Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education Implications - PowerPoint Presentation

Slide1

Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education ImplicationsAn Interactive Oncology Grand Rounds Series

Joyce O’Shaughnessy, MD

Chair, Breast Cancer Research Program

Baylor Charles A Sammons Cancer Center

Celebrating Women Chair in Breast Cancer Research

Texas Oncology

US Oncology

Dallas, Texas

Slide2

Oncology Grand Rounds: ER-Positive, HER2-Negative Breast Cancer

A 62-year-old woman with breast cancer is suffering from aromatase inhibitor-associated arthralgias

A 64-year-old woman with de novo metastatic disease receives letrozole and

palbociclib

A 56-year-old woman develops metastases during adjuvant endocrine therapy (ET), then receives

fulvestrant

and

ribociclib

A 63-year-old woman develops brain metastases after completion of adjuvant ET, then receives

exemestane

and

abemaciclib

A 69-year-old woman develops metastatic disease progression on

fulvestrant

and

palbociclib

, then receives

exemestane

and

everolimus

A 33-year-old woman stops taking adjuvant tamoxifen because of

weight gain

Slide3

Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education Implications

Module 1: Estrogen and Progesterone Receptors; Clinical Use of Endocrine Treatment

Incidence, subtypes, staging and treatment

Types of endocrine therapy; response and side effects

Module 2: First-Line Endocrine Therapy for Metastatic Disease: Role of CDK4/6 Inhibitors

CDK4/6 inhibitors: Overview

CDK4/6 inhibitors: Efficacy and side effects

Module 3: Second-Line Endocrine Therapy for Metastatic Disease: Role of mTOR Inhibitors

Crosstalk between ER and PI3K/AKT/mTOR signaling pathways

mTOR

inhibitors: Efficacy and side effects

Module 4: New Approaches Under Investigation

Triplet therapy: Endocrine therapy + CDK4/6 inhibitors + mTOR inhibitors

Efficacy and tolerability of emerging novel agents

Module 5: Assessing and Optimizing Treatment Adherence

Scope and clinical implications of adherence

Improving treatment adherence

Slide4

Incidence of Different Breast Cancer  Subtypes in Clinical Practice

Visiting Professors: Improving the Efficacy of Endocrine Treatment of Metastatic Breast Cancer survey. Research To Practice 2018; SEER Database 2018.

62%

10%

16%

12%

Focus of today’s

discussion

2018 SEER Breast Cancer Estimates:

New cases = 268,670

Deaths = 41,400

Slide5

Endocrine Therapies for ER-Positive Breast Cancer

Agent

Mechanism of action

Main toxicities

Tamoxifen

Antiestrogen

Menopausal symptoms, stroke, deep vein thrombosis

LHRH agonists

Ovarian suppression

Menopausal symptoms,

joint and muscle pain

Aromatase inhibitors

Aromatase blocking

Menopausal symptoms,

joint and muscle pain

Fulvestrant

Estrogen receptor antagonist

Hot flashes, bone and

muscle pain, GI symptoms

CDK4/6 inhibitors

Cell cycle progression blocking

GI symptoms, myelosuppression

Everolimus

mTOR

inhibitor

Stomatitis, infection, hepatotoxicity

Alpelisib

   

PI3K inhibitor     

 Hyperglycemia, rash

Slide6

What I Tell My Patients: Estrogen Receptor Signaling Pathway and Standard Endocrine Treatments — Premenopausal

Slide7

What I Tell My Patients: Estrogen Receptor Signaling Pathway and Standard

Endocrine Treatments —

Premenopausal

Slide8

What I Tell My Patients: Estrogen Receptor Signaling Pathway and Standard Endocrine Treatments — Postmenopausal

Slide9

What I Tell My Patients: Estrogen Receptor Signaling Pathway and Standard Endocrine Treatments — Postmenopausal

Slide10

What I Tell My Patients: Estrogen Receptor Signaling Pathway and Standard Endocrine Treatments

Slide11

What I Tell My Patients: Estrogen Receptor Signaling Pathway and Standard Endocrine Treatments

Slide12

Clinical Situations in Which Endocrine Therapy Is Used

Neoadjuvant therapy

– Reduce tumor size for breast conservation

Adjuvant therapy

– After surgery to reduce risk of relapse and increase rate of cure

Treatment of metastatic disease

–

Increase survival and provide disease palliation

Common metastatic disease scenarios:

Metastases are present at initial diagnosis

Metastasis occurs during adjuvant endocrine therapy

Metastasis occurs after completion of adjuvant endocrine therapy

Slide13

Endocrine Therapy (ET) versus Chemotherapy Induction Followed by Maintenance ET for ER-Positive Metastatic Breast Cancer (mBC)

Chemotherapy induces a more rapid tumor response but is more toxicInduction chemotherapy may be a better option for patients withRapidly progressive diseaseSymptomatic diseaseVisceral metastases with end-organ dysfunction ER-positive mBC is typically treated with first-line ET

Stockler

M et al.

Cancer Treat Rev

2000;26(3):151-68.

Slide14

Case 1

62

yo

F with 2.8-cm moderately differentiated cancer

(

ER+, PR+, 

HER2 1+) s/p lumpectomy and

SLNbx

(0/2 LN+)

Onco

type

DX® 

14

Received

postlumpectomy

XRT

2/2016 Started on

letrozole

Initially tolerated well with mild hot flashes and mild morning stiffness in fingers and knees

Gradually had worsening

arthralgias

in fingers, shoulders, knees, feet

Pain limited activities

Tried NSAID with only minimal relief

Slide15

Case 1

5/2016 Held

letrozole

for 3 weeks, pain improved

Switched to

exemestane

Pain recurred

Developed carpal tunnel symptoms

Tried duloxetine with minimal improvement

8/2016 Stopped

exemestane

9/2016 Started tamoxifen –

arthralgias

still mild problem but no longer limiting

Slide16

Common Endocrine Therapy-Related Side Effects

Side effectIncidenceAssociated agentsRisk factorsHot flashesUp to 80%TamoxifenAromatase inhibitorsPremenopausal statusGenetic variations in metabolizing enzymes (cytochrome P450 enzyme, CYP2D6)Coadministration with drugs that inhibit CYP2D6 activity (eg, SSRIs)Specific estrogen receptor genotypesArthralgias17%-36%Aromatase inhibitorsTamoxifenYounger ageAdjuvant chemotherapy (particularly taxanes)Use of granulocyte colony-stimulating factorHistory of arthralgia, arthritis or fibromyalgiaWeight gain50%-96%TamoxifenAromatase inhibitorsPremenopausal women

Santen RJ et al.

J

Clin

Endocrinol

Metabol

2017;102(10):3647.

Younus

J,

Kligman

L.

Curr

Oncol

2010;17(1):87-90.

Raghavendra

A et al.

Clin

Breast Cancer

2018;18(1):e7-13.

Slide17

Management of Hot Flashes

While estrogens and progestins are commonly used to treat hot flashes, such treatments are avoided for women with a history of breast cancerManagement strategiesSSRIs or SNRIs may interfere with tamoxifen metabolismSSRIs do not interfere with aromatase inhibitor metabolismGabapentin administered at bedtime, only for patients who experience hot flashes at night

Santen RJ et al.

J

Clin

Endocrinol

Metabol

2017;102(10):3647.

Slide18

Management of Aromatase Inhibitor-Induced Arthralgias

Lifestyle modifications: weight loss, exercise, morning warmupsPhysical therapy/occupational therapyPain relieversComplementary treatment:Vitamin D Massage therapyGlucosamineChondroitinZeel® injection, acupuncture, hypnosis, et cetera

Younus

J,

Kligman

L.

Curr

Oncol

2010;17(1):87-90.

Slide19

Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education Implications

Module 1: Estrogen and Progesterone Receptors; Clinical Use of Endocrine Treatment

Incidence, subtypes, staging and treatment

Types of endocrine therapy; response and side effects

Module 2: First-Line Endocrine Therapy for Metastatic Disease: Role of CDK4/6 Inhibitors

CDK4/6 inhibitors: Overview

CDK4/6 inhibitors: Efficacy and side effects

Module 3: Second-Line Endocrine Therapy for Metastatic Disease: Role of mTOR Inhibitors

Crosstalk between ER and PI3K/AKT/mTOR signaling pathways

mTOR

inhibitors: Efficacy and side effects

Module 4: New Approaches Under Investigation

Triplet therapy: Endocrine therapy + CDK4/6 inhibitors + mTOR inhibitors

Efficacy and tolerability of emerging novel agents

Module 5: Assessing and Optimizing Treatment Adherence

Scope and clinical implications of adherence

Improving treatment adherence

Slide20

Case 2

64

yo

F presented to local ED with RUQ pain in 1/2017. CT showed no gall bladder pathology but 2 liver lesions 2.1 and 1.5 cm.

Bx

of liver showed

adenoCA

ER+, PR+, 

HER2 2+, FISH-. Mammogram showed 3-cm R UOQ lesion.

Bx

showed same path as above. LFTs WNL. CA15.3 112

2/17 Started on

letrozole

+

palbociclib

3/17 Tolerating well clinically but ANC 700 on C2D1

Reduced dose from 125mg to 100mg

4/17 ANC 950 – continued at 100mg

CA15.3 64

6/17 CT: liver lesions 1.1 and 0.5 cm, no new lesions

CA15.3 44

Slide21

CDK4/6 Inhibitors: Mechanism of Action

Cyclin D1 binds and activates CDK4 and CDK6, and this complex phosphorylates the retinoblastoma protein (

Rb).The phosphorylation of Rb reduces its inhibitory control and promotes the initiation of S-phase, DNA synthesis and ultimately cell division. CDK4/6 inhibitors interfere with the phosphorylation of Rb and its ability to promote cell division.

Brufsky

AM,

Dickler

MN.

Oncologist

2018;

23(5):528-39

;

Brufsky

AM.

Cancer

Treat

Rev

2017;59:22-32

.

Slide22

Approved CDK4/6 Inhibitors in Combination with Endocrine Therapy

AgentInitial approval dateCurrent indications and usagePalbociclib2/20152/20164/2019Postmenopausal women, with an AI as initial endocrine-based therapyWith fulvestrant after disease progression on ETWith an AI or fulvestrant to include men with advanced or metastatic diseaseRibociclib3/20177/2018Pre-, peri- or postmenopausal women, with an AI as initial endocrine-based therapyPostmenopausal women, with fulvestrant as initial endocrine-based therapy or after disease progression on ET Abemaciclib9/201702/2018As monotherapy after ET and after chemotherapy in the metastatic settingWith fulvestrant after disease progression on ETPostmenopausal women, with an AI as initial endocrine-based therapy

Palbociclib package insert, revised 4/2019;

Ribociclib

package insert, revised 7/2018;

Abemaciclib

package insert, revised 2/2018

Slide23

Administration of CDK4/6 Inhibitors

All orally administered, with different dose schedules:Palbociclib: 125 mg qd 3 weeks on, 1 week offRibociclib: 600 mg qd 3 weeks on, 1 week offAbemaciclib: Monotherapy: 200 mg BID continuouslyWith fulvestrant: 150 mg BID continuouslyWith an aromatase inhibitor: 150 mg BID continuously

Palbociclib package insert, revised 2/2018;

Ribociclib

package insert, revised 7/2018;

Abemaciclib

package insert, revised 2/2018

Slide24

Key Studies: CDK4/6 Inhibitors as First-Line Therapy

Cross-trial comparisons are inappropriate for determining the relative efficacy of agents and regimens

Finn RS et al. N Engl J Med 2016;375(20):1925-36; Hortobagyi GN et al. Ann Oncol 2018; 29(7):1541-47; Tripathy D et al. Lancet Oncol 2018;19:904-15; Slamon DJ et al. Proc ASCO 2018;Abstract 1000; Johnston S et al. NPJ Breast Cancer 2019;5:5.

Trial

Treatment arms

mPFS

Hazard ratio

p

-value

PALOMA-2

Postmenopausal

Palbociclib

/

letrozole

,

n = 444

Placebo/

letrozole

,

n =

222

24.8

mo

14.5

mo

0.58

<0.001

MONALEESA-2

Postmenopausal

Ribociclib

/

letrozole

,

n = 334

Placebo/

letrozole

,

n = 334

25.3

mo

16.0

mo

0.57

9.63 x 10

-8

MONALEESA-7

Premenopausal

Ribociclib

/tam or NSAI, n = 335

Placebo/tam or NSAI,

n = 337

23.8

mo

13.0

mo

0.55

<0.0001

MONALEESA-3

Postmenopausal

Ribociclib

/

fulvestrant

, n = 238

Placebo/

fulvestrant

,

n = 129

Not reached

18.3

mo

0.58

NR

MONARCH 3

Postmenopausal

Abemaciclib

/NSAI, n = 328

Placebo/NSAI, n =

165

28.2

mo

14.8

mo

0.54

0.000002

Slide25

TrialTreatment armsmPFSHazard ratiop-valuePALOMA-2PostmenopausalPalbociclib/letrozole, n = 444Placebo/letrozole, n = 22224.8 mo14.5 mo0.58<0.001MONALEESA-2PostmenopausalRibociclib/letrozole, n = 334Placebo/letrozole, n = 33425.3 mo16.0 mo0.579.63 x 10-8MONALEESA-7PremenopausalRibociclib/tam or NSAI, n = 335Placebo/tam or NSAI, n = 33723.8 mo13.0 mo0.55<0.0001MONALEESA-3PostmenopausalRibociclib/fulvestrant, n = 238Placebo/fulvestrant, n = 129Not reached18.3 mo0.58NRMONARCH 3PostmenopausalAbemaciclib/NSAI, n = 328Placebo/NSAI, n = 16528.2 mo14.8 mo0.540.000002

Key Studies: CDK4/6 Inhibitors as First-Line Therapy

Cross-trial comparisons are inappropriate for determining the

relative efficacy of agents and regimens

A hazard ratio of 0.58 indicates that patients who received palbociclib/letrozole were approximately 42% less likely to have experienced progressive disease at the time of data analysis than those who received placebo/letrozole.

Finn RS et al.

N

Engl

J Med

2016;375(20):1925-36;

Hortobagyi

GN et al.

Ann Oncol

2018; 29(7):1541-47;

Tripathy

D et al.

Lancet

Oncol

2018;19:904-15

;

Slamon

DJ et al.

Proc ASCO

2018;Abstract 1000; Johnston S et al.

NPJ Breast Cancer

2019;5:5.

Slide26

Key Studies: CDK4/6 Inhibitors After Disease Progression on an Aromatase Inhibitor

Cross-trial comparisons are inappropriate for determining the relative efficacy of agents and regimens

TrialTreatment armsmPFSHazard ratiop-valuePALOMA-3Any menopausal statusPalbociclib/fulvestrant, n = 347Placebo/fulvestrant, n = 1749.5 mo4.6 mo0.46<0.0001MONALEESA-3PostmenopausalRibociclib/fulvestrant, n = 236Placebo/fulvestrant, n = 10914.6 mo9.1 mo0.57NRMONARCH 2Any menopausal statusAbemaciclib/fulvestrant, n = 446Placebo/fulvestrant, n = 22316.4 mo9.3 mo0.55<0.001

Cristofanilli

M et al.

Lancet Oncol

2016;17(4):425-39;

Slamon

DJ et al.

Proc ASCO

2018;Abstract 1000;

Sledge GW Jr et al.

J

Clin

Oncol

2017

;35(25):287

5

-84.

Slide27

CDK4/6 Inhibitors: Select ASCO 2019 Presentations

Hurvitz

S et al.

Phase III MONALEESA-7 trial of premenopausal patients with HR+/HER2− advanced breast cancer (ABC) treated with endocrine therapy ±

ribociclib

: Overall survival (OS) results.

Abstract LBA1008.

O’Leary B et al.

Genomic markers of early progression on

fulvestrant

with or without

palbociclib

for ER+ advanced breast cancer in the PALOMA-3 trial.

Abstract 1010.

Razavi

P et al.

Molecular profiling of ER+ metastatic breast cancers to reveal association of genomic alterations with acquired resistance to CDK4/6 inhibitors.

Abstract 1009.

Park Y et al.

A randomized phase II study of

palbociclib

plus exemestane with GNRH agonist versus capecitabine in premenopausal women with hormone receptor-positive metastatic breast cancer (KCSG-BR 15-10, NCT02592746).

Abstract 1007.

Slide28

Case 3

6/13 56

yo

F with 3.1-cm moderately differentiated cancer (ER+, PR-, HER2 1+) s/p lumpectomy and

SLNbx

negative.

Onco

type

DX 26

Received AC

Received XRT

10/13 Started on

letrozole

Tolerated well

12/17 Developed persistent L hip pain. Imaging showed sclerotic lesion in femur, several ribs. Femur

bx

showed

adenoCA

, ER+, PR-, HER2-. Tumor markers WNL

1/18 Started on

ribociclib

+

fulvestrant

, tolerated well

4/18 Pain much improved

CT shows increased sclerosis of known lesions and two “new” sclerotic rib lesions

Slide29

PALOMA-2: Select Adverse Events

Finn RS et al. N Engl J Med 2016;375(20):1925-36.

Adverse event

Palbociclib

/

letrozole

(n = 444)

Placebo/

letrozole

(n

= 222)

All grades

Grade 3/4

All grades

Grade 3/4

Neutropenia

79.5%

66.5%

6.3%

1.4%

Leukopenia

39.0%

24.8%

2.3%

0%

Fatigue

37.4%

1.8%

27.5%

0.5%

Nausea

35.1%

0.2%

26.1%

1.8%

Diarrhea

26.1%

1.4%

19.4%

1.4%

Anemia

24.1%

5.4%

9.0%

1.8%

Rash

17.8%

0.9%

11.7%

0.5%

Thrombocytopenia

15.5%

1.6%

1.4%

0%

Vomiting

15.5%

0.5%

16.7%

1.4%

Stomatitis

15.3%

0.2%

5.9%

0%

Slide30

Monitoring for Neutropenia in Patients Receiving CDK4/6 Inhibitors

AgentRecommended complete blood cell count monitoringPalbociclibPrior to start of therapyAt beginning of each cycleOn day 15 of the first 2 cyclesAs clinically indicatedRibociclibPrior to start of therapyEvery 2 weeks for the first 2 cyclesAt beginning of each of the subsequent 4 cyclesAs clinically indicatedAbemaciclibPrior to start of therapyEvery 2 weeks for the first 2 monthsMonthly for the next 2 monthsAs clinically indicated

Palbociclib package insert, revised 2/2018; Ribociclib package insert, revised 7/2018; Abemaciclib package insert, revised 2/2018; Spring LM et al. Oncologist 2018;22(9):1039-48.

Low incidence of febrile neutropenia

Typically reversible and resolves with drug interruption

Often decreases with subsequent cycles

Slide31

MONALEESA-2: Select Adverse Events

Hortobagyi

GN et al. N Engl J Med 2016;375:1738-48.

Ribociclib + letrozole(n = 334)Placebo + letrozole (n = 330)All gradesGrade 3-4All gradesGrade 3-4Neutropenia74.3%59.3%5.2%0.9%Nausea51.5%2.4%28.5%0.6%Infections50.3%4.2%42.4%2.4%Diarrhea35%1.2%22.1%0.9%Leukopenia32.9%21%3.9%0.6%Increased alanine aminotransferase (ALT)15.6%9.3%3.9%1.2%Increased aspartate aminotransferase (AST)15%5.7%3.6%1.2%

Slide32

Ribociclib: Dose Modification and Management of Hepatobiliary Toxicity

Grade 1 (>ULN to 3 x ULN)Grade 2 (>3 to 5 x ULN)Grade 3 (>5 to 20 x ULN)Grade 4 (>20 x ULN)AST and/or ALT elevations from baseline, total bilirubin <2 x ULNNo dose adjustmentDose interruption until recovery to baseline grade or better, resume at same dose; if Grade 2 recurs, resume at next lower doseDose interruption until recovery to baseline grade or better, then resume at next lower dose; if Grade 3 recurs, discontinueDiscontinueElevation in AST and/or ALT with total bilirubin increaseDiscontinueirrespective of baseline grade

Ribociclib package insert, revised 7/2018.

Perform liver function tests (LFTs) before initiating treatment. Monitor LFTs every 2 weeks for the first 2 cycles, at the beginning of each of the subsequent 4 cycles and as clinically indicated. If Grade ≥2 abnormalities are noted, more frequent monitoring is recommended. 

ULN = upper limit of normal

Slide33

Cardiotoxicity Monitoring for Patients Receiving Ribociclib

Monitor electrocardiograms (ECGs) and electrolytes prior to initiation of treatment. Repeat ECGs at approximately day 14 of the first cycle, at the beginning of the second cycle and as clinically indicated. Monitor electrolytes at the beginning of each cycle for 6 cycles and as clinically indicated.In the case of QTcF prolongation at any time during treatment, more frequent ECG monitoring is recommended.

Ribociclib package insert, revised 7/2018.

Slide34

Case 4

11/05 63

yo

F with 3.1-cm moderately differentiated cancer

(ER+, PR+, HER2 0) s/p lumpectomy and

SLNbx

negative.

Onco

type

DX 18

Received XRT

Started on

letrozole

, tolerated well

12/13 Stopped

letrozole

because of gradually worsening

arthralgias

1/18 Presented to ER with personality changes

MRI shows large L frontal lesion

Resection:

AdenoCA

ER+, PR-, HER2-

Staging studies show several subtle sclerotic rib lesions, TM negative

SRS to tumor bed

Started

abemaciclib

+

exemestane

8/18 Clinically well

Brain MRI shows no residual enhancement

CT: slight increase in sclerosis of rib lesions. No new lesions

Slide35

MONARCH 3: Select Adverse Events

Goetz MP et al. J Clin Oncol 2017;35(32):3638-46.

Adverse eventAbemaciclib + NSAI(n = 327)Placebo + NSAI(n = 161)All gradesGrade 3/4All gradesGrade 3/4Diarrhea81.3%9.5%29.8%1.2%Neutropenia41.3%21.1%1.9%1.2%Infections/infestations39.1%4.9%28.6%3.1%Nausea38.5%0.9%19.9%1.2%Anemia28.4%5.8%5.0%1.2%Vomiting28.4%1.2%11.8%1.9%Leukopenia20.8%7.6%2.5%0.6%Increased blood creatinine19.0%2.1%3.7%0%Increased ALT15.6%6.1%6.8%1.9%

Venous thromboembolic events occurred in 16 (4.9%) patients in the abemaciclib arm versus 1 (0.6%) in the placebo arm.

Slide36

Strategies to Manage Abemaciclib-Related Gastrointestinal Toxicity

Drink 8 to 10 glasses of water or fluid each day.Eat small, frequent meals throughout the day rather than a few large meals.Eat bland, low-fiber foods, such as bananas, applesauce, potatoes, chicken, rice and toast.Avoid high-fiber foods, such as raw vegetables, raw fruits and whole grains.Avoid foods that cause gas, such as broccoli and beans.Avoid lactose-containing foods, such as yogurt and milk.Avoid spicy, fried and greasy foods.At the first sign of loose stools, patients should start antidiarrheal therapy such as loperamide, increase oral fluids and notify your office.

Abemaciclib package insert, revised 2/2018; Hematology/Oncology Pharmacy Association Oral Chemotherapy Education sheet, revised 3/2018.

Slide37

CDK4/6 Inhibitor Drug and Food Interactions

Strong CYP3A inhibitors decrease CDK4/6 inhibitor concentrations. Avoid use of strong CYP3A inhibitors (and inducers) for patients receiving CDK4/6 inhibitors; if the patient must take a strong CYP3A inhibitor, reduce the dose of the CDK4/6 inhibitor. Avoid grapefruit, grapefruit juice, pomegranate and pomegranate juice. Proton pump inhibitors may decrease plasma concentration when patients are in a fasting state.

Palbociclib package insert, revised 2/2018; Ribociclib package insert, revised 7/2018; Abemaciclib package insert, revised 2/2018.

Slide38

MONARCH 1: Single-Agent Activity of Abemaciclib in Refractory ER-Positive, HER2-Negative mBC

N = 132 patients with HR-positive, HER2-negative breast cancer and a median of 3 prior systemic therapies in the metastatic settingAbemaciclib 200 mg administered orally on a continuous schedule every 12 hours until disease progression or unacceptable toxicityAt 12 months, confirmed objective response rate: 19.7%Clinical benefit rate at ≥6 months: 42.4%Median progression-free survival: 6.0 monthsMedian overall survival: 17.7 monthsMost common treatment-emergent adverse events of any grade:DiarrheaFatigueNausea

Dickler

MN et al.

Clin

Cancer Res

2017

;23(17):5218-24.

Slide39

Open-Label, Phase II Simon 2-Stage Trial

of

Abemaciclib

in CNS Metastases

Bachelot

T et al. San Antonio Breast Cancer Symposium 2017;Abstract P1-17-03.

Part A:

HR+, HER2+ MBC

23-56

pts

Part B:

HR+, HER2- MBC23-56 pts

Part D:NSCLC23-56 pts

Part E:Melanoma23-56 pts

Part C: Surgical: HR+ MBC, NSCLC or melanoma8-12 pts

Part F:HR+ MBC, NSCLC or melanoma with leptomeningeal metastasesa15 pts

Multiple exploratory endpoints

Primary endpoint: OIRR (CR+PR)bSecondary endpoints:CNS responseb: BOR, DoR, CBRPeripheral responsec: BOR, DoR, CBROverall response: PFSSafety and tolerability

Exploratory

Patients with brain metastases secondary to HR+ breast cancer, NSCLC or melanoma

a

+/- Parenchymal brain metastases (BM);

b

Per RANO-BM5;

c

Per RECIST V1.1

Slide40

CNS Response to

Abemaciclib

Bachelot

T et al. San Antonio Breast Cancer Symposium 2017;Abstract P1-17-03.

HR+, HER2-

HR+, HER2+

Change from baseline (%)

Change from baseline (%)

Patients previously treated with WBRTPatients previously treated with SRS therapyReceived concomitant endocrine therapy

Patients previously treated with WBRTPatients previously treated with SRS therapyReceived concomitant endocrine therapyReceived concomitant trastuzumab treatment at baseline

CRPRSDPDNE

Patients with response

N = 23

OIRR

2

(

8.7%)CR0PR2 (8.7%)SD13 (56.5%)SD ≥6 months2 (8.7%)PD8 (34.8%)CBR4 (17.4%)

Patients with responseN = 23OIRR0CR0PR0SD12 (52.2%)SD ≥6 months1 (4.3%)PD11 (47.8%)CBR1 (4.3%)

CRPRSDPDNE

Slide41

Select Phase II and III Clinical Trials of CDK4/6 Inhibitors in Metastatic Breast Cancer

StudyStatusPhaseEnrollmentSettingRandomizationPATINA (NCT02947685)OngoingIII4962L+Palbociclib + Anti-HER2 + ETAnti-HER2 + ETPACE (NCT03147287)OngoingII2202L-3LFulvestrantPalbociclib + FulvestrantPalbociclib + Fulvestrant + AvelumabnextMONARCH 1 (NCT02747004)OngoingII2252L-3LAbemaciclib + TamoxifenAbemaciclibAbemaciclib + LoperamidemonarcHER (NCT02675231)OngoingII225≥3LAbemaciclib + Trastuzumab + FulvestrantAbemaciclib + TrastuzumabTrastuzumab + SoC ChemotherapyNCT02941926OngoingIII3,7751L-2LRibociclib + LetrozoleNCT03096847OngoingIII5001LRibociclib + Letrozole (+ Goserelin for premenopausal pts)

www.clinicaltrials.gov

. Accessed; August 1, 2018.

Slide42

Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education Implications

Module 1: Estrogen and Progesterone Receptors; Clinical Use of Endocrine Treatment

Incidence, subtypes, staging and treatment

Types of endocrine therapy; response and side effects

Module 2: First-Line Endocrine Therapy for Metastatic Disease: Role of CDK4/6 Inhibitors

CDK4/6 inhibitors: Overview

CDK4/6 inhibitors: Efficacy and side effects

Module 3: Second-Line Endocrine Therapy for Metastatic Disease: Role of mTOR Inhibitors

Crosstalk between ER and PI3K/AKT/mTOR signaling pathways

mTOR

inhibitors: Efficacy and side effects

Module 4: New Approaches Under Investigation

Triplet therapy: Endocrine therapy + CDK4/6 inhibitors + mTOR inhibitors

Efficacy and tolerability of emerging novel agents

Module 5: Assessing and Optimizing Treatment Adherence

Scope and clinical implications of adherence

Improving treatment adherence

Slide43

Case 5

4/14 69

yo

F with 2.5-cm moderately differentiated cancer (ER+, PR+, HER2 1+) s/p lumpectomy and

SLNbx

negative

Received XRT

Started on

letrozole

, tolerated well

5/17 presented with gradually increasing mid-back pain

MRI showed sclerotic and lytic lesions in T and L spine. No cord involvement

CT showed small pulmonary nodules and iliac bone lesion

Bx

of iliac lesion

adenoCA

, weak ER+, PR+, HER2-

XRT to T/L spine

6/17 Started on

palbociclib

+

fulvestrant

Tolerated well once dose reduced to 100mg

5/18 tumor markers rising, CT shows slight increase in pulmonary lesions (still <1 cm), new rib lesion

Started on

exemestane

+

everolimus

8/18 Tumor markers decreasing

Slide44

mTOR Inhibitors: Mechanism of Action

mTOR activates ER in a

ligand-independent mannerEstradiol suppresses apoptosis induced by mTOR blockadeHyperactivation of the mTOR pathway is observed in endocrine therapy-resistant breast cancer cellsmTOR is a rational target to enhance the efficacy of hormonal therapy

Brufsky

AM,

Dickler

MN.

Oncologist

2018;

23(5):528-39

;

Brufsky

AM.

Cancer

Treat

Rev

2017;59:22-32

.

Slide45

Approved mTOR Inhibitor in Combination with Endocrine Therapy

AgentTargetApproval dateIndications and usageEverolimusmTOR7/20/2012Postmenopausal women; in combination with exemestane after failure of letrozole or anastrozole

Everolimus package insert, revised 4/2018

Dosing

Orally administered 10 mg/

qd

continuously

Dose modification recommended for patients with hepatic impairment or for those taking drugs that inhibit or induce P-glycoprotein (P-

gp

) and CYP3A4

Indication

Postmenopausal women with advanced ER-positive, HER2-negative BC in combination with

exemestane

after failure of treatment with

anastrozole

or

letrozole

Slide46

Advances in Therapy

2013;30:870-84.

Slide47

BOLERO-2 Phase III Study of Exemestane +/- Everolimus

N = 724 postmenopausal womenER-positive, HER2-negative metastatic breast cancerDisease recurrence or progression while receiving previous therapy with an NSAI in the adjuvant setting, to treat advanced disease or bothRandomly assigned (2:1)Everolimus + exemestanePlacebo + exemestaneMedian progression-free survival (HR = 0.45, p < 0.0001)Everolimus + exemestane: 7.8 monthsPlacebo + exemestane: 3.2 monthsObjective response rate (p < 0.001)Everolimus + exemestane: 9.5%Placebo + exemestane: 0.4%

Baselga

J et al.

N

Engl

J Med

2012;366(6):520-9.

Yardley DA et al.

Adv

Ther

2013;30(10):870-84.

Slide48

Common Grade 3 or 4 toxicitiesAdverse eventEverolimus/exemestane(N = 482)Placebo/exemestane(N = 238)Stomatitis8%<1%Fatigue5%1%Dyspnea6%1%Anemia8%1%Hyperglycemia6%<1%

Yardley DA et al. Adv Ther 2013;30(10):870-84.

Rate of treatment-related adverse events leading to discontinuationEverolimus/exemestane: 21.4%Placebo/exemestane: 3.4%Most common adverse events leading to discontinuation (everolimus/exemestane): Stomatitis (2.7%) and pneumonitis (5.6%)

BOLERO-2 Phase III Study of

Exemestane

+/-

Everolimus

Slide49

Slide50

PrE0102 Randomized Phase II Study of Fulvestrant with Everolimus or Placebo

N = 131 postmenopausal womenER-positive, HER2-negative locally advanced or metastatic breast cancerDisease recurrence or progression while receiving previous therapy with an aromatase inhibitor in the adjuvant setting, to treat advanced disease or bothRandomly assigned (1:1)Everolimus + fulvestrantPlacebo + fulvestrantMedian progression-free survival improved by 39% (p = 0.02)Everolimus + fulvestrant: 10.3 monthsPlacebo + fulvestrant: 5.1 monthsObjective response rate (p = 0.01)Everolimus + fulvestrant: 18.2%Placebo + fulvestrant: 12.3%

Kornblum N et al.

J

Clin

Oncol

2018;36(16):1556-63.

Slide51

Common Grade 3 or 4 toxicitiesAdverse eventEverolimus/fulvestrant(N = 64)Placebo/fulvestrant(N = 65)Oral mucositis11%0%Pneumonitis6%0%

Kornblum N et al. J Clin Oncol 2018;36(16):1556-63.

Adverse events, primarily Grade 1/2, occurring more frequently with everolimus/fulvestrant:Oral mucositisFatigueRashAnemiaDiarrheaHyperglycemiaHypertriglyceridemiaPneumonitis

PrE0102 Randomized Phase II Study of

Fulvestrant

with

Everolimus

or Placebo

Slide52

Select Phase II and III Clinical Trials of Everolimus for Metastatic Breast Cancer

StudyStatusPhaseEnrollmentSettingRandomizationFEVEX (NCT02404051)OngoingIII7452LEverolimus + Exemestane  FulvestrantFulvestrant  Everolimus + ExemestaneMAIN-A (NCT02511639)Active, not recruitingIII2532LEverolimus + AIAI onlyBOLERO-5 (NCT03312738)OngoingII1602L-3LEverolimus + ExemestanePlacebo + ExemestaneDESIREE (NCT02387099)OngoingII1562L+Everolimus only (conventional dosing)Everolimus only (dose escalation)

www.clinicaltrials.gov

. Accessed August 10, 2018.

Slide53

Everolimus-Associated Stomatitis

Grade 1Grade 2Grade 3Grade 4Clinical examErythema of the mucosaPatchy ulcerations or pseudomembranesConfluent ulcerations or pseudomembranes, bleeding with minor traumaTissue necrosis, significant spontaneous bleedingFunctional symptomsMinimal symptoms, normal dietSymptomatic but can swallow and eat a modified dietSymptomatic and unable to adequately aliment or hydrate orallySymptoms associated with life-threatening consequences

de Oliveira MA et al.

Oral

Oncol

2011

Ferté  C et al.Eur J Cancer 2011

Cawley M et al.

Clin J Oncol Nurs

2005

Slide54

Proportion of Patients with Stomatitis at Week 8 in SWISH and BOLERO-2

SWISH: A Phase II study (N = 82 evaluable) of everolimus-related stomatitis prevention using prophylactic oral dexamethasone mouthwash

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

Slide55

Management of Stomatitis

Everolimus FDA insert revised 4/2018.

Grade

1

Initiate dexamethasone alcohol-free mouthwash when starting treatment with

everolimus

.

Grade 2

Withhold

everolimus

 until improvement to Grade 0 or 1; resume at same dose. If recurs at Grade 2, withhold until improvement to Grade 0 or 1.

Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.

Grade 3

Withhold until improvement to Grade 0 or 1. Resume at 50% of previous dose; change to every other day dosing if the reduced dose is lower than the lowest available strength.

If toxicity recurs at Grade 3, permanently discontinue 

everolimus

.

Grade 4

Permanently discontinue 

everolimus

.

Slide56

Everolimus-Associated Noninfectious Pneumonitis

Women who received everolimus + fulvestrant versus placebo + fulvestrant showed an increase in noninfectious pneumonitisAny grade: 17% vs 0%Grade 3-4: 6% vs 0%Management: Monitor for clinical symptoms or radiological changes; withhold or permanently discontinue based on severity

Kornblum

N et al.

J Clin

Oncol

2018;

36(16):1556-63.

Everolimus

FDA insert

revised

4/2018.

Slide57

Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education Implications

Module 1: Estrogen and Progesterone Receptors; Clinical Use of Endocrine Treatment

Incidence, subtypes, staging and treatment

Types of endocrine therapy; response and side effects

Module 2: First-Line Endocrine Therapy for Metastatic Disease: Role of CDK4/6 Inhibitors

CDK4/6 inhibitors: Overview

CDK4/6 inhibitors: Efficacy and side effects

Module 3: Second-Line Endocrine Therapy for Metastatic Disease: Role of mTOR Inhibitors

Crosstalk between ER and PI3K/AKT/mTOR signaling pathways

mTOR

inhibitors: Efficacy and side effects

Module 4: New Approaches Under Investigation

PI3K Inhibitors: Efficacy and side effects

Triplet therapy: Endocrine therapy + CDK4/6 inhibitors + mTOR inhibitors

Efficacy and tolerability of emerging novel agents

Module 5: Assessing and Optimizing Treatment Adherence

Scope and clinical implications of adherence

Improving treatment adherence

Slide58

PI3K Inhibitor Therapy for ER-Positive

Locally Advanced or Metastatic

Breast Cancer with a PI3K mutation

Slide59

Efficacy and Safety Data from PI3K Inhibitor Studies in ER-Positive Locally Advanced or Metastatic Breast Cancer

Clinical studyRandomizationNORR1mPFS1HR1Most common Grade 3/4 AEs2SOLAR-1NCT02437318Alpelisib + fulvestrantPlacebo + fulvestrant57226.6%12.8%11.0 mo5.7 mo0.65Hyperglycemia (36.6%); rash (9.9%)SANDPIPERNCT02340221Taselisib + fulvestrantPlacebo + fulvestrant51628.0%11.9%7.4 mo5.4 mo0.70Diarrhea (11.5%); hyperglycemia (10.8%)

André F et al. Proc ESMO 2018;Abstract LBA3_PR; Baselga J et al. Proc ASCO 2018;Abstract LBA1006.

1

Efficacy was measured in the population with PI3KCA mutations

2

Most common Grade 3 and 4 adverse events were assessed in the overall population

Slide60

Triplet Therapy with ET, CDK4/6 Inhibitors

and PI3K or

mTOR

Inhibitors

Slide61

Efficacy and Safety Data from Triplet Therapy* Studies in ER-Positive, HER2-Negative Advanced Breast Cancer

Clinical studyTriplet combinationNORRCBR (24 wk)DCRMost common Grade 3/4 AEsNCT018571931 prior AI in advanced BC settingRibociclib + everolimus + exemestane8313%34%73%Neutropenia, ↓ neutrophils, ↓ WBCNCT01872260No prior AI in advanced BC settingRibociclib + alpelisib + letrozole4316%26%70%↑ ALT, ↑ AST, neutropenia, hyperglycemiaNCT020571331 prior AI in mBCAbemaciclib +everolimus +exemestane1926%58%79%Diarrhea, anemia, ↓ neutrophils, ↓ WBC, ↓ lymphocytes

Cortes J et al. Cancer Treat Rev 2017;61:53-60.

*

CDK4/6 inhibitor + PI3K or

mTOR

inhibitor + ET

Slide62

ER-Positive, HER2-Positive Metastatic

Breast Cancer

Slide63

EligibilityPostmenopausalHR+, HER2+ breast adenocarcinomaMust have receivedTaxaneT-DM1At least 2 anti-HER2 agents for advanced diseaseNo prior fulvestrant

Abemaciclib

+ trastuzumab + fulvestrant

Trastuzumab + standard chemotherapy

www.clinicaltrials.gov. Accessed August 2018.

monarcHER

: A Phase II Randomized Trial of Abemaciclib in Locally Advanced or Metastatic BC

Trial Identifier: NCT02675231Enrollment: 225 (Active, not recruiting)

Abemaciclib

+

trastuzumab

R

Primary endpoint:

Progression-free survival

Slide64

PATINA Phase III Study Design

Primary endpoint:

Progression-free survival

R

Eligibility

HR+, HER2+

mBC

Received standard first-line treatment for HER2+ disease as induction therapy

No prior treatment in the advanced setting beyond induction treatment

No evidence of disease progression after induction treatment

Palbociclib

+anti-HER2 therapy +endocrine therapy

Anti-HER2 therapy +endocrine therapy

Trial Identifier: NCT02947685Target Accrual: 496 (Recruiting)

Metzger-Filho O et al. San Antonio Breast Cancer Symposium 2017;Abstract OT3-05-07;

www.clinicaltrials.gov

. Accessed August 2018.

Slide65

ESR1 Tumor Mutations

ESR1 mutations are rarely observed in primary tumors (<2%)but commonly observed in metastatic disease (27%-37%)More common in patients with prior AI exposureESR1 mutations are associated with AI resistance but are sensitive to selective ER downregulators (SERDs)Might it be possible to overcome resistance by administering SERDS combined with CDK4/6 inhibitors, PI3K inhibitors, mTOR inhibitors?

Toy W et al.

Nature Genetics

2013; Fanning SW et al.

Elife

2016;5:e12792;

Ross DS et al.

Mod Pathol

2019;32(1):81-7

; Toy W et al.

Cancer

Discov

2017;7(3):277-87; Turner NC et al.

Proc ASCO

2016;

Clatot

F et al.

Oncotarget

2016;7(46):74448-59;

Chandarlapaty

S et al.

JAMA Oncol

2016;2(10):1310-5;

Spoerke

et al.

Nat

Comm

2016

;7:11579

.

Slide66

Other Novel Agents and Combinations Utilizing the PI3K/AKT/mTOR Pathway

StudyPhaseEnrollmentAgent/CombinationTargetRandomizationPIKNIC(NCT02506556)II34AlpelisibPI3KSingle armNCT01277757II30MK2206AKTSingle armSTAKT (NCT02077569)II48AZD5363AKTAZD5363PlaceboNCT02871791I/II32Palbociclib + Everolimus + ExemestaneCDK4/6 + mTORSingle armTRINITI-1(NCT02732119)I/II51Ribociclib + Everolimus + ExemestaneCDK4/6 + mTORSingle arm

www.clinicaltrials.gov

.

Accessed August

23, 2018.

Slide67

Endocrine Treatment of Metastatic Breast Cancer: New Advances; Patient Education Implications

Module 1: Estrogen and Progesterone Receptors; Clinical Use of Endocrine Treatment

Incidence, subtypes, staging and treatment

Types of endocrine therapy; response and side effects

Module 2: First-Line Endocrine Therapy for Metastatic Disease: Role of CDK4/6 Inhibitors

CDK4/6 inhibitors: Overview

CDK4/6 inhibitors: Efficacy and side effects

Module 3: Second-Line Endocrine Therapy for Metastatic Disease: Role of mTOR Inhibitors

Crosstalk between ER and PI3K/AKT/mTOR signaling pathways

mTOR

inhibitors: Efficacy and side effects

Module 4: New Approaches Under Investigation

Triplet therapy: Endocrine therapy + CDK4/6 inhibitors + mTOR inhibitors

Efficacy and tolerability of emerging novel agents

Module 5: Assessing and Optimizing Treatment Adherence

Scope and clinical implications of adherence

Improving treatment adherence

Slide68

Case 6

33

yo

F with 1.9-cm poorly differentiated cancer

(

ER+, PR+, 

HER2 0) s/p mastectomy and

SLNbx

(1/4 LN+)

Received

ddACT

Received PMRT

6/17 Started on tamoxifen then added leuprolide acetate

Tolerated well with moderate hot flashes that improved over first 3 months

1/18 Came to clinic and admitted to not taking tamoxifen over past month because of weight gain (10lb)

Met with nutrition

6/18 Still not taking tamoxifen

Switched to AI

Slide69

Miaskowski C et al. Clin J Oncol Nurs 2008;12(2):213-21.

Slide70

Adherence to Endocrine Therapyin Clinical Practice

“Because breast cancer can be life threatening in the short term, healthcare providers had assumed that all women would be highly motivated to adhere to treatment regimens that would significantly lower their risk for disease recurrence (Waterhouse, Calzone, Mele, & Brenner, 1993). However, many women consider themselves ‘cured’ after initial surgery, chemotherapy, and/or radiotherapy. Such women may fail to recognize the benefits of adjuvant endocrine therapy and take a more relaxed view of the long-term endocrine therapy that follows (Davidson, Vogel, & Wickerham, 2006).”

Miaskowski

C et al.

Clin J

Oncol

Nurs

2008;

12(2):213-21.

Slide71

Rates of Nonadherence to AdjuvantEndocrine Therapy in Major Clinical Trials

Miaskowski C et al. Clin J Oncol Nurs 2008;12(2):213-21.

T = tamoxifen; P = placebo; A = anastrozole; E = exemestane; ATAC = Arimidex, Tamoxifen, Alone or in Combination trial; IES = Intergroup Exemestane Study

Slide72

Signs and Predictors of Poor Adherence

PatientChronic disease (long treatment duration)Missed medical appointmentsUnfilled prescriptionsLack of expected therapeutic responseHistory of poor adherence (eg, to mammography screening)Lack of belief in treatmentLack of support from family and friendsPsychological problems, particularly depressionHealthcare professionalComplex dosing regimenInadequate follow-upPoor patient-provider communicationHealthcare systemAdverse effects from medicationHigh cost of medicationPrescriptions filled at retail pharmacies instead of by mail order

Miaskowski

C et al.

Clin J

Oncol

Nurs

2008;

12(2):213-21.

Slide73

Modified Morisky Scale

Do you ever forget to take your medication?Are you careless at times about taking your medication?When you feel better, do you sometimes stop taking your medication?Sometimes if you feel worse when you take your medication, do you choose to stop taking it?One point is assigned for each affirmative answer. Patients with scores of 0 or 1 typically show high levels of adherence, whereas those with higher scores are more likely to require interventions to improve adherence.

Miaskowski

C et al.

Clin J

Oncol

Nurs

2008;

12(2):213-21.

Slide74

Strategies to Help Improve Patient Adherence

Assess the patient’s understanding of the need for the prescribed treatment and its goals.Provide written information about the treatment.Review potential side effects of the treatment, and develop management strategies as needed.Explore the patient’s psychosocial dynamics, including prescription coverage, access to filling prescriptions and support systems.Provide the patient with professional contact information, especially a phone number, in the event of questions, side effects or concerns.Schedule follow-up contacts on a regular basis to reassess and reiterate the treatment plan.Provide a list of organizations and support groups that the patient can consult for more information and advice.

Miaskowski

C et al.

Clin J

Oncol

Nurs

2008;

12(2):213-21.