Hormonoterapia y Nuevas Terapias Biológicas en Cáncer de...

Hormonoterapia y Nuevas Terapias Biológicas en Cáncer de Mama

Avanzado: Una realidad

Diego Soto de Prado Otero

Hospital Clínico Universitario de Valladolid

Esquema de la presentación

1. Introducción. Mecanismo de acción.

2. Inhibidores de CDK 4/6

3. Inhibidores de m-TOR y PI3K

4. Conclusiones

MECANISMO DE ACCIÓN DE LA HORMONOTERAPIA

SuprarrenalSuprarrenal

AndrostendionaAndrostendiona TestosteronaTestosterona

AromatasaAromatasa

EstronaEstrona EstradiolEstradiol

x Inhibidores de la Aromatasa


x Ooforectomía

Irradiación ovárica

x Análogos LHRH


x SERM’s

Tamoxifeno, Toremifeno

Fulvestrant


TERAPIAS DIRIGIDAS EN TUMORES LUMINALES

Año Hormonoterapia Mecanismo de acción

1977 SERMs

Tamoxifeno

Toremifeno

Antagonistas del RE en el tejido

mamario

1990 IA

Anastrozol

Exemestano

Letrozol

Inhiben la síntesis de estrógenos en

mujeres postmenopáusicas.

2000 SERDs

Fulvestrant

Se une al RE, impide su

dimerización y acelera su

degradación.

Análogos de la LHRH Goserelina

Klijn JG, et al. J Natl Cancer Inst. 2000;92:903-911.

Overall Survival

EORTC Premenopausal: Survival Benefit for Ovarian Suppression and TAM

AI, aromatase inhibitor; TAM, tamoxifen.

Mouridsen, et al. Oncologist 2004;4:489–496; Bonneterre, et al. Cancer 2001;92:2247–2258;

Paridaens, et al. J Clin Oncol 2008;26:4883.

First-Line Therapy: Aromatase Inhibitors Showed Consistent Superiority over Tamoxifen (Postmenop)

Pro

po

rtio

n w

ith

ou

t p

rog

ressio

n

Time (months)

0

0.6

1.0

0 36

0.4

0.8

0.2

TAM

30 24 12 6 18

TTP (months) P

Letrozole Tamoxifen

9.4 6.0

<0.0001

Anastrozole Tamoxifen

10.7 6.4

0.022

Exemestane Tamoxifen

10.5 5.5

0.028

AI

• Phase III SWOG S0226 study

Mehta RS, et al. N Engl J Med. 2012;367:435-444.

FULVESTRAN

Bergh J, et al. J Clin Oncol. 2012;30:1919-1925.

FACT Study

Di Leo A, et al. J Natl Cancer Inst. 2014;106(1):djt337.

Second Line (AI Resistant): CONFIRM Long-term Benefits in OS (ITT)

Di Leo A, et al. J Clin Oncol. 2010;28:4594-4600.

Erratum in: J Clin Oncol. 2011;29:2293.

FIRST (Fase IIB)

PI3K

AKT ER

GRB2

P

P

P P

ER

CoA

ER CoA

AP-1

P

CoA

TFs

EREs AP-1/SP-1 TFs-REs

P ER

S6KI

mTOR inhibitors

SOS Shc

Rb

E2F E2F

Gene transcription

Cyclin D

CDK4/6

P P P

P P

Cyclin D

CDK4/6

CDK4/6 inhibitors

P P

mTOR

Estrogen receptor downregulator

Growth factor receptor (eg, EGFR)

Ras

Raf

MAPK

Src

PI3K inhibitors

Aromatase inhibitors

MEK p21

p16

G1

S G2

M

p53

Cell cycle

Tyrosine kinase inhibitors

Regulation of the G1/S Checkpoint in Breast Cancer

Pl3K/Akt

STATs MAPKs

ER/PR/AR Wnt/β-catenin

NF-κB

p16

p21

p53

CDK4/6 Cyclin D

RB

RB

Gene transcription

G2 S

M

G1

G0

P P P

P

Inactive

Active tumor suppressor

E2F

E2F

R

D-type cyclins regulated in response to mitogenic stimuli, including activation of RTKs and steroid hormone receptors1

• Cyclin D1 is amplified in 15–20% of breast cancers

INHIBIDORES DE CDK 4/6

1. PALBOCICLIB (PFIZER)

2. RIBOCICLIB (NOVARTIS)

3. ABEMACICLIB (LILLY)

Palbociclib Inhibidor selectivo de CDK4/6. Previene la P-pRB, induciendo una “arresto” de la célula en G1. Toxicidad más frecuente: NEUTROPENIA y TROMBOPENIA

N = 66

1:1

Part 1: All Comers

ER+, HER2– BC

R A N D O M I Z A T I O N

PD 0332991 125 mg QDa +

Letrozole 2.5 mg QD

Letrozole

2.5 mg QD

Part 2: Biomarker-Positive

N = 99

1:1 ER+, HER2–

BC with CCND1 amp

and/or loss of p16

R A N D O M I Z A T I O N

PD 0332991 125 mg QDa +

Letrozole 2.5 mg QD

Letrozole

2.5 mg QD

PALOMA-1 :Phase 2 Trial


FINN Lan Oncol 2015

Median PFS LET-PALBO 20.2 m (95%CI 13.8-27.5)

LET 10.2 m (95%CI 5.7-12.6)


FINN Lan Oncol 2015

Median PFS

LET 5.7 m (95%CI 2.6-10.5)

LET-PALBO 26.1 m (95%CI 11.2-NE)

Median PFS

LET 11.1 m (95%7.1-16.4)

LET-PALBO 18.1 m (95%CI 13.1-27.5)

PALOMA-2

PALOMA3 Study Design

Placebo (3 wks on/ 1wk off)

+ Fulvestrant†

(500 mg IM q4w)

Palbociclib (125 mg QD;

3 wks on/1 wk off) +

Fulvestrant† (500 mg IM q4w)

†administered on Days 1 and 15 of Cycle 1.

● Visceral metastases

● Sensitivity to prior

hormonal therapy

● Pre-/peri- vs Post-

menopausal

Clinicaltrials.gov NCT01942135

2:1 Randomization

N=521

Stratification:

• Post-menopausal patients must have progressed on prior aromatase inhibitor therapy.

n=347

n=174

• HR+, HER2– ABC

• Pre-/peri-* or post-menopausal

• Progressed on prior endocrine therapy:

– On or within 12 mo adjuvant

– On therapy for ABC

• ≤1 prior chemotherapy regimen for advanced cancer

*All received goserelin.

Cristofanilli M. SABCS 2015

ESTUDIO PALOMA-3

2ª Línea Hormonoresistentes.

Pre/ postmenopausicas.

PFS: 9,5 m vs 4,6 m

HR: 0,46

● MONALEESA-1: Letrozol Ribociclib (Neoadjuvant)

● MONALEESA-2: Letrozol Ribociclib (mBC, 1L)

● MONALEESA-3: Fulvestrant Ribociclib (mBC, 1L)

● MONALEESA-7: TAM/NSAI + goserelin Ribociclib (premenop, mBC)

Inhibidor selectivo de CDK4/6. Previene P-pRb

Sinergico con inhibidores de PI3K/Akt/mTOR (Everolimus y Buparlisib)

Tóxicidad: GI (35%) y Neutropenia (40%)

RIBOCICLIB

Abemaciclib

La principal toxicidad es Gastrointestinal (52% diarrea; 30% nauseas) y Neutropenia (16%). Atraviesa la BHE.

Datos de actividad sinérgica con Gemcitabina.

Dos estudios con datos para el 2017 :

MONARCH-1 : Fase II de Abemaciclib en 2ª línea en pacientes postmenopaúsicas RE+ HER2- pretratadas con QT. Objetivo 1º: T. Resp.

MONARCH-2: Fase III de Abemaciclib +/- FULV en 1ª ó 2ª línea en pacientes postmenopaúsicas RE+ HER2- en progresión a HT. Objetivo 1º: PFS

Inhibidores de mTOR

CBR

P = 0.045 (exploratory analysis)

TTP

• TAM: 4.5 months

• TAM + EVE: 8.6 months

• HR (95% CI) = 0.54 (0.36-0.81)

• P = 0.0021 (exploratory analysis)

Abbreviations: CI, confidence interval; EVE, everolimus;

HR, hazard ratio; TAM, tamoxifen.

Bachelot T, et al. J Clin Oncol. 2012;22(30):2718-2724.

TAM TAM + EVE

42.1

% (29-56)

61.1% (47-74)

0

10

20

30

40

50

60

70

CB

R, %

of

Pa

tien

ts (

95

% C

I)

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Months

0.0 0.1 0.2 0.3 0.4 0.5

0.6 0.7 0.8 0.9 1.0

TT

P P

rob

ab

ilit

y

TAM

At risk

57

54 45 39 34 28 26 25 20 19 17 14 10 3 3 2 1

44 30 24 22 16 13 11 7 6 4 2 2 1 0 0

TAM + EVE

TAMRAD: Phase II randomised study; ABC; relapsed or progressed on

previous AI (n=111)

TAM

TAM + EVE

0,0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1,0

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 36 38 40

Pro

bab

ilit

y o

f S

urv

ival

Months

TAMRAD

Primary resistance

• N (%) of events

• TAM: 15 (54%)

• TAM + EVE: 12 (46%)

• HR = 0.73; 95% CI, 0.34-1.55


Secondary resistance

• N (%) of events

• TAM: 16 (55%)

• TAM + EVE: 4 (15%)

• HR = 0.21; 95% CI, 0.07-0.63


TAMRAD: Phase II randomised study; ABC; relapsed or progressed on

previous AI (n=111)

TAM

TAM + EVE

ESTUDIO BOLERO-2

Baselga J et al, New Engl J Med 2012

1.0

0.8

0.6

Pro

bab

ilit

y o

f

Pro

gre

ss

ion

-Fre

e S

urv

ival

0.4

0.2

0

28 26 24 22 20 18 16 14

Time (months)

12 10 8 6 4 2 0

0 0

1 0

4 0

10 1

13 1

23 2

42 6

57 9

99 17

147 27

194 42

236 61

318 103

394 146

485 239

EVE+EXE PBO+EXE

No. at risk

HR = 0.45 (95% CI, 0.38-0.54) Log-rank P < .0001

Kaplan-Meier medians EVE+EXE: 7.8 months PBO+EXE: 3.2 months

Censoring times EVE+EXE (n/N = 310/485) PBO+EXE (n/N = 200/239)

BOLERO: Phase III study, ABC, relapsed or progressed on previous NSAI (n=724) PFS Based on Local Assessment

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival.

Yardley DA, et al. Adv Ther. 2013;30:870-884. 15

03

0340

34

PFS based on local assessment at 18-mo follow-up

BOLERO-2 (39-mo f/up): Overall Survival

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; 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 = .1426

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

15

03

0340

34

Various PI3K/AKT/mTOR Pathway Alterations Have Been Detected in HR+ Breast Cancer

RTKs can be

overexpressed

or overactivated

in cancer

PTEN

AKT

PIP2

PIP3

Tumor growth and progression

Resistance to anticancer therapy

PIK3CA mutation is the

most frequent genetic

alteration

mTORC1 PRAS40 p27 GSK3 FOXO Casp9 BAD AS160 MDM2 eNOS

mTORC2

PI3K

AKT

INHIBIDORES DE PI3k

Pan-PI3K class I inhibitors

• Inhibit all four isoforms of class I PI3K (α, β, γ, δ) and provide the broadest inhibition of PI3K3,6

• May be better suited to combination therapy and in tumour types lacking PIK3CA mutations4

First-generation

Dual PI3K/mTOR inhibitors

• Target homologous regions in the catalytic sites of PI3K and downstream components mTORC1 and mTORC23,6

• Targeting two levels of the pathway may provide the potential advantage of stronger inhibition3,6

Isoform specific inhibitors

• Characterised by greater and PI3K isoform-specific activity3

• Provide the potential to completely block a specific target while limiting toxicities associated with a broader inhibition5

PI3K inhibitors in development

• Three generations of PI3K inhibitors have now been developed

Second-generation Third-generation

INHIBIDORES DE PI3k

1. BUPARLISIB (NOVARTIS)

2. ALPELISIB (NOVARTIS)

3. PICTILISIB (ROCHE)

4. TASELISIB (ROCHE)

Regulatory

subunit

Catalytic

subunit p110

p85

PI3K

PI3K

Isoforms

α

β

γ

δ

Buparlisib: Los “Belle”

Paninhibidor PI3k eficaz en líneas PI3k-mut En líneas PI3k-MUT y resistentes a HT o a Everolimus, la combinación con Fulvestran revierte las resistencias

Randomization (1:1) Stratification based on PI3K pathway activation status* and

presence/absence of visceral disease

Main study cohort n≈842

Buparlisib + fulvestrant†

n≈421

Placebo + fulvestrant†

n≈421

PI3K unknown cohort n≈308

Buparlisib + fulvestrant†

n≈154

Placebo + fulvestrant†

n≈154

Postmenopausal patients with HR+/HER2– locally advanced

or metastatic breast cancer refractory to aromatase inhibitor N≈1150

Molecular screening for PI3K pathway activation status*

Study objectives:

Co-primary: PFS (local assessment)‡

Co-key secondary: OS‡

Secondary: Efficacy (ORR,‡§ CBR,‡§ PFS,§ OS§), safetyII, PK¶, patient-reported outcomes‡, ECOG PS‡§

Beneficio en mutaciones con ctDNA PIK3CA mutations

BELLE-2 Safety Profile Was Characterized by Transaminitis, Hyperglycemia, Rash, and Mood Disorders

Buparlisib + Fulvestrant n=573

Placebo + Fulvestrant n=570

Adverse event, % All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

Total 99.5 63.2 14.1 93.0 27.4 4.6

Increased ALT 40.1 18.7 6.8 6.8 1.1 0

Increased AST 37.3 15.0 3.0 9.3 2.8 0

Hyperglycemia 43.1 15.2 0.2 7.7 0.2 0

Rash 32.1 7.7 0.2 6.3 0 0

Anxiety 22.3 5.2 0.2 8.2 0.9 0

Fatigue 31.9 4.9 0 23.9 1.6 0

Depression 26.2 3.7 0.7 8.9 0.4 0

Diarrhea 34.2 3.7 0 14.6 1.1 0

Asthenia 20.1 2.8 0 10.5 1.1 0

Stomatitis 21.6 2.1 0 6.5 0.5 0

Nausea 38.7 1.7 0 23.2 1.4 0

Decreased appetite 29.8 1.6 0 11.1 0.2 0

Phase III randomized study of buparlisib + fulvestrant in patients with HR+/HER2– mBC previously treated with AI and refractory to mTORi1

Randomization (2:1) Stratification based on presence/absence of visceral disease

Postmenopausal patients with HR+/HER2–, locally advanced or mBC, pre-treated with AI

and refractory to endocrine and mTORi combination therapy N≈420

Buparlisib + fulvestrant*

n≈280

Placebo + fulvestrant*

n≈140

Study objectives:

Co-primary: PFS (local assessment)

Co-key secondary: OS

Secondary: Efficacy (ORR, CBR), safety, PK, patient-reported outcomes, time to ECOG PS deterioration

Resistance to everolimus may be linked to feedback activation of the PI3K pathway

Buparlisib + fulvestrant controls tumor growth in everolimus-resistant* xenografts (ZR75-1)1

*Resistance to everolimus acquired by daily treatment with everolimus10 mg for >45 days.

ZR75-1: wild-type PIK3CA, PTEN mutation and loss of function.

1. O’Brien HA, et al. SABCS 2013:PD1−5 (Poster).

Buparlisib

Everolimus

Tu

mo

r vo

lum

e (

mm

3)

Time of treatment (days)

0 42 6 12 18 24 30 36

0

400

200

1000

800

600

Buparlisib + fulvestrant

Everolimus

Alpelisib • Inhibidor PI3k alfa-selectivo

• MDT: 400 mg/día con FULV o 300 mg/día con IA

• Toxicidad semejante a Buparlisib

PI3

K

RTK

PIP2

PIP3

AK

T

PTE

N

mTORC1

mTORC2

Alpelisib PI3Kα

0

50

100

150

200

250

300

350

400

450

500

0 5 10 15 20 25

Treatment days

Alpelisib significantly decreases tumor volume in the MCF7 (breast)

E545K model

Alpelisib + fulvestrant showed greater

antitumor activity than either agent alone in an

everolimus-resistant, ER-positive breast cancer

model

Combination Neo-adjuvant mBC

Letrozol

Fulvestrant

TAM + goserelin

T-DM1

CBYL719A2201: Letrozole ± BKM120 or

BYL719 (Phase II)

46

CBYL719XUS03T Letrozole + BYL719

(Phase Ib)

CLEE011X2107:

Letrozole + LEE011 ±BYL719 (Phase I/II)

CBYL719X2101 Fulvestrant+ BYL719

(Phase I) CLEE011X2108:

Fulvestrant + LEE011 ±

BKM120 or BYL719 (Phase I/II) SOLAR-1

Fulvestrant ± BYL719 (Phase III) (1/2L)

15

05

0353

78

B-YOND:

TAM + Goserelin with

BKM120 or BYL719 (Phase Ib)

BYL719 + T-DM1 (Phase Ib)

Screening assessments

Randomization (1:1)

PIK3CA-mutant cohort (n≈340) PIK3CA-nonmutant cohort (n≈220)

Randomization (1:1)

Men and postmenopausal women with HR+/HER2– ABC, whose disease progressed on prior AI treatment (N≈560)

A Phase III Randomized Double-blind, Placebo Controlled Study of Alpelisib in Combination With Fulvestrant for Men and Postmenopausal Women With HR+/HER2– Advanced Breast Cancer Which Progressed on or After

Aromatase Inhibitor Treatment

Alpelisib (300 mg QD) + fulvestrant*

(500 mg IM q4w)

Placebo (QD) + fulvestrant*

(500 mg IM q4w)

Alpelisib (300 mg QD) + fulvestrant*

(500 mg IM q4w)

Placebo (QD) + fulvestrant*

(500 mg IM q4w)

Stratification by: • Liver and/or lung

metastases • Prior treatment with any

CDK4/6 inhibitor

Primary endpoint: Progression free survival (PFS; local assessment; PIK3CA-mutant cohort)

Key secondary endpoint: Overall survival (OS; PIK3CA-mutant cohort)

SOLAR-1

PICTILISIB

En neoadyuvancia demostró asociado a ANA un aumento de

la capacidad antiproliferativa de ANA, sobretodo en Luminal B

Phase II FERGI: Combination of fulvestrant and pictilisib in ER+, AI-resistant

advanced BC associated with high rate of toxicity and no significant improvement in

PFS

TASELISIB

Inhibidores PI3K

CONCLUSIONES

1. Dentro de los mecanismos de resistencia al tratamiento hormonal la vía PI3k-

AKT-mTOR y las ciclinas dependientes de kinasas juegan un papel crucial

2. Las líneas de investigación van dirigidas a aumentar la eficacia de los

tratamientos disponibles y recuperar la sensibilidad hormonal:

Fulvestran a “altas” dosis ha demostrado ser superior a IA y probablemente se

instaure en 1ª línea (Estudio FALCON)

CONCLUSIONES

Inhibidores de ciclinas : datos muy positivos en 1ª y 2ª línea.

Inhibidores de m-TOR: papel en las resistencias secundarias (2ª líneas y

sucesivas)

Inhibidores de PI3k: eficacia a costa de una importante toxicidad. Fase III con

beneficio en pacientes PI3k mutadas. Pendientes de resultados con

inhibidores más selectivos.

Muchas gracias…

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