Sys te m ic Tre a tm e nt of Lum ina l Ea rly and Advance d Bre as t

Cance r

Alexandru ENIU, MD, PhDMedical Oncologist

Department of Breast TumorsCancer Institute Ion Chiricuţă

Cluj-Napoca, Romania

Coordinator, ESO Eastern Europe and Balkan Region programme (EEBR)

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Adjuvant Tamoxifen: EBCTCG Oxford Meta-analysis

38% RR

RR 30%

EBCTCG, Lancet 2011

Effect on Recurrence Rate and Survival Irrespective of Age, Stage, Grade, PR and Tumor Diameter.

N>10,000, 44% N+, 51% chemotherapy

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Δ 8%Δ 8.8%

Δ 14.2%

The longer – The better

1 year of tamoxifen

5 years of tamoxifen

2 years of tamoxifen

EBCTCG Metaanalysis, Lancet , 2011

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MAJOR PUBLISHED STUDIES OF ADJUVANT ENDOCRINE THERAPY WITH AN AI IN

POSTMENOPAUSAL WOMEN

« STANDARD THERAPY »

Challenged by

• 1) Upfront AI ATAC

BIG 1-98

• 2) Earlysequential AI

IES (BIG 2-97)

ABCSG + ARNO

• 3) Latesequential AI

MA17 (BIG 1-97)ABCSG – 6A

N=8010

N=4742

N=5187andN=856

N=28177

Tamoxifen x 5y

Anastrozole x 5 years

Tamoxifenx 2-3y

Exemestanex 3-2y

Tamoxifen x 5yLetrozole x 5y

Anastrozole* x 3y

Tam x 2y

Anastrozole x 3y

N=3123Letrozole x 5 years

N=6241

*Anastrozol is not approved for extended therapy

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Aromatase inhibitors vs. Tamoxifen meta-analysisAI (5y) vs. Tam (5y)Tam→AI (5y) vs. Tam (5y)

Dowsett et al, JCO, 2010

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Presented by: Honghchao Pan, EBCTCG

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MA.17R Trial DesignAI x 5 yrs - Following Prior 5 years of AI - preceded or not by Tamoxifen

•1900 pts•54% N+ve•58% Adjuvant chemotherapy

RANDOMIZE

Placebo

4.5-6 yrs of Aromatase Inhibitor Letrozole 2.5 mg po od

Any duration of prior Tamoxifen

Let PlacSubjects who had a DFS event

67 (7.0%) 98 (10.2%)

Distant recurrence 42 (4.4%) 53 (5.5%)Loco-regional recurrence

19 30

Bone 28 37Contralateral breast cancer§ CBC

13 (1.4%) 31 (3.2%)

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1. Is OS+ TAM ( or AI) superior to Tam alone

2. Is an OS + AI superior to OS + Tamoxifen?ESO-ESMO E

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No chemo group: low risk clinicopthologic features: 90% >40y, 91% N0, 85% T<2 cm, 41% Grade 1

Francis, NEJM, 2015, 2018(SOFT trial)

For women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal,

the addition of ovarian suppression improved disease outcomes

SOFT: Ovarian ablationor not?

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Francis, NEJM, 2018(TEXTtrial)

TEXT: If Ovarian ablation,TAM or AI?

In premenopausal women with hormone-receptor–positive early breast cancer, adjuvant treatment with exemestaneplus ovarian suppression, as compared with a tamoxifen

plus ovarian suppression, significantly reduced recurrencePagani, NEJM, 2014(TEXT trial)

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Risk Hormone therapy Chemotherapy Factors to consider

Low risk T1, N0, Grade 1,or low “gen risk”

PRE TAM No chemo No Ovarian Sup.5 years enough

POST TAM or AI No chemo 5 years enough AI in Lobular C

Interm risk, pN0High/interm HR

pT1c, pT2, pN0 or G2/G3, interm “gen risk”

PRE OFS+TAMor OFS+AI

Consider chemo for some 10 years of TAM for some

POST AI upfront Chemo in many cases Bisphosphonates

Interm risk, pN1High/interm HR

pT1c, pT2, pN1 (1-3) or G2/G3, interm “gen risk”

PRE OFS +AI (benefit larger

<35y)

Chemo in many cases Extended HT with TAM

POST AI upfront for 3-5 years

Chemo in many cases Extended HT with AI Bisphosphonates

High risklow/interm HR

pT3,pN2-3High grade

Younger

PRE OFS +AI Chemotherapy for most Consider Extended HT with AI

POST AI Chemotherapy for most Extended HT with AI Bisphosphonates

ER+ breast cancer- circa 2019

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If the results of tumour biology in the metastatic lesion differ from the primary tumour, it is currently unknown which result should be used for treatment-decision making. Since a clinical trial addressing this issue is difficult to undertake, we recommend considering the use of targeted therapy (ET and/or anti-HER-2 therapy) when receptors are positive in at least one biopsy, regardless of timing(LoE: Expert opinion) (87%).

PRIMARY ENDOCRINE RESISTANCE is defined as:Relapse while on the first 2 years of adjuvant ET, orPD within first 6 months of 1st line ET for MBC, while on ET

SECONDARY (ACQUIRED) ENDOCRINE RESISTANCE is defined as:Relapse while on adjuvant ET but after the first 2 years, orRelapse within 12 months of completing adjuvant ET, orPD ≥ 6 months after initiating ET for MBC, while on ET

(LoE: Expert opinion) (67%%)

3rd ESO-ESMO International ConsensusGuidelines for Advanced Breast Cancer (ABC3)

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First line Hormonal therapy

Hong-Bin Xu et al Clinical Breast Cancer 11 (4); 246, 2011

Significant difference in favouring AIs over TAM ORR (OR, 1.56; 95% CI, 1.17-2.07; P .002) and CB (OR, 1.70; 95% CI, 1.24-2.33; P .0009)

Trend toward an improved OS not significant (OR, 1.95; 95% CI, 0.88-4.30; P .10)

ORR

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Robertson, Lancet, 388:10063

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Combining Other Targeted Agents and Endocrine Therapy

SOSRAS

RAF

BasalTranscription

Machineryp160

ERE ER Target Gene Transcription

ER CBPPP P P

ER

Pp90RSK

Akt P

MAPK P

CellSurvivalTam

Cytoplasm

Nucleus

ER

AI

P13-KPP

PPP

P

CellGrowth

MEKP

PlasmaMembrane

EGFR/HER2

IGFRGrowth FactorEstrogenTamoxifen

EGF30008

mTOR

CellCycle

CDK 4/6 Inhibitors HDAC InhibitorEntinostat

Transcription Silencing

BOLEROTAMRAD

HORIZON

TANDEMeLEcTRA

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Baselga et al. NEJM. Epub

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CDK4 & 6 in Breast Cancer

• D type cyclins activate CDK4 & 6 which phosphorylate Rb resulting in G1 to

S progression

• Estrogen stimulates cyclin D1 in HR+ breast cancer1

• Continuous inhibition of CDK4 & 6: prolonged cell cycle arrest 3

• Hypothesis: continuous target inhibition may be an effective strategy

1Altucci L et al. 1996 Oncogene 12:2315-242Gelbert et al. 2014 Invest New Drugs 32: 825-373Beckman et al. AACR Annual Meeting 2016

G2

M

S

G1

Cyclin D

CDK4Cyclin D

CDK6

Rb

Proliferation

PO4

PO4

PO4 Rb

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PALOMA-2: Study Design (1008)1

Placebo (3/1 schedule)

+ letrozole(2.5 mg QD)

Palbociclib (125 mg QD, 3/1 schedule)

+ letrozole(2.5 mg QD)

• Postmenopausal• ER+, HER2– advanced breast

cancer• No prior treatment for

advanced disease• AI-resistant patients excluded R

AN

DO

MIZ

ATI

ON

Primary endpointInvestigator-assessed PFS

Secondary endpointsResponse, OS, safety, biomarkers, patient-reported outcomes

Stratification factors–Disease site (visceral, non-visceral)–Disease-free interval (de novo

metastatic; ≤12 mo, >12 mo)–Prior (neo)adjuvant hormonal

therapy (yes, no)

N=666a

2:1

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MONALEESA-3(Ribociclib)

0.57 18.7 Not Reached

ORR:32.4

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Second line: Fulvestrant vs CDK4/6 inh + Fulvestrant

PALOMA 3

MONARCH 2

MONALEESA 3- second line

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FDA pooled CDKi Analysis

Average cost of CDK inh: 13.500 USD per month=162.000 USD per yearAI: 500 USD/monthTAM: 150 USD/month

• Clearly there are subgroups of patients that do very well with HT alone

• No predictive biomarkers- we are unable to select patients

• We have the option ( if reimbursed) to offerCDK4/6 inhibitors to all our first and secondline NOW

• What will happen when they progress?-

• Which sequence?ESO-ESMO E

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SOLAR-1

PIK3CA-non-mutant cohort

(n=231)

ALP 300 mg QD PO + FUL 500 mg IM*

n=115

PBO+ FUL 500 mg IM*

n=116

• Men or post-menopausal women with HR+, HER2– ABC

• Received prior AI• Identified PIK3CA status

(in archival or fresh tumor tissue)

• Measurable disease or ≥1 predominantly lytic bone lesion

• ECOG performance status ≤1

(N=572)

ALP 300 mg QD PO + FUL 500 mg IM*

n=169

PBO + FUL 500 mg IM*

n=172

PIK3CA-mutant cohort

(n=341)R

1:1, stratified by presence of liver/lung metastases and prior

CDK4/6 inhibitor treatment

Primary endpoint• PFS in PIK3CA-mutant cohort

(locally assessed)Secondary endpoints include:• OS (PIK3CA-mutant cohort)

• PFS (PIK3CA-non-mutant cohort)

• PFS (PIK3CA-mutation in ctDNA)

• OS (PIK3CA-non-mutant cohort)

• ORR/CBR• Safety

R

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ENDOCRINE THERAPY• Endocrine therapy (ET) is the preferred option for HR+ disease, even

in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response

• The optimal sequence of endocrine-based therapy is uncertain. It depends on which agents were previously used (in the (neo)adjuvant or advanced settings), the burden of the disease, patients’ preference, costs and availability.

•Available options include AI, tamoxifen, fulvestrant, AI/fulvestrant + CDK4/6 inhibitor, AI/tamoxifen/fulvestrant + everolimus. In later lines, also megestrol acetate and estradiol, as well as repetition of previously used agents, may be used.(LoE/GoR : I/A) (95%)

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ER POSITIVE / HER-2 NEGATIVE ABCThe addition of a CDK4/6 inhibitor to an aromatase inhibitor, in patients naïve or pre-exposed to ET, provided a significant improvement in median PFS (~10 months), with an acceptable toxicity profile, and is therefore one of the preferred treatment options*. Patients relapsing < 12 months from the end of adjuvant AI were not included in the published studies and may not be suitable for this combination. OS results are still awaited. QoL was comparable to that with ET alone.(LoE/GoR : I/A) (90%)

ESMO-MCBS: 3

The addition of a CDK4/6 inhibitor to fulvestrant, in patients previously exposed to ET, provided significant improvement in median PFS (6 to 7 months), a non-statistically-significant improvement in OS (7 months) and an improvement in QoL, and is the preferred treatment option, if a CDK4/6 inhibitor was not previously used.

(LoE/GoR : I/A) (90%)ESMO-MCBS: 4ATTENTION: PROPOSED CHANGES. NOT YET VOTED NOR APPROVED!ESO-E

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aster

class

2019

ER POSITIVE / HER-2 NEGATIVE ABCThe addition of everolimus to an AI is a valid option for some patients previously exposed to endocrine therapy, since it significantly prolongs PFS, albeit without evidence of OS benefit. The decision to treat must take into account the toxicities associated with this combination, lack of statistical significant OS benefit, cost and availability. (LoE/GoR : I/B) (88%)Tamoxifen or fulvestrant can also be combined with everolimus. (LoE/GoR : II/B) (80%)Adequate prevention, close monitoring and proactive treatment of adverse events is needed, particularly in older patients treated with everolimus due to the increased incidence of toxic deaths reported in the Bolero-2 trial. (LoE/GoR : I/B) (97%) ESMO-MCBS: 2

Everolimus and CDK4/6 inhibitors should NOT be used after disease progression on that specific agent (i.e. beyond progression). (LoE/GoR : NA/E) (74%)

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