Management of metastatic hormone receptor-positive breast cancer - - PowerPoint PPT Presentation

Debates and Didactics in Hematology and Oncology July 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 2.2017

Stage IV HR + breast cancer Premenopausal Postmenopausal Visceral crisis OFS plus endocrine therapy as for postmenopausal women Or Selective ER modulators Aromatase inhibitor

• r

Selective ER modulators

• r

Palbociclib + letrozole (category 1)

• r

Ribociclib + letrozole (category 1) Consider 1st line 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 ABC Dec 2016

Recent advances in the first line setting

• Combination endocrine therapy AI + FAS 250

Mehta et al NEJM 2012 FACT 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.EstrogenCDK 4/6 + Cyclin D 2.CDK4/6 +Cyclin D RB1 3.RB1 E2F A, E, CDK 2 4.Cyclin E+CDK2 HYPER- phosphorylate RB1E2F 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= 165 P2 n=666 Palbociclib 125 mg daily po for 3 weeks q28 d Letrozole 2.5 mg /day po Letrozole 2.5 mg /day po Progression Intolerance Withdrawal Death Placebo Primary endpoint: PFS 2ary endpoints: Response, OS, safety, biomarkers

Paloma 1- Primary endpoint PFS

Median PFS: 20·2 months vs 10·2 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 Ribociclib 600 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/HER2neu IGF1R

IRS PI3K Akt

PTEN

TSC1/2 mTORC1 mTOR Raptor

PRAS40 mLST8 Gene expression Anti-apoptosis Cell Proliferation Angiogenesis Rapamycin S6K1/4EBP1

mTORC2 mTOR Rictor

Estrogen Receptor

Ras Raf MAPK NFκB

Src mLST8

Rheb GSK3-β Cyclin D1 Cyclin E Cell membrane

DEPTOR DEPTOR

Estrogen FGFR MET

Bolero-2

Advanced/met astatic ER + HER2 – Breast cancer Progressed on non-steroidal AI Everolimus 10 mg po QD N=485 Primary endpoint: PFS 2ary endpoints: OS, ORR, QoL, safety Randomized 2:1 Placebo N=239 OR Exemestane 25 mg QD Exemestane 25 mg QD

BOLERO 2

• Panel A shows

progression-free survival on the basis

• f local assessment
• f 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 cancer Progressed on prior treatment or within 12 mo

• f adjuvant ET

1 or more prior chemo Palbociclib 125 mg daily po for 3 weeks q28 d PLUS FAS 500 mg N=347 Placebo PLUS FAS 500 mg N=174 Randomized 2:1 OR

Paloma-3

Cristofanilli M et al 2016 TheLancet

Cristofanilli M et al 2016 TheLancet

Monarch-1

Phase II, single arm,

• pen 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-2

Phase 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 d PLUS FAS 500 mg N=446 Placebo PLUS FAS 500 mg N=223 OR Primary endpoint: PFS 2ary 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

Postmenop ausal ER + Hormone Resistant (6 mo) Her2- negative (IHC +1 or +2) MBC

Continue Most Recent Endocrine Therapy (ET)

R A N D O M I Z E*

EVE

10 mg daily

TRAS

every 21 days P R O G R E S S I O N 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) Tamoxifen 5 (16.7) 7 (29.2) Fulvestrant 10 (33.3) 8 (33.3) Exemestane 8 (26.7) 9 (37.5) Megace 2 (6.7)

Poster presented at SABCS December 6-10, 2016

PFS (mo) 1st progression

Poster presented at SABCS December 6-10, 2016

PFS (mo) 2nd progression- after crossover

Poster presented at SABCS December 6-10, 2016

What is the optimal sequence?

NCCN Guidelines 2.2017

Stage IV HR + breast cancer Premenopausal woman Postmenopausal woman Visceral crisis OFS plus endocrine therapy as for postmenopausal women Or Selective ER modulators Aromatase inhibitor

• r

Selective ER modulators

• r

Palbociclib + letrozole (category 1)

• r

Ribociclib + letrozole (category 1) Consider initial chemotherapy Prior ET? If yes, when???

No

Prior Adjuvant ET?

AI Sel ER modulators FAS+AI Palbociclib/Ribocicli b +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 1st line

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??