0.90) 0.53 (0.39–0.72) Bone-only disease at baseline Yes No 103 (23.2) 341 (76.8) 48 (21.6) 174 (78.4) 0.36 (0.22–0.59) 0.65 (0.51–0.84) Measurable disease Yes No 338 (76.1) 106 (23.9) 171 (77.0) 51 (23.0) 0.66 (0.52–0.85) 0.35 (0.22–0.57) Prior chemotherapy Yes No 213 (48.0) 231 (52.0) 109 (49.1) 113 (50.9) 0.53 (0.40–0.72) 0.61 (0.44–0.84) Most recent therapy Aromatase inhibitor Antiestrogen 91 (20.5) 154 (34.7) 44 (19.8) 75 (33.8) 0.55 (0.34–0.88) 0.56 (0.39–0.80) Number of disease sites 1 138 (31.1) 306 (68.9) 66 (29.7) 156 (70.3) 0.51 (0.34–0.77) 0.61 (0.47–0.79) Histopathological classification Ductal carcinoma Lobular carcinoma 356 (80.2) 68 (15.3) 184 (82.9) 30 (13.5) 0.59 (0.46–0.75) 0.46 (0.27–0.78)

In favor of PAL + LET In favor of PCB + LET

0.2 0.4 0.6 0.8 1.00 2.00

MONALEESA-2

− Las evaluaciones tumorales se realizaron cada 8 semanas por 18 meses, posteriormente cada 12 semanas − Análisis final planeado después de 302 eventos de supervivencia libre de progresión (SLP)

• Poder de 9 . % para dete tar u a redu ió del riesgo de % CR . e u a ola α= . % − Análisis preliminar planeado después de ~70% de eventos de SLP (211 de 302 eventos)

• Criterios de interrupción de Haybittle-Peto de dos ías: o ie te de riesgo . y p . 9

Aleatorización 1:1 Estratificado por la presencia/ausencia de metástasis hepáticas y/o pulmonares

Ribociclib (600 mg/día) 3 semanas en tx/1 semana sin tx + Letrozol (2.5 mg/d) n=334 Placebo + Letrozol (2.5 mg/d) n=334

Objetivo primario • SLP (evaluada localmente por RECIST v1.1) Objetivos secundarios • Sobrevida global (principal) • Tasa de respuesta global • Tasa de beneficio clínico • Seguridad

• Mujeres postmenopáusicas con cáncer de mama avanzado RH+/HER2- • Sin terapia previa para enfermedad avanzada • N=668

MONALEESA-2: Estudio fase III, doble ciego, controlado con placebo de ribociclib + letrozol

RH, receptor hormonal; HER2, receptor 2 de factor de crecimiento epidérmico humano ; tx, tratamiento; CR, cociente de riesgo. Hortobagyi, et al., N Engl J Med 2016, 375:1738-1748

MONALEESA-2: Progression-free Survival

Hortobagyi G, et al. ASCO 2017. 3. Hortobagyi G, et al. NEJM 2016.

MONALEESA-2 (ASCO 2017) (investigator assessed mPFS)

Blinded independent central review (BICR)

Ribo + LET PBO + LET mPFS, months (95% CI)

25.3 (23.0–30.3) 16.0 (13.4–18.2) HR (95% CI) 0.568 (0.457–0.704)

p value 9.63 × 10-8

Subgrupo n (%) Cociente de riesgo (IC 95%) Todos los pacientes 668 (100) 0.556 (0.429–0.720) Edad <65 años

años 373 (56) 295 (44) 0.523 0.608 (0.378–0.723) (0.394–0.937) Raza Asiática No asiática 51 (7.6) 568 (85) 0.387 0.607 (0.166–0.906) (0.459–0.804) EF ECOG 0 1 407 (61) 261 (39) 0.588 0.528 (0.422–0.820) (0.348–0.801) Estado RE/RPg RE+ y RPg+ Otra 546 (82) 122 (18) 0.616 0.358 (0.461–0.823) (0.198–0.647) Sin afectación hepática o pulmonar No Sí 295 (44) 373 (56) 0.547 0.569 (0.360–0.832) (0.409–0.792) Sólo enfermedad ósea No Sí 521 (78) 147 (22) 0.541 0.690 (0.405–0.723) (0.381–1.249) Enfermedad de novo

No Sí 441 (66) 227 (34) 0.603 0.448 (0.447–0.814) (0.267–0.750) Terapia endocrina (neo)adyuvante previa

IANEs y otros* Tamoxifeno o exemestano Ninguna 53 (7.9) 293 (44) 322 (48)

0.448 0.570 0.570 (0.193–1.038) (0.393–0.826) (0.380–0.854)

Quimioterapia (neo)adyuvante previa No Sí 377 (56) 291 (44) 0.548 0.548 (0.373–0.806) (0.384–0.780)

Análisis por subgrupo: combinación eficaz entre los subgrupos

*Excluye pacientes que habían recibido tamoxifeno. EF, estado funcional; IANE, inhibidor de aromatasa no esteroideo.

Favorece a Placebo + Let Favorece a Ribociclib + Let

0.556 0,1 1 10

Hortobagyi, et al., N Engl J Med 2016, 375:1738-1748

Secondary Endpoints Ribociclib + Letrozole Placebo + Letrozole

Overall survival data were immature at the cut-off date for interim analysis

41 28

020406080

100

ORR

All Patients p=0.000155

Rate (%)

Overall Response Rate

53 37

020406080

100

ORR

Patients With Measurable Disease p=0.00028

Rate (%)

Overall Response Rate Clinical benefit rate in patients with measurable disease: 80% ribociclib arm vs. 72% placebo arm (p=0.02)

Hortobagyi et al NEJM 2016

Efficacy of endocrine therapy in the first line setting in Breast Cáncer RH+ HER2-1,2,3

6 8,2 6 5,8

13,8 14,5

8,2 8,3 9,4 9,9

16,6

24,8

0

5

10

15

20

25

30

Sledge et al(Chemotherapy) Bonneterre et al Mouridsen et al Paridaens et al FALCON PALOMA 2

Palbocicl

ib+Letrozo

l

1. Finn RS, Palbociclib and Letrozol in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936 2. Robertson JF, Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005 3. Kümler I, Knoop AS, Review of hormone-based treatments in postmenopausal patients with advanced breast cancer focusing on aromatase inhibitors and fulvestrant.

* *SLAm/

mTTP en

meses

Placebo +

Letrozol

Paclitaxe

l+Doxo

Paclitaxe

l

Exemestan

o Tamo

xifeno

Letrozol

Tamoxifen

o

Tamoxifen

o Anas

trazol

Fulvestran

t Anas

trazol

Progression after first line therapy/ resistance?

Study Brazos del estudio DoR TP 0020/0021 Fulvestrant / Anastrozol 16.7 m/13.7 m 5.5 m / 4.1 m EFECT Fulvestrant / Exemestano 13.5 m / 9.8 m 3.7 m / 3.7 m

SoFEA Fulvestrant + Anastrozol / Fulvestrant + Placebo/ Exemestano 12.3 m / 17.2 m / 17.2 m 4.4 m / 4.8 m / 3.4 m

Fulvestrant 250: PHASE III STUDIES AFTER PROGRESSION FROM AI

DDR, duración de respuesta; TP, tiempo hasta la progresión; IA, inhibidores de aromatasa Bergh J et al. JCO 2012;30-1919-1925. Robertson et al. Cancer 2003. Jonhston, et al. Lancet Oncol. 2013; 14: 989–98

Mechanisms of resistance to hormones •Loss of ER expression •Truncated ER-ἁ / mutations of ESR 1 • Alternative signaling (receptor TK signaling):

•activation of PI3K pathway •mTOR activation

•Postranscriptional activation: •MYC mutations •Overexpression of cyclines

PI3K/AKT/mTOR Pathway Inhibitors

Crosstalk Between ER and PI3K/AKT/mTOR Signaling: Rationale for Dual Inhibition • mTORC1 activates ER in a ligand-independent fashion1

• Hyperactivation of the PI3K/AKT/mTOR pathway is observed in endocrine-resistant breast cancer cells2due to1,2: -Increased HER2-mediated signaling -Mutational inactivation or loss of PTEN -Activating mutation or amplification of PIK3CA

• mTOR is a rational target to enhance the efficacy of endocrine therapy Abbreviations: AKT, protein kinase B; EGFR, epidermal growth factor receptor; ER, endocrine

receptor; ERE, endocrine response element; HER2, human epidermal growth factor receptor-2; IGF-1R, insulin-like growth factor-1 receptor; MAPK, mitogen-activated protein kinase; mTOR, mammalian target of rapamycin; mTORC1, mTOR complex 1; PI3K, phosphatidylinositol-3-kinase; PTEN, phosphatase and tensin.

1. Yamnik RL, et al. J Biol Chem. 2009;284(10):6361-6369; 2. Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413.

Adapted from Johnson SR. Clin Breast Cancer. 2009;9(suppl 1):S28-S36.

Rationale for PI3K/mTOR Inhibitors in HR+ Breast Cancer

39

ER Fulvestrant

BYL719 BKM120

E2F BCL2

Proliferation Survival

Aromatase Inhibitors ERBB3 IGF1R

S6K1 mTOR Everolimus Temsirolimus

pS167

GATA3

CDK4/6

pRB Cyclin D1

PI3K

Palbociclib LEE011

Hormone therapy plus mTOR inhibitors in patients previously exposed to AI TAMRAD BOLERO

CR, cociente de riesgo; IA, inhibidor de aromatasa; IC, Intervalo de confianza; SLP, Supervivencia libre de progresión.

Bachelot T et al., J Clin Oncol 2012;30:2718 Baselga J et al., N Engl J Med 2012;366:520

BOLERO-2: Phase III Study of Exemestane ± Everolimus in Patients with ABC Progressing After NSAIs

• Stratification 1. Sensitivity to prior endocrine therapy 2. Presence of visceral disease • No crossover

Everolimus 10 mg/day + Exemestane 25 mg/day (n = 485) Placebo + Exemestane 25 mg/day (n = 239)

Primary endpoint PFS Secondary endpoints OS, ORR, CBR, safety, QOL, bone markers

Baselga J, et al. N Engl J Med. 2012;366(6):520-529.

N = 724 PMW 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

41

SLP: Valoración local

84 0 20 40 60 80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 90 96 Tiempo (semanas)

Probabili

dad (%) d

el Evento

CR = 0.44 (IC del 95%, 0.36-0.53) Valor de P de Log rank: < 1 × 10-16 EVE + EXE: 7.4 meses PBO + EXE: 3.2 meses

EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239)

Everolimus Placebo Número de pacientes que permanecen en riesgo 485 436 365 303 246 188 136 96 64 45 34 21 13 9 2 2 0 239 190 131 95 63 45 29 19 12 8 6 6 4 2 0 0 0

CR = 0.36 (IC del 95%, 0.28-0.45) Valor de P de Log rank: < 1 × 10-16 EVE + EXE: 11.0 meses PBO + EXE: 4.1 meses

SLP: Valoración central

Everolimus Placebo 485 422 351 284 224 176 119 86 57 38 32 22 12 7 2 2 0 239 179 112 74 56 36 23 18 8 5 4 4 3 1 0 0 0

0 20 40 60 80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 Probabili

dad (%) d

el Evento

EVE + EXE (E/N = 155/485) PBO + EXE (E/N = 127/239)

Tiempo (semanas)

CR, cociente de riesgo; SLP, Supervivencia libre de progresión; CI, intervalo de confianza. Yardley D et al. Adv Ther. 2013; 30(10):870-884.

BOLERO-2: Final Analysis of Progression-free Survival by Local and Central Assessment

Número de pacientes que permanecen en riesgo

BOLERO-2 (39-mo) Final Overall Survival Analysis

43

One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS®. Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System; PBO, placebo. Piccart M, et al. EBCC 2014. Abstract 1LBA.

232 109

248 113

266 120

279 130

292 145

311 153

330 162

347 170

373 182

399 194

414 201

429 211

448 220

471 232

485 239

EVE+EXE PBO+EXE

No. at risk

HR = 0.89 (95% CI, 0.73-1.10) Log-rank P = .14

Kaplan-Meier medians EVE+EXE: 30.98 months PBO+EXE: 26.55 months

Censoring times

11 5

23 8

39 18

58 28

91 41

118 56

154 77

196 98

216 102

0 0

1 1

• At 39 months’ median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013)

– 55% deaths (n = 267) in the EVE+EXE arm vs 60% deaths (n = 143) in the PBO+EXE arm

PrECOG 0102: FUL + EVE or PBO in postmenopausal women with HR+, HER2– MBC resistant to AI therapy • Objective: To evaluate the efficacy of FUL + EVE vs FUL + PBO in pts with HR+, HER2– AI-resistant MBC • Methodology:

Kornblum et al. (Abstract #S1-02 – oral)

*FUL 500 mg administered on day 1 and 15 of cycle 1, then on day 1 of cycles 2-12 (28 days cycle)

Arm A & B (week 48) Unblind and continue FUL ± EVE

Induction Phase (treat until progress or unacceptable toxicity. Maximum of 48 wks) Continuation Phase

If no PD or unacceptable toxicity N=130

• Postmenopausal women with HR+, HER2– MBC relapsed on and/or resistant to prior AIs • ECOG PS 0-1 • prior he otherapy regi e for etastasis • Measurable and/or non-measurable disease (RECIST 1.1) • 2 doses of FUL permitted within 28 days prior to randomization

Arm A: FUL (500 mg)* + EVE (10 mg) PO QD (n=66) Arm B: FUL (500 mg)* + PBO (PO QD) (n=65)

R 1:1

Endpoints Primary: • PFS (by investigator assessment) Secondary: • Safety, OS, ORR and TTP

Stratification factors: ECOG PS (0 vs 1), measurable disease, prior chemotherapy for

*1 Gr4 AE was reported and was not specified

Figure 2: Overall Survival Figure 1: Progression Free Survival (by investigator assessment – primary study endpoint)

Buparlisib (BKM120): A Potent Oral Pan-PI3K Inhibitor • BKM120 is a potent oral pan-class I PI3K inhibitor that selectively inhibits all 4 class I PI3K isoforms (α,β, , )1,2 • Demonstrated antiproliferative and pro-apoptotic activity in 6 human tumor cell lines that model TRAS resistance (ie, dysregulated PI3K pathways)1 • Potent antitumor activity in tumor xenograft models2 • Phase 1 dose-escalation and expansion study completed3 • 26 registered trials of BKM120 (single-agent or in combination) in BC patients4

– Target enrollment > 4000 patients

1. Voliva CF, et al. AACR 2010, Abstr 4498 (poster); 2. Maira M, et al. Mol Cancer Ther 2011;11:317-328; 3. Rodon J, et al. Invest New Drugs. 2014; DOI: 10.1007/s10637-014-0082-9; 4. http://clinicaltrials.gov/ct2/results?term=BKM120%2C+breast+cancer&Search=Search

Reprinted from Rodon J, et al. SABCS 2011, Abstr P3-16-01 (poster). Based on data from Cully M, et al. Nat Rev Cancer. 2006;6(3):184-192.

45

BKM120 more potent than RAD001 in inducing apoptosis in ER+ estrogen-deprived cells with PIK3CA mutation or PTEN loss

Sanchez et al., Breast Canc Res 2011

RAD001

RAD001

BKM120

BKM120

| OMIC | Targeting the PI3K Pathway in Breast Cancer | 12 June 2014 | Business Use Only 46

BELLE-2: PFS Prob

abilidad de

supervive

ncia libre

de progre

sión %

Probabilid

ad de supe

rvivencia

libre de p

rogresión

%

ctADN, ADN tumoral circulante; CR, cociente de riesgo; IC, intervalo de confianza; SLP, supervivencia libre de progresión.

(IC 95%) CR (95% IC) (IC 95%) CR (95% IC)

Baselga J, et al. SABCS 2015. S6-01.

BYL719 A Specific Inhibitor of the p110α Catalytic Isoform of PI3K • BYL719 is an α-isoform-specific inhibitor of class I PI3K1 • BYL 9 i hi ited p α a d p α mutants (IC50=5 nM) and is selective (>50-fold) against a wide range of protein kinases.1 • In breast cancer cell lines harboring PI3KCA mutations, BYL719 inhibited the PI3K.

Gonzalez-Angulo et al. ASCO 2013, Abstract 2531.

TASELISIB (GDC0032)

Via

bil

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CT

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Via

bil

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Taselib: Letrozol:

Taselib: Letrozol:

Hoeflich KP, et al., Genes & Cancer 2016;7.

Molécula pequeña que inhibe de forma selectiva las isoformas de la clase I PI3K Muy potente para inhibir la isoforma PI3Kβ Modelos preclínicos hay sinergia entre letrozol y taselisib

PALOMA-3: Phase III Study Design

• Primary endpoint: investigator-assessed PFS • Se o dary e dpoi ts: ORR, CBR CR, PR, or SD for ks , OS, pt-reported outcomes, safety

Pts with HR+/HER2- MBC; PD after

endocrine therapy; ≤ 1 chemotherapy

regimen for advanced BC

(N = 521)

Palbociclib 125 mg QD 3 wks on/1 wk off +

Fulvestrant 500 mg IM Q4W (n = 347)

Tx to PD, toxicity, or study

withdrawal

Placebo 3 wks on/1 wk off + Fulvestrant 500 mg IM Q4W

(n = 174)

Cristofanilli M, et al. SABCS 2015. Abstract P4-13-01.

Stratified by visceral metastases (yes/no), sensitivity to previous endocrine therapy,

menopausal status

347 333 281 273 247 244 202 197 91 85 32 0 23 7 7 1 Palbociclib + fulvestrant 174 165 112 105 83 80 59 58 22 22 13 0 7 2 1 0 Placebo + fulvestrant No. at risk

PFS (%)

Time (months) 0

10 20 30 40 50 60 70 80 90

100

0 1 2 3 4 5 6 7 8 9 10 15 11 12 13 14 Placebo + fulvestrant Palbociclib + fulvestrant

PALOMA-3 Final Analysis: Investigator-assessed PFS (ITT Population)

FUL, fulvestrant; HR, hazard ratio; PAL, palbociclib; PBO, placebo Cristofanilli M, et al. Lancet Oncol 2016 2016 Apr;17(4):425–39

PAL + FUL (n=347) PBO + FUL (n=174) Median PFS, months (95% CI) 9.5 (9.2–11.0) 4.6 (3.5–5.6) HR (95% CI) 0.46 (0.36–0.59) P value <0.0001

Primary Endpoint: PFS (ITT)

Presented By George Sledge at 2017 ASCO Annual Meeting

PALOMA-3 and MONARCH 2 Characteristics

Presented By George Sledge at 2017 ASCO Annual Meeting

ASCO Guidelines 2016

Rugo H, et al., J Clin Oncol 34:3069-3103

Take home messages Patients with ER+ ABC should be treated with hormone therapy except for those with a is eral risis or those with already proven resistance to endocrine therapy. There are many proven therapeutic options Sequencing remains a challenge as most trials are not designed to answer this question. A better understanding of resistance mechanisms is needed (and this will require new tissue or blood biopsies at progression). Future efforts should identify more sensitive molecularly defined populations, allowing for more intelligent and personalized treatment.

ABC 3 RECOMMENDATIONS • We strongly recommend the use of objective scales, such as the ESMO Magnitude of Clinical benefit or the ASCO Value Framework to evaluate the real magnitude of benefit provided by a new treatment and help prioritize funding, particularly in countries with limited resources • Premenopausal women, usually not included in the trials should have adecuate ovarian supression or ablation and be treated the same as post menopausal women • The addition of Everolimus to an AI is a valid option since it significantly improves PFS ( no OS benefit), taking into account toxicities . It can be combined with tamoxifen or fulvestrant.

• The addition of a CDK 4/6 inhibitor to an AI in patients naive or pre exposed to endocrine therapy is one of the preferred treatment options , it has an aceptable toxicity profile. Patients relapsing within 12 months from the end of adjuvant therapy were not included. • We are still awaiting OS • In patients previously exposed to ET, the addition of CDK4/6 inhibitor to fulvestrant is one of the preferred options if this drugs were not previously used • OPTIMAL SEQUENCE is uncertain

ABC 3 RECOMMENDATIONS

Thank you