Debates and Didactics in Hematology and OncologyJuly 29, 2017

Elisavet Paplomata, MD Assistant Professor

Winship Cancer Institute of Emory University

Management of metastatic hormone receptor-positive breast cancer

Outline

• Background • Current guidelines • Definition of endocrine resistance • First line therapy • Recent progress with cell cycle pathway targeting • 2nd line therapies • The role of mTOR inhibition • What is the optimal sequencing?

Background • Appr. 2/3 of breast cancers are HR positive • Endocrine therapy, with AIs in

postmenopausal patients has been the standard of care for metastatic HR + BC

• However many cancers develop resistance • 2nd line mTOR inhibition has been studied• Recent advances in 1st line therapy and

beyond have improved PFS • What is the optimal sequence?

NCCN Guidelines 2.2017Stage IV HR + breast cancer

PremenopausalPostmenopausal

Visceral crisis

OFS plus endocrine therapy as for postmenopausal women Or Selective ER modulators

Aromatase inhibitororSelective ER modulators orPalbociclib + letrozole (category 1) or Ribociclib + letrozole (category 1)

Consider 1stline chemotherapy

1st line Endocrine Therapy (ET)

Response then progression

2nd line ET

Response then progression

3rd line ET

1st line AI

Author Treatment AI (mo)

TAM(mo)

AI + FAS(mo)

Nabholtz et al. 2000 Anastrozole vs TAM 11.1 5.6

Bonneterre et al. 2001 Anastrozole vs TAM 8.2 8.3

Mouridsen et al. 2001 Letrozole vs TAM 9.4 6

Paridaens et al. 2008 Exemestane vs TAM 9.9 5.8

Mehta et al. 2012 AI vs AI + FAS 13.5 15

Bergh et al. 2012 AI vs AI + FAS 10.2 10.8

Endocrine resistance

Adjuvant Endocrine therapy (ET)Early

relapse x 1 year

Late relapse

Endocrine resistant Endocrine sensitive Endocrine resistant

2 years > 2 years of ET

Primary endocrine resistance

Secondary (acquired) endocrine resistance

First 6 months of 1st line ET for MBC

≥ 6 months on ET for MBC ESMO guidelines for ABCDec 2016

Recent advances in the first line setting

• Combination endocrine therapy AI + FAS 250

Mehta et al NEJM 2012FACT SWOG

Bergh et al JCO 2012

Mehta et al NEJM 2012

John F R Robertson et al. 2017

FALCON: FAS 500 vs AI

CDK4/6 inhibition • Dysregulation of the cell cycle is one of the defined hallmarks of

cancer• For a cell to divide, it has to go through strictly predefined stages,

and this has to happen in a orderly fashion to avoid genetic damage; this is called the cell cycle

• Cyclin- dependent kinases (CDKs) are a large family of serine threonine kinases that together with their regulatory protein partners, the cyclins, have a crucial role in the controlled progression through the cell cycle

• CDK 4/6 have a pivotal role in the G0/G1-to- S phase cell cycle transition

• Palbociclib, abemaciclib and ribociclib are orally active, potent and highly selective inhibitors of CDK4 and CDK6

O’Leary et al. 2016 Nature reviews

Classical model of cell cycle 1.EstrogenCDK

4/6 + Cyclin D2.CDK4/6 +Cyclin

D RB1 3.RB1 E2F A,

E, CDK 2 4.Cyclin E+CDK2 HYPER-phosphorylate RB1E2F G1- to- S phase.

1

2

3

4

Chemical structure of selective CDK4/6 inhibitors

O’Leary et al. 2016 Nature reviews

Clinical trials

• Paloma-1: 1st line MBC + LET • Paloma-2: 1st line MBC + LET • Paloma-3: >1st line MBC + FAS

Palbociblib

• Monarch-1: > 1st line MBC• Monarch-2: 1st line ABE+ FAS

Abemaciclib

• Monaleesa -2: 1st line + LET

Ribociclib

Paloma-1 and 2

Advanced ER +

HER2 –Breast cancer

No prior treatment P1 n= 165P2 n=666

Palbociclib 125 mg daily po for 3 weeks q28 d

Letrozole 2.5 mg /day po

Letrozole 2.5 mg /day po ProgressionIntoleranceWithdrawal

Death Placebo

Primary endpoint: PFS 2ary endpoints: Response, OS, safety, biomarkers

Paloma 1- Primary endpoint PFS

Median PFS: 20·2 months vs10·2 months

Paloma-2 – Primary endpoint Progression-free Survival.

Finn RS et al. 2016 N Engl J Med

Palbociclib: Pooled analysis

Rugo HS et al. SABCS 2016 P4-22-03

Monaleesa-2

Advanced ER +

HER2 –Breast cancer

No prior treatment

n=668

Ribociclib600 mg QD

po for 3 weeks q28

d

Primary endpoint: PFS 2ary endpoints: OS, ORR, CBR, safety

Randomized 1:1

Placebo

OR

Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Monaleesa-2

Hortobagyi et al. 2016 NEJM

Hortobagyi et al. 2016 NEJM

2nd line therapy and beyond

EGFR/HER2neuIGF1R

IRSPI3K

Akt

PTEN

TSC1/2

mTORC1mTORRaptor

PRAS40mLST8

Gene expressionAnti-apoptosisCell ProliferationAngiogenesis Rapamycin

S6K1/4EBP1

mTORC2mTORRictor

Estrogen Receptor

Ras

Raf

MAPK

NFκB

Src

mLST8

Rheb

GSK3-βCyclin D1

Cyclin E

Cell membrane

DEPTOR

DEPTOR

Estrogen FGFRMET

Bolero-2

Advanced/metastatic ER +

HER2 –Breast cancerProgressed on non-steroidal

AI

Everolimus 10 mg po

QDN=485

Primary endpoint: PFS 2ary endpoints: OS, ORR, QoL, safety

Randomized 2:1

PlaceboN=239

OR

Exemestane 25 mg QD

Exemestane 25 mg QD

BOLERO 2

• Panel A shows progression-free survival on the basis of local assessment of radiographic studies, and Panel B shows central assessment

Baselga J et al 2012 NEJM

Baselga J et al 2012 NEJM

Paloma-3

Advanced ER + HER2 –

Breast cancerProgressed on

prior treatment or within 12 moof adjuvant ET 1 or more prior

chemo

Palbociclib 125 mg daily po for 3 weeks

q28 dPLUS

FAS 500 mgN=347

PlaceboPLUS

FAS 500 mgN=174

Randomized 2:1OR

Paloma-3

Cristofanilli M et al 2016 TheLancet

Cristofanilli M et al 2016 TheLancet

Monarch-1 Phase II,

single arm, open label,

Single ABE

HR+/HER2− ABC

progressed while

receiving prior ET,

within 1 year from

adjuvant AND had 1-2

chemo for MBC

Dickler et al. CCR 2017

ABE 200 bid N= 132

Monarch-1

Dickler et al. CCR 2017

Monarch-1

Dickler et al. CCR 2017

Dickler et al. CCR 2017

Monarch-2Phase III,

randomized, double-blind,

placebo-controlled

study

FAS +/- ABE

HR+/HER2− ABC

progressed while

receiving prior ET,

within 1 year from

adjuvant

Randomized 2:1

ABE 150 mg bid daily q28 dPLUS

FAS 500 mgN=446

PlaceboPLUS

FAS 500 mgN=223

OR

Primary endpoint: PFS2ary endpoints: ORR, BCR, safety, tolerability

Sledge et al. JCO 2017

Monarch 2 results

Investigator assessed Central assessment

Sledge et al. JCO 2017

Sledge et al. JCO 2017

Sledge et al. JCO 2017

EVE + FAS

Kornblum Noah et al SABCS 2016

Kornblum Noah et al SABCS 2016

Everolimus in hormone resistant MBC

Postmenopausal ER + Hormone

Resistant (6 mo)

Her2-negative

(IHC +1 or +2)

MBC

ContinueMost Recent

EndocrineTherapy (ET)

RANDOMIZE*

EVE 10 mg daily

TRAS every 21

days

PROGRESSION

Add TRAS

Add EVE

* In 2014 based on interim results, the protocol was amended and the TRAS arm was closed. All patients were treated with EVE and TRAS was added upon progression

Poster presented at SABCS December 6-10, 2016

Treatment on trial

Endocrine Agent on Trial (%)

Everolimus (n=30) Trastuzumab(n=24)

Non-steroidal AI 5 (16.7) 0Tamoxifen 5 (16.7) 7 (29.2)

Fulvestrant 10 (33.3) 8 (33.3)Exemestane 8 (26.7) 9 (37.5)

Megace 2 (6.7) 0

Poster presented at SABCS December 6-10, 2016

PFS

(mo)

1st

prog

ress

ion

Poster presented at SABCS December 6-10, 2016

Initial treatment

No. of Subject

Event

Censored

Median PFS(95% CI)

EVE

30

24 (80%)

6 (20%)

5.7 (3.9, 8.9)

TRAS

24

24 (100%)

0 (0%)

2 (1.6, 4.1)

PFS

(mo)

2nd

prog

ress

ion-

afte

r cro

ssov

er

Poster presented at SABCS December 6-10, 2016

Cross over treatment

No. of Subject

Event

Censored

Median Survival (95% CI)

Add EVE

16

13 (81%)

3 (19%)

6.3 (2.6, 10.5)

Add TRAS

12

12 (100%)

0 (0%)

3.1 (1.8, 6.7)

What is the optimal sequence?

NCCN Guidelines 2.2017Stage IV HR + breast cancer

Premenopausal woman Postmenopausal woman Visceral crisis

OFS plus endocrine therapy as for postmenopausal women Or Selective ER modulators

Aromatase inhibitororSelective ER modulators orPalbociclib + letrozole (category 1) or Ribociclib + letrozole (category 1)

Consider initial chemotherapy

Prior ET? If yes, when???

No

Prior Adjuvant ET?

AISel ER modulators FAS+AI Palbociclib/Ribociclib +AI

Yes

Early relapse within 1 year Late relapse

Prior TAM

AI

FAS

AI+CDK4/6

Prior AI

FAS+CDK4/6

EXE+EVE

FAS+EVE

EXE

TAM

Prior TAM

AI

FAS+/-AI

AI+CDK4/6

TAM

Prior AI

AI

AI+CDK4/6

FAS

TAM

1stline

Conclusions and remaining questions

• New agents recently approved and under clinical trials

• Do all patients need combination therapy upfront?

• What do you use after progression on CDK4/6 inhibitor?

• The choice depends on cancer biology, patient characteristics and side effect profile

Thank you

Questions??

Slide Number 1Outline Background NCCN Guidelines 2.20171st line AI Endocrine resistance Recent advances in the first line setting Slide Number 8Slide Number 9CDK4/6 inhibition Classical model of cell cycle Chemical structure of selective CDK4/6 inhibitors�Clinical trials Paloma-1 and 2 Paloma 1- Primary endpoint PFS Slide Number 16Slide Number 17Palbociclib: Pooled analysisMonaleesa-2 Monaleesa-2Slide Number 212nd line therapy and beyond Slide Number 23Bolero-2 BOLERO 2 Slide Number 26Paloma-3Paloma-3 Slide Number 29Monarch-1 Slide Number 31Slide Number 32Slide Number 33Monarch-2Monarch 2 results Slide Number 36Slide Number 37EVE + FAS Slide Number 39Everolimus in hormone resistant MBC Treatment on trial PFS (mo) 1st progression Slide Number 43What is the optimal sequence? NCCN Guidelines 2.2017Prior Adjuvant ET? Conclusions and remaining questions Questions??