Management of metastatic hormone receptor-positive breast cancer Debates and Didactics in Hematology and Oncology July 29, 2017 Elisavet Paplomata, MD Assistant Professor Winship Cancer Institute of Emory University
Outline • Background • Current guidelines • Definition of endocrine resistance • First line therapy • Recent progress with cell cycle pathway targeting • 2 nd 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 • 2 nd line mTOR inhibition has been studied • Recent advances in 1 st line therapy and beyond have improved PFS • What is the optimal sequence?
NCCN Guidelines 2.2017 Stage IV HR + breast cancer 1 st line Response then progression Visceral crisis Endocrine Therapy (ET) 2 nd line ET Response then progression Consider 1 st Postmenopausal 3rd line ET Premenopausal line chemotherapy Aromatase inhibitor or Selective ER modulators OFS plus endocrine or therapy as for Palbociclib + letrozole (category 1) postmenopausal or women Or Selective ER Ribociclib + letrozole (category 1) modulators
1 st line AI Author Treatment AI TAM AI + FAS (mo) (mo) (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 Endocrine resistant Endocrine resistant Endocrine sensitive Early Late relapse relapse x 1 Adjuvant Endocrine therapy (ET) year > 2 years of ET 2 years Primary Secondary (acquired) endocrine endocrine resistance resistance ESMO guidelines for ABC First 6 months of ≥ 6 months on ET for MBC 1 st line ET for MBC Dec 2016
Recent advances in the first line setting • Combination endocrine therapy AI + FAS 250 Mehta et al NEJM 2012 Bergh et al JCO 2012 SWOG FACT
Mehta et al NEJM 2012
FALCON: FAS 500 vs AI John F R Robertson et al. 2017
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 1 HYPER- phosphorylate 2 RB1 E2F G1- to- S 3 phase. 4
Chemical structure of selective CDK4/6 inhibitors O’Leary et al. 2016 Nature reviews
Clinical trials Palbociblib • Paloma-1: 1 st line MBC + LET • Paloma-2: 1 st line MBC + LET • Paloma-3: >1 st line MBC + FAS Abemaciclib • Monarch-1: > 1 st line MBC • Monarch-2: 1 st line ABE+ FAS Ribociclib • Monaleesa -2: 1 st line + LET
Paloma-1 and 2 Advanced ER + HER2 – Palbociclib 125 mg daily po for 3 weeks q28 d Breast Letrozole 2.5 mg /day po Progression cancer Intolerance No prior Withdrawal treatment Placebo Death P1 n= 165 Letrozole 2.5 mg /day po P2 n=666 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 Ribociclib 600 mg QD Letrozole po for 3 2.5 mg QD weeks q28 Advanced d ER + HER2 – OR Breast Randomized 1:1 cancer No prior treatment n=668 Letrozole Placebo 2.5 mg QD Primary endpoint: PFS 2ary endpoints: OS, ORR, CBR, safety
Monaleesa-2 Hortobagyi et al. 2016 NEJM
Hortobagyi et al. 2016 NEJM
2 nd line therapy and beyond
Estrogen EGFR/HER2neu MET FGFR IGF1R Cell membrane Estrogen Receptor Src PI3K IRS Ras PTEN Rictor mTORC2 Akt mTOR Raf mLST8 DEPTOR TSC1/2 Cyclin D1 MAPK GSK3- β Cyclin E Rheb NFκB Raptor mTORC1 mTOR S6K1/4EBP1 Gene expression PRAS40 mLST8 Anti-apoptosis DEPTOR Cell Proliferation Rapamycin Angiogenesis
Bolero-2 Everolimus 10 mg po Exemestane QD 25 mg QD N=485 Advanced/met astatic ER + HER2 – OR Randomized 2:1 Breast cancer Progressed on non-steroidal AI Placebo Exemestane N=239 25 mg QD Primary endpoint: PFS 2ary endpoints: OS, ORR, QoL, safety
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 Palbociclib 125 mg daily po for 3 weeks q28 d Advanced ER + PLUS HER2 – FAS 500 mg Breast cancer N=347 Progressed on prior Randomized 2:1 treatment or OR within 12 mo Placebo of adjuvant ET PLUS 1 or more prior chemo FAS 500 mg N=174
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 ABE 200 bid while receiving N= 132 prior ET, within 1 year from adjuvant AND had 1-2 chemo for MBC Dickler et al. CCR 2017
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, ABE 150 mg bid daily placebo- q28 d controlled PLUS study FAS 500 mg N=446 FAS +/- ABE Randomized 2:1 HR+/HER2− OR ABC progressed Placebo while PLUS receiving FAS 500 mg prior ET, N=223 within 1 year from adjuvant 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 P R Postmenop EVE R Add O ausal ER + Continue A TRAS 10 mg G Hormone Most Recent N Endocrine daily R Resistant (6 Therapy (ET) D E mo) O S Her2- M S negative I I (IHC +1 or Z O +2) TRAS E* N MBC Add every 21 EVE days * 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 Everolimus (n=30) Trastuzumab Trial (%) (n=24) Non-steroidal AI 5 (16.7) 0 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) 0 Poster presented at SABCS December 6-10, 2016
PFS (mo) 1 st progression Poster presented at SABCS December 6-10, 2016
PFS (mo) 2 nd progression- after crossover Poster presented at SABCS December 6-10, 2016
What is the optimal sequence?
NCCN Guidelines 2.2017 Prior ET? Stage IV HR + breast cancer If yes, when??? Premenopausal woman Visceral crisis Postmenopausal woman Consider Aromatase inhibitor OFS plus endocrine initial or therapy as for chemotherapy Selective ER modulators postmenopausal or women Or Selective ER Palbociclib + letrozole (category 1) modulators or Ribociclib + letrozole (category 1)
Prior Adjuvant ET? Yes No Early relapse 1 st Late relapse within 1 year line AI Sel ER modulators FAS+AI Prior TAM Prior AI Prior TAM Prior AI Palbociclib/Ribocicli b +AI AI FAS+CDK4/6 AI AI FAS EXE+EVE FAS+/-AI AI+CDK4/6 AI+CDK4/6 FAS+EVE AI+CDK4/6 FAS EXE TAM TAM TAM
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
Questions?? Thank you
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