Medical Update: Hormone-Receptor Positive Metastatic Breast Cancer

Neil Vasan, MD, PhD

Assistant Attending Physician

Breast Medicine Service

Memorial Sloan Kettering Cancer Center

April 6, 2019

Disclosures • Novartis (consulting)

Outline • Natural history of ER+ breast cancer and historical paradigm of therapy

• Guidelines and standard of care therapies

• New therapies in clinical trials

• Managing side effects

Some maxims (for physicians and patients)

• Know why you are on a particular therapy at a particular time

• Understand prognostic reality while not extinguishing hope

• Guidelines are helpful but they are not the gospel • Don’t take a therapy worse than the disease • Live your best life and strive to manage burnout

A show of hands • Initial diagnosis of breast cancer was metastatic disease (de novo)

• Developed metastatic disease

– 5 years after surgery for localized breast cancer

– 10 years after surgery for localized breast cancer

– 15 years after surgery for localized breast cancer

Living with and beyond ER+ breast cancer • How do we bend the curve?

– Deeper responses to therapy

– Solving drug resistance

– Managing side effects

– Earlier detection

Pan, et al. NEJM 2017; 377:1836-1846

No LN

1-3 LN

4-9 LN

Retrospective study of >60000 patients with ER+ breast cancer after stopping endocrine therapy

Tumor size 0-2cm

Overestimate of risk (pts from 1976-2011) but pattern is important Semantics

Therapeutic strategies to treat ER+ MBC

Goal of therapy: Alter estrogen synthesis and/or activity

Anti-estrogen Therapy

Class Mechanism of Action Agents LHRH agonists •Decrease ovarian estrogen

production in premenopausal women leuprolide, goserelin, oophorectomy

Aromatase inhibitors (AIs)

•Inhibit conversion of androgens to estrogen in postmenopausal women

letrozole, anastrozole, exemestane

Selective estrogen receptor modulators (SERMs)

•Bind to ER •Downregulate ER transcriptional activity

tamoxifen, toremifene, raloxifene

Selective estrogen •Bind to ER fulvestrant receptor degraders •Downregulate ER transcriptional (SERDs) activity

•Degrade the ER

Precursor molecules Estrogen Estrogen receptor

X

X

ER+ breast cancer

Endocrine therapies can control ER+ metastatic breast cancer for long periods of time (months to years)

Chemotherapy options for metastatic breast cancer Chemotherapy Options for

Metastatic Breast CancerSingle Agents Combinations

DoxorubicinEpirubicinPegylated liposomal doxorubicin

Paclitaxel (+ bevacizumab)DocetaxelAlbumin-bound paclitaxel

CapecitabineGemcitabine

VinorelbineEribulin

Anthracyclines CAF/FAC (cyclophosphamide/doxorubicin/fluorouracil)

FEC (fluorouracil/epirubicin/cyclophosphamide)

AC (doxorubicin/cyclophosphamide)

EC (epirubicin/cyclophosphamide)

AT (doxorubicin/docetaxel; doxorubicin/paclitaxel)

CMF (cyclophosphamide/methotrexate/fluorouracil)

Docetaxel/capecitabine

GT (gemcitabine/paclitaxel)

Taxanes

Antimetabolites

Other microtubule inhibitors

Other Single Agents Other Combinations

CyclophosphamideMitoxantroneCisplatinEtoposide (po) VinblastineFluorouracil Ixabepilone

Ixabepilone + capecitabine

Preferred First-Line Agents for HER2+ Disease

With Trastuzumab + Pertuzumab For Trastuzumab-Exposed Patients

PaclitaxelDocetaxelVinorelbine

Ado-trastuzumab emtansineLapatinib + capecitabineTrastuzumab + other first-line agentsTrastuzumab + capecitabineTrastuzumab + lapatinib (without cytotoxic therapy)

Adapted from NCCN

Adapted from NCCN

Generally, chemotherapy controls ER+ breast cancer

for short periods of time (months)

Current NCCN Treatment Algorithm for MBC

Adapted from NCCN

Is there an optimal sequence or best approach in ER+ MBC?

1st line

2nd line

3rd line

Ovarian suppression improves survival in premenopausal women

Aromatase inhibitors improve time to progression in postmenopausal women

SWOG 0226: Firstline AI + fulvestrant improves overall survival, more in endocrine-naïve patients

Mehta, RS, et al. NEJM 2012;367:435-444.

Mehta, RS, et al. NEJM 2019;380:1226-1234

FALCON: Fulvestrant improves PFS vs AI in de novo ER+ MBC

HR 0.797 (95% CI 0.637, 0.999); p=0.0486

Median PFS

Fulvestrant: 16.6 months

Anastrozole: 13.8 months

Number of patients at risk:

Fulvestrant

Anastrozole

230

232

187

194

171

162

150

139

124

120

110

102

96

84

81

60

63

45

44

31

24

22

11

10

2

0

0

0

Pro

po

rtio

n o

f p

ati

en

ts a

live

an

d

pro

gre

ss

ion

fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0 3 6 9 12 15 18 21 24 27 30 36 33 39

0.2

Fulvestrant (n=230)

Anastrozole (n=232)

Robertson JFR et al. Lancet. 2016;388:2997–3005.

Increasing role for fulvestrant (or combinations) in 1st line therapy for de novo disease

Uncovering mechanisms of endocrine therapy resistance

• 1. Upregulation of cell cycle pathways

– CDK4/6 pathway

• 2. Activation of signaling pathways

– PI3K/Akt/mTOR pathway

• 3. Deregulation of ER itself

– ESR1 activating mutations

Role of CDK4/6 pathway in ER+ breast cancer

Battisti, et al. Ther Adv in Med Onc 2018

• All cells cycle through phases of growth, DNA synthesis, and cell division

• Phases are tightly controlled by brake mechanisms

• CDK4/6 proteins turn on Rb, which release the brakes on E2F to cause cell cycle progression

• Inhibiting CDK4/6 prevents cell cycle progression and decrease cell growth

• In combination with endocrine therapy, inhibiting CDK4/6 can cause ER+ breast cancer cell death

Three FDA-approved CDK4/6 inhibitors Palbociclib

(Ibrance, Pfizer)

Ribociclib

(Kisqali, Novartis)

Abemaciclib

(Verzenio, Lilly)

Dose/schedule 125 mg daily,

3 weeks on/1 week off

600 mg daily

3 weeks on/1 week off

Combination: 150 mg BID

Monotherapy: 200 mg BID

Continuous

Completed Phase III Trials 1st line: PALOMA-2

2nd line: PALOMA-3

1st line: MONALEESA-2

MONALEESA-7

2nd line:

MONALEESA-3

1st line:

MONARCH-3

2nd line:

MONARCH-2

Monotherapy:

MONARCH-1

FDA approval status 2015: 1st line (with AI)

2016: 2nd line (with fulvestrant)

2017: 1st line (with AI)

2018: 1st or 2nd line (with fulvestrant)

2017: 2nd line with fulvestrant

2017: Post ET and chemo as

single agent

2018: 1st line (with AI)

Key side effects Decreased white blood cells and platelets Decreased white blood cells and

platelets

Decreased white blood cells,

diarrhea, fatigue

Monitoring Blood counts Blood counts, liver function tests,

electrolytes, electrocardiogram

Blood counts, liver function tests

-In firstline setting CDK4/6 inhibitor + AI improves PFS by ~10 months, vs AI alone -Overall survival data of palbociclib + fulvestrant 35 vs 28 mo, not statistically significant (PALOMA-3, NEJM 2019) -Endocrine sensitive patient subset overall survival analysis: 40 vs 30 mo

Lack of biomarkers for benefit from CDK4/6 inhibitors

• Aside from ER positivity, no biomarkers that predict clinical response to PI3K inhibitors

A framework for firstline therapies in ER+ MBC

Combination firstline therapy AI + CDK4/6 inhibitor (DFI >1 yr) Fulvestrant + CDK4/6 inhibitor (DFI <1 yr) Fulvestrant + anastrozole (de novo)

Single agent firstline therapies AI (DFI >1 yr) Fulvestrant (DFI <1 yr) Fulvestrant (de novo)

DFI = disease free interval (amount of time since completing adjuvant endocrine therapy)

PI3K/mTOR signaling pathway

• PI3K/Akt/mTOR is a signaling pathway

• Upregulated in ER+ breast cancer

• PIK3CA gene codes for subunit of PI3K complex

– Mutated in 40% of ER+ breast cancer

• Difficult pathway to drug

– Multiple “versions” (isoforms) of PI3K

• Drugs that target one “version” are FDA-approved in leukemia and lymphoma

– Diabetic like side effects

• Initial efforts focused on mTOR inhibition

Easter Island “Rapa Nui” Rapamycin (everolimus)

2nd line therapy: Everolimus improves on all endocrine therapy

• BOLERO-2

– Everolimus + exemestane (7.8 mo) > exemestane (3.2 mo)

• PrECOG 0102

– Everolimus + fulvestrant (10.3 mo) > fulvestrant (5.1 mo)

• TAMRAD

– Everolimus + tamoxifen (8.6 mo) > tamoxifen (4.6 mo)

Baselga J et al. NEJM 2012;366:520-529.

Kornblum NS, et al. JCO 2018;36:1556-1563.

Bachelot, T. et al. JCO 2012;30:2718-2724.

Aside from ER positivity, no biomarkers that predict clinical response to everolimus

Side effects of everolimus -Mouth sores (stomatitis) -High blood sugar/diabetes -Lung inflammation (pneumonitis) -Fatigue

SWISH: Steroid rinse decreases mouth sores from everolimus

Rugo HS et al. Lancet Oncol. 2017;18:654–62.

PI3K/mTOR signaling pathway

• PI3K/Akt/mTOR is a signaling pathway

• Upregulated in ER+ breast cancer

• PIK3CA gene codes for subunit of PI3K complex

– Mutated in 40% of ER+ breast cancer

– Ample preclinical data that PIK3CA-mutant breast cancer responds preferentially to PI3K inhibitors

Targeted therapy: Alpelisib (PI3Kα inhibitor) + fulvestrant

-New standard of care in ER+ PIK3CA mutated breast cancer?

-Resistance due to releasing brakes on insulin signaling adding ketogenic diet?

André, F., et al. ESMO 2018

Hopkins, et al. Nature 2018

Why do some patients become resistant to AI therapy?

• A war of clones

• Mutations in the estrogen receptor (ESR1) acquired on AI can drive AI resistance

Chandarlapaty, S. et al. JAMA Onc 2016;2:1310-1315

Razavi, P. et al. Cancer Cell 2018;34: 427-438

Mutated estrogen receptor

Fribbens et al. JCO. 2016.

ESR1 Mutant ESR1 Wildtype

ESR1 mutant ER+ breast cancer responds better to fulvestrant than AI

Drugs in ongoing clinical trials in ER+ MBC

Epigenetic therapies: Chidamide, entinostat

• Epigenetic changes alter DNA and modify gene expression

• One family of “erasers” is histone deacetylases (HDAC)

• HDAC inhibitors are FDA-approved in lymphoma and myeloma

• Randomized phase 3 clinical trial in China

– Chidamide + exemestane (7.4 mo) > exemestane (3.8 mo) [PFS]

• Randomized phase 2 clinical trial in USA

– Entinostat + exemestane (4.3 mo) > exemestane (2.3 mo) [PFS]

– Entinostat + exemestane (28.1 mo) > exemestane (19.8 mo) [OS]

www.zenithepigenetics.com

Jiang, Z. et al. ESMO 2018

Yardley, et al. JCO 2013;31: 2128-2135.

Antibody-drug conjugate: Sacituzumab govitecan (anti-TROP2)

Bardia, A. et al. ASCO 2018

Can we optimize SERD’s: “oral fulvestrant” • ER is expressed and remains functional even in the endocrine resistant state

• Intramuscular fulvestrant has

– Poor bioavailability

– Variable ER downregulation even at high dose

• We need more potent SERDs

– With oral bioavailability

– Down-regulate both wildtype and mutant ER

Oral SERDs in trials AZD9496 (Astra Zeneca) GDC-9545 (Genentech) LSZ102 (Novartis) SAR439859 (Sanofi) RAD1901 (Radius) G1T48 (G1 Therapeutics)

Precursor molecules Estrogen Estrogen receptor

ER+ breast cancer

SERD mechanism

New targeted therapies in ER+ breast cancer

*

FGFR1 HER2 mutations (3% of ER+ BC) Targetable by neratinib -Approved in adjuvant setting in HER2+ BC

FGFR1 amplification (8% of ER+ BC) Targetable by: -AZD4547 (Astra Zeneca) -Debio 1347 (Debiopharm) -Lucitanib (Clovis)

Immunotherapies in ER+ metastatic breast cancer

Zacharakis, N. et al. Nature Med 2018;24:724-730

Checkpoint blockade -Atezolizumab (anti-PDL1) + nab-paclitaxel Improved PFS FDA accelerated approval in metastatic TNBC for PD-L1 positive patients MORPHEUS trial (NCT03280563) -Testing atezolizumab + multiple therapies in ER+ metastatic breast cancer

The future is bright