Clinical Debates in the Management of Pretreated Metastatic Breast Cancer

Clinical Debates in the Management of Pretreated Metastatic Breast Cancer

William J. Gradishar, MD, FASCO, FACPBetsy Bramsen Professor of Breast Oncology

Northwestern University Feinberg School of Medicine

Disclosures

Dr. Gradishar has no relevant financial relationships to disclose.

Learning Objectives

Evaluate predictive and prognostic markers in treatment planning for patients with pretreated MBC

Assess efficacy and safety data on conventional and novel therapies for pretreated MBC

Describe supportive care considerations in treatment planning for patients with pretreated metastatic breast cancer

MBC = metastatic breast cancer.

Breast Cancer Is a Family of Diseases Convergence of clinical and genomic data

Unclear how many distinct members of this family

At a minimum: HER2+ Basal-like or triple-negative ER+ (luminal A) ER+ (luminal B)

ER = estrogen receptor; PR = progesterone receptor; HER2 = human epidermal growth factor receptor 2.NCCN, 2016.

What We Do in the Clinic

Incidence Therapy

ER± PR+ 65% EndocrineChemotherapy

HER2+ 15-20% Anti-HER2

Triple-negative 10-15% Chemotherapy

ACS, 2016.

Rules of the Road for the Treatment of MBC

Receptor subtype (ER/PR, HER2) Prior therapy and DOR Disease burden, distribution, and

comorbidities/baseline symptoms Patient preference (toxicity vs RR/PFS/OS)

DOR = duration of response; RR = response rate; PFS = progression-free survival; OS = overall survival.

ER-Positive MBC

Case Study: ER+ MBC

64-year-old woman diagnosed with right-sided IDC 8 years earlier: T2N1M0; ER+/HER2-; BCS/SLN-0/3

Received TC x 4 followed by anastrozole x 5 years completing 2 years ago

Presents now with diffuse skeletal pain; re-evaluation with bone scan shows diffuse bone metastases and 2 liver metastases (1 cm)

Performance status 1 Liver function tests and other labs normal Liver biopsy: consistent with ER+

adenocarcinomaIDC = invasive ductal carcinoma; T2 = invasive part of tumor larger than 20 mm but smaller than 50 mm; N1 = cancer spread to 1-3 axillary or sentinel lymph nodes and is at least 2 mm in size; M0 = disease has not metastasized; BCS = breast-conserving surgery; SLN = sentinel lymph node; TC = docetaxel/carboplatin.

Overview

Where we were/are Focus on resistance mechanisms

ER mutations and implications CDK 4/6 inhibitors mTOR inhibitors PI3K inhibitors HDAC inhibitors

CDK = cyclin dependent kinase; mTOR = mammalian target of rapamycin; PI3K = phosphinositide 3-kinase; HDAC = histone deacetylase.

NCCN, 2016b.

Follow-Up Therapy for Endocrine Treatment of Recurrent or Stage IV Disease

NCCN Guidelines: Invasive Breast Cancer

Follow-Up Therapy for Endocrine Treatment of Recurrent or Stage IV Disease (cont.)


aExemestane + everolimus can be considered for patients who meet the eligibility criteria for BOLERO-2 (progressed within 12 mo or on nonsteroidal aromatase inhibitor [AI], or any time on tamoxifen).bPalbociclib in combination with letrozole may be considered as first-line therapy for postmenopausal patients with hormone receptor-positive (HR+), HER2 MBC. cFor postmenopausal women or for premenopausal women receiving ovarian suppression with an LHRH agonist, with HR+ and HER2 MBC that has progressed on endocrine therapy. NCCN, 2016c.

ab

c

Combating Endocrine Resistance

60-70% of breast cancers are HR+; current treatments aim to decrease estrogen levels or block the estrogen receptor

Some cancers are refractory to such therapies initially (de novo resistance) and others become resistant over time (acquired resistance)

Resistance to estrogen deprivation involves activation of growth factor pathways to bypass endocrine dependence

Novel therapeutics are needed to combat endocrine therapy resistance

Spoerke et al, 2016.

Acquisition of Subclonal ESR1 Mutations Through Low E2

States

E2 = estradiol.

What is the prevalence of mutation?

D538G, Y537S/N/C Circulating mutation

frequency 44/144 patients

mutated (30.6%) 63 mutations

Agreement with other studies of cfDNA in large populations of AI treated patients: Spoerke et al (37%) Chandarlapaty et al

(28.8%)Augusto et al, 2016; Turner et al, 2016; Spoerke et al, 2016; Chandarlapaty et al, 2015; Fribbens et al, 2016.

Patients at risk for mutation?

Turner et al, 2016; Augusto et al, 2016.

Treatments Wild Type (n=100)

Mutant (n=44)

P Value

All exposure before progression (mo)<3 4 (4) 0 0.0023-6 25 (25) 2 (5)>6 71 (71) 42 (95)

Median duration of exposure 10.5 15 0.02

ESR1 Mutation Analysis by Digital PCR in the Randomized Phase III SoFEA Study

PCR = polymerase chain reaction.Johnston et al, 2013; O’Leary et al, 2016; Fribbens et al, 2016.

ESR1 Mutant ESR1 Wild type

HR = 0.52 (95% CI: 0.30–0.92) P = 0.02

Fulvestrant-containingmedian PFS 5.7 months

Exemestanemedian PFS 2.6 months

Fulvestrant-containingmedian PFS 5.4 months

Exemestanemedian PFS 8.0 months

HR = 1.07 (95% CI: 0.68–1.67)P = 0.77

Prog

ress

ion-

Free

Sur

viva

l (%

)

Prog

ress

ion-

Free

Sur

viva

l (%

)

Time From Randomization (months)

Time From Randomization (months)Number at risk

(events):ExemestaneFulvestrant-

containing

18 (12) 6 (4) 2 (2) 0 (0) 045 (23) 22 (10) 12 (5) 6 (5) 1

39 (18) 21 (9) 12 (5) 0 (0) 359 (31) 27 (7) 19 (8) 8 (2) 5

Key Points

ESR1 mutations more common after AI responsive disease (not seen post-TAM). Frequency 29%

In the PALOMA-3 study, ESR1 mutations were neither prognostic nor predictive

In the SoFEA study, ESR1 mutations were more common (about 40%: 63/161 tested). ESR1 mutations were predictive of fulvestrant benefit (vs exemestane) but outcomes of ESR1 mutants were similar to WT if treated with fulvestrant

TAM = tamoxifen; WT = wild type.Fribbens et al, 2016; O’Leary et al, 2016.

Evolution of ER+ Breast Cancer

1977 1995 2012 201519991997 20102002 20051970

Tamoxifen(1977)

Anastrozole

(1995)

Exemestane

(1999)

Palbociclib

(2015)

Toremifene

(1997)

Letrozole(1997)

19901980

Everolimus

(2012)

Fulvestrant

250 mg(2002)

Fulvestrant

500 mg(2010)

Cell Cycle Regulation and Dysregulation

Four key phases Highly regulated by

both “activators” and “brakes”

When properly regulated Responsible for normal

physiologic cell division Loss of cell cycle control

is a hallmark of cancer

Mitosis

Gap 1

Gap 2

Synthesis

Murphy & Dickler, 2015; Dickson, 2014.

PalbociclibPD 0332991

CDK 4/6 InhibitorsFDA

Approved(February 2015)

In Development

RibociclibLEE011

AbemaciclibLY2835219

Murphy & Dickler, 2015.

PALOMA-1/TRIO-18 Study Design (NCT00721409)

Randomized phase II open-label trial involving 50 centers in 12 countries Key eligibility criteria: inoperable ER+/HER2- locally recurrent disease, postmenopausal status,

no prior therapy for advanced breast cancer, no prior CDK inhibitors, no letrozole within 12 months, no prior/current brain metastases, measurable disease (RECIST 1.0) or bone-only disease, ECOG performance status ≤1, adequate bone marrow and renal function

Palbociclib 125 mg/db

+ Letrozole 2.5 mg/d

Letrozole 2.5 mg/d

ER+/HER2−

advanced breast cancer

1:1

RANDOMIZATIONa

Palbociclib 125 mg/db

+ Letrozole 2.5 mg/d

Letrozole 2.5 mg/d

ER+/HER2− advanced

breast cancer with

CCND1 amplificatio

n and/or loss of p16

1:1

n=66

n=99

RANDOMIZATIONa

Cohort 1

Cohort 2

aRandomization stratified by disease site and disease-free interval.bPalbociclib schedule 3/1 (28-day cycles).ECOG = Eastern Cooperative Oncology Group. Finn et al, 2015.

PALOMA-1/TRIO-18: PFS (ITT Population)

ITT = intent-to-treat; CI = confidence interval.Finn et al, 2015.

0

10

20

30

40

50

60

70

80

90

100

Number at riskPalbociclib plus letrozole

Letrozole51

83

2814

216

4728

3619

8481

133

6748

6036

1

Palbociclib plus letrozoleLetrozole

HR 0.488 (95% CI 0.319–0.748; one-sided P=0.0004)

Prog

ress

ion-

Free

Sur

viva

l, %

0 4 8 12 16 20 24 28 32 36 40Months

PALOMA-1/TRIO-18: All-Causality AEs Occurring in ≥10% of Patients (Safety

Population) (1/2) Adverse Event, %

PAL + LET (n=83)a LET (n=77)All

GradesGrade

3/4All

GradesGrade

3/4Any adverse event 99 76 84 21

Neutropenia 75 54 5 1Leukopenia 43 19 3 0Fatigue 41 5 23 1Anemia 35 6 6 1Nausea 25 2 13 1Arthralgia 23 1 16 3Alopecia 22 N/A 3 N/ADiarrhea 20 4 10 0Hot flush 21 0 12 0Thrombocytopenia 17 2 1 0Decreased appetite 16 1 7 0Dyspnea 16 2 8 1Nasopharyngitis 16 0 10 0Back pain 11 0 16 1

No cases of febrile neutropenia were reported.aOne (1%) grade 5 event occurred in the PAL + LET group (from disease progression); none occurred in the LET group.AE = adverse event; PAL = palbociclib; LET = letrozole. Finn et al, 2015.

A5481008/TRIO 22/PALOMA-2: Study Design

Detect PFS improvement from 9 monthsa (SOC) to 14 months (HR=0.64) with 90% power, 1-sided =0.025; 1-IA

Efficacy/Futility

Postmenopausal women

ER+/HER2- breast cancer

No prior systemic anticancer treatment for advanced disease

Letrozole 2.5mg QD+

Placebo 3/1 weeks

Letrozole 2.5mg QD+

PD 0332991 125 QD 3/1 weeks

2:1

Ra

ndom

izatio

n

a9 Month benchmark based on Mouridsen et al (2016).OR = objective response; DC = disease control; PRO = patient-reported outcomes; QTc = corrected QT; DFI = disease-free interval. SOC = standard of care.

Letrozole 2.5 mg/d+

Placebo 21 days on / 7 days off

Letrozole 2.5 mg/d+

Palbociclib 125 mg/d21 days on / 7 days off

N=450. Double-blind, multicenter, placebo-controlled Primary end point: PFS (239 events needed) by local assessment Secondary end points: OS, OR, DOR, DC, safety, PRO, biomarkers, trough PK, QTc Stratification factors: DFI, previous therapy, disease site

Placebo (3 weeks on/1 week

off)+

Fulvestrantb (500 mg IM q4w)

Palbociclib (125 mg QD;

3 weeks on/1 week off)+

Fulvestrantb

(500 mg IM q4w)

● Visceral metastases● Sensitivity to prior

hormonal therapy● Pre-/peri- vs post-

menopausal

2:1 RandomizationN=521

Stratification:

Postmenopausal patients must have progressed on prior AI therapy.

n=347

n=174

• HR+, HER2- ABC• Pre-/peri-a or post-

menopausal • Progressed on prior

endocrine therapy:–On or within 12

months adjuvant–On therapy for

ABC• ≤1 prior

chemotherapy regimen for advanced cancer

PALOMA-3: Phase III Study Design

aAll received goserelin.bAdministered on Days 1 and 15 of cycle 1.ABC = advanced breast cancer; IM = intramuscularly.Finn et al, 2016.

Consistent Clinical Benefit Seen Across PALOMA Studies

1003 (PALOMA-1)

1008 (PALOMA-2)

1023(PALOMA-3)

Design Phase II

open label Phase IIIplacebo control

Phase IIIplacebo control

Endocrine partner Letrozole Letrozole FulvestrantPatients on study, n 165 666 521 Efficacy (palbociclib vs control arm)Primary end point: PFSHR 0.49 0.58 0.46

Median PFS, months 20.2 vs 10.2 ( 10 mo)

24.8 vs 14.5 ( 10.3 mo)

9.5 vs 4.6

Secondary end points, %

ORR (ITT, measurable disease) 43 vs 33, 55 vs 39

42 vs 35, 55 vs 44

19 vs 9,25 vs 11

CBR (ITT) 81 vs 58 85 vs 70 67 vs 40ORR = overall response rate; CBR = clinical benefit rate.Finn et al, 2015; Cristofanilli et al, 2016; Finn et al, 2016

October 2015: Abemaciclib Breakthrough Therapy Designation

MONARCH-1 Results

TEAE, % Grade 1 Grade 2 Grade 3 Grade 4 All Grade

DiarrheaFatigueNauseaDecrease appetiteAbdominal painVomitingHeadache

41.721.239.428.022.022.713.6

28.831.120.514.414.410.66.8

19.712.94.53.02.31.50

0000000

90.265.264.445.538.634.820.5

Creatinine increasedWBC decreasedNeutrophil decreasedAnemiaPlatelet count decreased

46.918.517.730.028.9

50.844.643.138.510.2

0.827.722.3

02.3

00

4.600

98.590.887.768.541.4

Discontinuation due to AEs

7.6%

Prior Therapy for ABC

Median of 3 Lines (Range: 1-8); 2 Prior Chemotherapies

ORR 19.7% (95% CI: 13.3-27.5; 15% not excluded)CBR 42.4%PFS 6.0 mo OS 17.7 mo

TEAE = treatment-emergent adverse event.Dickler et al, 2016; Clinicaltrials.gov, 2016c.

Targeting mTOR

Target of Rapamycin

Highly conserved from yeast to mammals 2 distinct complexes: mTORC1 and

mTORC2 Regulate different processes Not equally effected by rapalogs/mTOR

inhibitors Different associated proteins (complexes)

Phase II TAMRAD in ER+ MBC

PMW = postmenopausal women; TTP = time to progression; EVE = everolimus. Bachelot et al, 2012.

PFS as Function of Intrinsic Hormone Resistance

Bachelot et al, 2012.

BOLERO-2 Trial Design

NSAI = nonsteroidal aromatase inhibitor.Baselga, Campone, et al, 2012.

PFS Benefit With Everolimus (EVE) + Exemestane (EXE) Regardless of Genetic Alteration

PBO = placebo. Hortobagyi et al, 2013; Yardley et al, 2014.

BOLERO-2: Final Analysis of OS

Piccart et al, 2014.

39-Month Follow-Up

The Cancer Genome Atlas: Distribution of Mutations by Breast Cancer Subtype

The Cancer Genome Atlas, 2012.

FERGI Study Design: Part I

PTEN = phosphatase and tensin homologue; PK = pharmacokinetics. aAdministered on D1 of each 28 day cycle and C1D15; bTumor assessments performed every 8 weeks; cExons 9 and 20 in the codons encoding amino acids E542, E545, and H1047 were detected by RT-PCR; dDisease relapse during or within 6 months of completing AI treatment in the adjuvant setting, or disease progression within 6 months of starting AI treatment in the metastatic setting. Clinicaltrials.gov, 2016d.

• ER+, HER2-, postmenopausal women with advanced or MBC

• Prior AI in adjuvant (PD <6 mo) or metastatic setting

• ECOG PS 0, 1• No diabetic patients• 0-1 chemotherapy or ≤2

prior endocrine therapies

Fulvestrant 500mga +pictilisib (GDC-

0941) 340 mg QD

R

Treat to

PDb

Treat to

PDb N=168

Stratification Factors 1° Objective 2° Objectives• PIK3CA-MT and PTEN lossc

• Measurable disease• 1o vs 2o resistanced

• PFS in the ITT• PFS in PIK3CA-MT pts• Safety

• Objective response rate• Duration of objective response• PK

Pictilisib +

fulvestrant

Crossover1:1

Median duration of follow up 17.5 months

Fulvestrant 500 mga +

placebo QD

Progression-Free Survival Based on Tumor PIK3CA Mutation Status

PIK3CA-Mutant Population PIK3CA “Wild-Type” Population

PIK3CA mutation status does not predict benefit of the addition of pictilisib to fulvestrant

Clinicaltrials.gov, 2016d.

BELLE-2 Study Design and End Points

aPI3K pathway activation (activated, nonactivated, unknown) was assessed in archival tumor tissue provided at screening, defined as PIK3CA mutation by Sanger sequencing (any mutations in exons 1, 7, 9, or 20) and/or loss of PTEN expression by immunohistochemistry (1+ expression in <10% of cells).bctDNA PIK3CA status was assessed by BEAMing technology.BEAMing = beads, emulsification, amplification, and magnetics; ctDNA = circulating tumor DNA.Baselga et al, 2015; Clinicaltrials.gov, 2016e.

Primary End Points• PFS in the main population (PI3K

activated and nonactivated, excluding status unknowna)

• PFS in the PI3K activated groupa (PIK3CA mutation and/or PTEN loss in archival tissue)

• PFS in the full population (local assessment)

Key Secondary End Point• Overall survivalOther Secondary End Points• Overall response rate• Clinical benefit rate• Safety, pharmacokinetics,

quality of lifeExploratory End Point• PFS by ctDNA PIK3CA mutation

statusb

Randomization (1:1)Stratification by PI3K pathwaya and visceral disease

status

Postmenopausal women with HR+/HER2- locally advanced or metastatic breast cancer that

progressed on/after AI therapyN=1,147

Buparlisib (100 mg/day) + fulvestrant (500 mg)

n=576

Placebo + fulvestrant (500 mg)

n=571

BELLE-2: PFS Improvement in the Full and Main Population

HR = hazard ratio.Baselga et al, 2015.

A similar PFS improvement was observed in the main population (HR 0.80 [95% CI: 0.68–0.94]; one-sided P=0.003)Follow-up for OS analysis is ongoing, with a prespecified target of 588 deaths in the full population

At the time of primary PFS analysis, OS data were immature (281 deaths in the full population), with a trend in favor of the buparlisib arm

Full Population (N=1,047)

Buparlisib +

Fulvestrant

n=576

Placebo + Fulvestra

ntn=571

Median PFS, mo (95% CI)

6.9(6.8-7.8)

5.0(4.0-5.2)

HR (95% CI) 0.78 (0.67-0.89)

One-sided P value <0.001

Prob

abili

ty o

f Pr

ogre

ssio

n-Fr

ee S

urvi

val (

%)

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 26 3022 24 28

Buparlisib + fulvestrant (n/N=349/576)Placebo + fulvestrant (n/N=435/571)

PFS Increase in the PI3K Activated Group Was Not Statistically Significant

aPFS in the PI3K activated group was tested at a one-sided α=0.01 level of significance.Baselga et al, 2015.

PI3K Activated Group (N=372)

Buparlisib +

Fulvestrant

n=188

Placebo +

Fulvestrant

n=184


6.8(4.9-7.1)

4.0(3.1-5.2)

HR (95% CI) 0.76 (0.60-0.97)One-sided P valuea 0.014

Time (Months)

Prob

abili

ty o

f Pr

ogre

ssio

n-Fr

ee S

urvi

val (

%)

100

60

0

80

40

20

0 4 8 14 182 6 1012 16 20 26 302224 28


Buparlisib and Fulvestrant Produced a Clinically Meaningful PFS Improvement in Patients With ctDNA PIK3CA Mutations

ctDNA PIK3CA Mutantn=200

Buparlisib + Fulvestrant

n=87

Placebo + Fulvestra

ntn=113


7.0 (5.0-10.0)

3.2 (2.0-5.1)

HR (95% CI) 0.56 (0.39-0.80)One-sided nominal P value <0.001

ctDNA PIK3CA Nonmutantn=387

Buparlisib + Fulvestrant

n=199

Placebo + Fulvestra

ntn=188

Median PFS, mo(95% CI)

6.8 (4.7-8.5)

6.8 (4.7-8.6)

HR (95% CI) 1.05 (0.82-1.34)One-sided nominal P value 0.642

Prob

abili

ty o

f Pr

ogre

ssio

n-Fr

ee S

urvi

val (

%)

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 1012 16 20 26282224


Prob

abili

ty o

f Pr

ogre

ssio

n-Fr

ee S

urvi

val (

%)

Time (Months)

100

60

0

80

40

20

0 4 8 14 182 6 10 12 16 20 22


Baselga et al, 2015.

Reversible Histone Acetylation Regulates Gene Expression

HAT = histone acetyl transferase; Pol2 = RNA polymerase II; Ac = acetylation. Yoo & Jones, 2006; Marks et al, 2000; Kouzarides, 1999; Van Lint et al, 1996.

Histoneacetylation

Pol2 mRNA

Activated Chromatin(hyper-acetylated histones)

Ac-

Ac-

Ac-

Ac-

Ac-

Ac-

Ac-

Ac-

HAT

TranscriptionalFactors

Corehistones

(hypo-acetylated histones)

Repressed Chromatin

Repressed Chromatin

Cofactors

HDACsHistone

deacetylation

HDACInhibitor

Exemestane + Placebo

Exemestane + Entinostat

Entinostat and Exemestane

Yardley et al, 2013.

N=130

1:1

NSAI settingBone only

Region

• Postmenopausal ER+ advanced breast cancer

• Progressed on/or relapsed while receiving a NSAI

Entinostat and Exemestane (cont.)

Yardley et al, 2013.

PFS: 2.3 to 4.3 moHR 0.73 95% CI 0.5-1.07

OS: 19.8 to 28.1 moHR 0.59 95% CI 0.36-0.97

Entinostat and Exemestane Phase III

Piccart et al, 2014.

Targeted Combination Therapies Are Superior to Their Monotherapy

Comparators

Ibrance® prescribing information, 2015; Turner et al, 2015; Afinitor® prescribing information, 2015; Bachelot et al, 2012.

Clinical Issues/No Answers

Who are the exceptional responders to endocrine monotherapy?

Can biomarkers be identified to define optimal therapy?

CDK 4/6 inhibitors in sequence? Optimal sequence or combination of

targeted therapy with endocrine therapy?

Endocrine Refractory Metastatic Triple-Negative Breast Cancer

Case Study: TNBC

37-year-old woman presents with recurrent MBC involving multiple small liver lesions (0.5-1.0 cm), small pulmonary effusion, and bony metastases

Diagnosed 2 years earlier with EBC (T2N1M0; TNBC); elected mastectomy and subsequently received dose-dense AC followed by T and chest wall RT (4 nodes positive)

Recently presented with more fatigue and bone pain; w/u included liver biopsy confirming TNBC; bili normal; transaminases slightly above normal

TNBC = triple-negative breast cancer; EBC = early breast cancer; AC = doxorubicin/cyclophosphamide; RT = radiation therapy.

General Principles of Managing Stage IV TNBC

All treatment is palliative!

Chemotherapy is mainstay Single agent > polychemotherapy Unless symptomatic or rapidly progressive

Targeted therapy is the hope of the future

ToxicityEfficacy


NCCN, 2016a.

TNBC Subtypes21 publicly available gene expression breast cancer datasets, 587

TNBCs

Lehmann et al, 2011; Lehmann et al, 2015.

Basal-like 1 (BL1): Cell-cycle, proliferation, and DNA damage response genesBasal-like 2 (BL2): Growth factor signaling (EGF, MET, Wnt/β-catenin, IGF1R)

Immunomodulatory (IM): Immune cell and cytokine signaling (overlap with medullary signature)Mesenchymal (M): Cell motility and differentiation (Wnt, ALK, TGF-β) Mesenchymal stem-like (MSL): Similar to M, but increased growth factor signaling, low proliferation, enrichment of stem cell genesLuminal androgen receptor (LAR): Enriched in hormonally-regulated pathways, androgen receptor signaling. Displays luminal expression patterns (molecular apocrine carcinomas)

BRCA Mutations and TNBC

Up to 20% of unselected patients Up to 50% of patients with a strong family

history 50% of mutation carriers do not have a

strong family history

Gonzalez-Angulo et al, 2011; Bayraktar et al, 2011.

Adjuvant Cytotoxic and Biologic Therapy

80

175

100

35

Paclitaxel

Docetaxel

AC

AC TAXANERT

HORMONALTHERAPY

P3

P1

D3

D1

A – 60 mg/m2

C – 600 mg/m2

Every 3 weeks

Stratification Factors:

ER/PR ExpressionNo. Pos Nodes

T Size (<5 vs >5 cm)Mastectomy vs BCS

mg/m2

700

960

420

400Docetaxel

Paclitaxel

mg/m2

Dose/CycleMaximum Total Dose

Sparano et al, 2015.

E1199 Schema and Patient Population:Stage IIA/IIIA Breast Cancer

Log-rank P =0.094

10-year rate (95% CI)-----------------------------

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

OS p

roba

bilit

y

243 218 184 156 143 129 77D1248 214 186 159 144 139 87D3274 245 218 196 179 167 102P1261 232 190 168 149 134 84P3

Number at risk

0 2 4 6 8 10 12

Years since Randomization

P3 65.6% (59.2, 71.2)P1 75.1% (69.4, 79.9)D3 68.7% (62.3, 74.2)D1 68.6% (62.1, 74.1)

0.95 (0.70, 1.28)

0.93 (0.69, 1.25)0.69 (0.50, 0.94)OS: P1/P3

OS: D3/P3

OS: D1/P3

.5 1 1.5 2

Hazard ratios and 95% CI from stratified Cox models

HR for P1/P3 HR for D3/P3 HR for D1/P395% CI for P1/P3 95% CI for D1/P3 95% CI for D3/P3

Log-rank P =0.032

10-year rate (95% CI)-----------------------------

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

DFS

pro

babi

lity

243 197 160 133 109 88 49D1248 195 160 134 120 106 52D3274 226 197 175 159 127 61P1261 207 166 138 126 102 47P3

Number at risk

0 2 4 6 8 10 12

Years since Randomization

P3 58.7% (52.1, 64.6)P1 69.0% (63.0, 74.3)D3 62.3% (55.6, 68.2)D1 56.8% (50.0, 63.1)

0.99 (0.75, 1.30)0.94 (0.71, 1.23)

0.69 (0.52, 0.91)DFS: P1/P3

DFS: D3/P3

DFS: D1/P3

.5 1 1.5 2Hazard ratios and 95% CI from stratified Cox models

HR for P1/P3 HR for D3/P3 HR for D1/P395% CI for P1/P3 95% CI for D1/P3 95% CI for D3/P3

Exploratory Analysis in Triple-Negative Disease (N=1,025)

Sparano et al, 2015.

Node-Positive or High-Risk Node-Negative Triple-Negative Breast Cancer

AC x 4 Paclitaxel q wk x 12

Randomization

AC x 4 Paclitaxel q wk x 12+ Carboplatin

Beginning With WP

AC: 60 mg/m2 /600 mg/m2 (standard or dose-dense AC) Paclitaxel: 80 mg/m2 IV weeklyCarboplatin: AUC of 5 IV q 3 weeks for 4 cycles

NRG-BR003

NRG Oncology, 2016.

Adjuvant Bevacizumab in TNBC:Impact of DFS

BEATRICE E5103

No. 2,591 1,079

HR 0.87 0.77

95% CI 0.73-1.03 0.58-1.03

DFS = disease-free survival. Cameron et al, 2013; Miller, 2014.

Need for development and validation of a predictive marker

E5103 Study Design

AC q 2 or q 3 weekly, investigator choice. HRx and radiation per SOC

RANDOMIZE

1:2:2

All arms unblinded on C8D1

Arm B: BAC > BT

Paclitaxel 80 mg/m2/wk x 12Bevacizumab 15 mg/kg q 21 d x 4

AC + Bevacizumab x 4

Arm A: AC > T

AC + Placebo x 4

Paclitaxel 80 mg/m2/wk x 12 + Placebo 15 mg/kg q 21 d x 4

Arm C: BAC > BT > B

AC +Bevacizumab x 4

Bevacizumab 15 mg/kg q 21 d x 10

Paclitaxel 80 mg/m2/wk x 12 Bevacizumab 15 mg/kg q 21 d x 4

Miller et al, 2014.

Invasive Disease-Free Survival

Miller et al, 2014.

Group N HR 95% CI

Overall 3008 0.87 (0.71, 1.06)

Age <40 364 1.09 (0.60, 1.99)

Age 40-64 2359 0.77 (0.61, 0.97)

Age > 65 285 1.04 (0.57, 1.90)

ER negative 1079 0.77 (0.58, 1.03)

ER positive 1925 0.93 (0.71, 1.22)

LN negative 822 1.02 (0.65, 1.59)

1-3 LN 1226 0.71 (0.50, 1.00)

> 4 LN 958 0.94 (0.70, 1.26)

Tumor 0-2 cm 1151 0.88 (0.59, 1.31)

Tumor >2 - < 5 cm 1545 0.83 (0.64, 1.08)

Tumor > 5 cm 309 1.00 (0.59, 1.69)

Grade I 248 0.48 (0.18, 1.27)

Grade II 987 0.73 (0.50, 1.07)

Grade III 1079 1.01 (0.78, 1.30)

Favors bevacizumab

Favors placebo

Cytotoxic and Biologic Therapy for Metastatic Breast Cancer

Eribulin Study 301Global, randomized, open-label phase III trial (Study

301)

Capecitabine 1,250 mg/m2 BID orally

D 1-14, q 21 days

Eribulin mesylate 1.4 mg/m2 2- to 5-min IV

D 1, 8, q 21 days

Randomization 1:1

Coprimary end point:• OS and PFS

Secondary end points:

• Quality of life• ORR• Duration of response• 1-, 2-, and 3-year

survival• Tumor-related

symptom assessments

• Safety parameters • Population PK

Patients (N=1,102)

Locally advanced or MBC• ≤3 prior

chemotherapy regimens (≤2 for advanced disease)

• Prior anthracycline and taxane in (neo)adjuvant setting or for locally advanced or MBC

BID = twice a day.Kaufman et al, 2012

Overall 0.879 (0.770, 1.003) 15.9 14.5HER2 status

Positive 0.965 (0.688, 1.355) 14.3 17.1

Negative 0.838 (0.715, 0.983) 15.9 13.5

ER status

Positive 0.897 (0.737, 1.093) 18.2 16.8

Negative 0.779 (0.635, 0.955) 14.4 10.5

Triple negative

Yes 0.702 (0.545, 0.906) 14.4 9.4

No 0.927 (0.795, 1.081) 17.5 16.6

Subgroup

HR (95% CI) EribulinCapecitabineMedian (months)

ITT population

Overall Survival By Receptor Status

0.2 0.5 1.0 2 5

N = 755

N = 449

N = 284

Favors eribulin Favors capecitabineKaufman et al, 2012.

Tutt et al, 2014.

Trial Design

HRD = homologous recombination deficiency.Tutt et al, 2014.

Objective Response

Tutt et al, 2014.

Progression-Free Survival

Tutt et al, 2014.

Objective Response: BRCA 1/2 Status

Tutt et al, 2014.

PARP Inhibitors

PARP Inhibitors: Single-Agent Development in BRCA Mutation-Associated Breast Cancer

Best Response (ITT)

Olaparib 400 BID(n=27)

Olaparib 100 BID(n=27)

CR 1 (4%) 0PR 10 (37%) 6 (22%)SD 12 (44%) 12 (44%)PD 4 (15%) 9 (33%)

Median PFS 5.7 mo 3.8 mo

MRD 141-144 daysCR = complete response; PR = partial response; SD = stable disease; PD = progressive disease.Tutt et al, 2010.

Olaparib Not Effective in Sporadic TNBC

PO = by mouth.Gelmon et al, 2011.

Olaparib 400 mg PO BID

Phase III OlympiAD: Olaparib in MBC

Physician’s choice (capecitabine, vinorelbine, eribulin)

Olaparib

Primary end point: PFS (no cross-over)Secondary: OS, PFS2

Planned sample size: 310 patientsNearly identical studies planned with niraparib (BIG/EORTC) and BMN-673 (industry sponsored).

Clinicaltrials.gov, 2016f.

MBC and BRCA mutation carrier

Prior anthra/taxane0-2 prior for

MBCNo prior platinum

HER2-Positive MBC

Case Study: HER2+ MBC

44-year-old woman presents with a large left breast mass and a palpable axillary node; no prior mammograms

Imaging confirms 6-7 cm mass in breast and multiple suspicious ax nodes. Biopsy confirms HER2+/ER- disease

CT CAP shows 3 liver lesions, largest 2 cm; bone scan and MRI brain is normal

Labs are normal

CAP = chest abdomen pelvis.

Trastuzumab, Pertuzumab, Lapatinib, T-DM1: Complementary Mechanisms

HER2

Dimerizationdomain

Pertuzumab

HER1/3/4

Trastuzumab

Subdomain IV

Trastuzumab:• Inhibits ligand-independent HER2

signaling• Activates ADCC• Prevents HER2 ECD shedding

Pertuzumab:• Inhibits ligand-dependent

HER2 dimerization and signaling

• Activates ADCC

Lapatinib

Lapatinib:• Inhibits intracellular kinase

domain of HER2, HER1 (EGFR)

T-DM1:• Immunoconjugat

e with emtansine• Internalizes and

dissociates• Few molecules

kill cell

T-DM1

T-DM1 = ado-trastuzumab emtansine; ADCC = antibody-dependent cellular cytotoxicity; ECD = extra cellular domain. Verma et al, 2013.

HER2+ MBC: Serial Improvements in Survival With Newer Agents and Combinations

Verma et al, 2013.

Timeline of HER2 Targeted Drug Approval for HER2+ BC

Chemotherapy + Trastuzumab in MBC

aPaclitaxel.BTrastuzumab.Hudis, 2007; Slamon et al, 2001; Marty et al, 2005.

Slamon et al

n=469Marty et al

n=186

Treatment ArmsAC or Ta

vsAC or T→Hb

Docetaxelvs

Docetaxel→Hb

Time to disease progression (mo) 4.6 7.4

P Value6.1 11.7

P Value

<0.001 0.0001Response rate 32% 50% <0.001 34% 61% 0.0002Median overall survival (mo)

20 25 0.046 23 31 0.0325

Chemo + Trastuzumab: Lessons

No new toxicity signals Almost any chemotherapy will work with

trastuzumab Laboratory models of “synergy” were of

some but not definitive help Probably not a process worth repeating

with other anti-HER2 agents

Capecitabine vs Capecitabine + Lapatinib

LABC = locally advanced breast cancer.Geyer et al, 2006.

Capecitabine vs Capecitabine + Lapatinib:

Time to Progression

Geyer et al, 2006.

Phase III Study to Test Whether Total HER2+ Blockade Improves Clinical

Outcome

Blackwell et al, 2010.

Progression-Free Survival: Lapatinib vs Lapatinib + Trastuzumab

Blackwell et al, 2010.

Borderline statistically significant improvement in overall survival observed.

CLEOPATRA Study Design

Baselga, Cortes, et al, 2012.

Patients WithHER2+ MBC

centrally confirmed(N=808)

Placebo + Trastuzumab

1:1

Randomization was stratified by geographic region and prior treatment status (neo/adjuvant chemotherapy received or not)

Docetaxel≥6 cycles recommended

n=406

n=402

Pertuzumab + Trastuzumab

Docetaxel≥6 cycles recommended

PD

PD

CLEOPATRA: Significant Improvement in Median PFS (and OS) with Pertuzumab

D = docetaxel; Ptz = pertuzumab; T = trastuzumab.Baselga et al, 2011; Baselga et al, 2012; Swain et al. 2012.

CLEOPATRA: Final OS Analysis

Swain et al, 2014.

Pertuzumab + Trastuzumab + DocetaxelPlacebo + Trastuzumab + Docetaxel

EMILIA Study Design

Verma et al, 2012.

Progression-Free Survival by Independent Review

Cap = capecitabine; Lap = lapatinib.Verma et al, 2012.

Overall Survival

Verma et al, 2012.

TH3RESA Study Schema

Krop et al, 2014.

PFS by Investigator Assessment

Krop et al, 2014.

Median follow-up: TPC, 6.5 months; T-DM1, 7.2 months.Unstratified HR=0.521 (P<0.0001).

First Interim OS Analysis

Krop et al, 2014.

44 patients in the TPC arm received crossover T-DM1 treatment after documented progressionUnstratified HR=0.57 (P=0.004)


aThere is no compelling evidence that combination regimens are superior to sequential single agents.NCCN, 2016a.

Chemotherapy Regimens for Recurrent or MBCa

HER2 Issues

All patients develop progressive disease Strategies to overcome resistance needed

(additional HER2 agents, agents added to overcome resistance)

Cost of therapy Emergence of biosimilars

Key Takeaways: Unmet Needs

All subtypes of MBC remain incurable so new agents are needed

Validating the clinical utility of tissue-based and “liquid” biopsy for clinical decision making is critical We can do it, but should we? Do the decisions we make on the information

alter outcome?

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Clinical Debates in the Management of Pretreated Metastatic Breast Cancer

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