Aromasin (Exemestane) in Breast Cancer - Physicians' …e-syllabus.gotoper.com/_media/_pdf/SOBO13_Mod7_1330_O... · 2013-11-09 · Endocrine Therapy of Advanced Breast Cancer ...

Endocrine Therapy of Advanced Breast Cancer School of Breast Oncology

November 9th 2013

Ruth M. O’Regan, MD Professor and Vice-Chair for

Educational Affairs, Department of Hematology and Medical Oncology,

Emory University, Chief of Hematology and Medical

Oncology, Georgia Cancer Center for Excellence, Grady Memorial Hospital

Outline General principles

Endocrine agents

Fulvestrant dosing

Combinational targeting of ER

Endocrine-resistance – HER2-positive

Role of ER signaling in HER2-positive breast cancers

Principle 1: Likelihood of benefit from endocrine therapy can be predicted by…

Disease Free

Interval

DFI Age Menopausal Status # Organ Sites ECOG PS ER/PR status Well differentiated Low S phase, diploid Primary/Previous Rx

Median Survival

Change in receptor status impacts outcome in the metastatic setting

Receptor discordance in primary and metastatic breast cancers relatively common resulting in treatment changes in up to 15% of patients

Changes in receptors impact prognosis

Most common change is in hormone receptors especially PgR going from positive to negative (represents a change from luminal A to luminal B?)

Changes in HER2 less common

Recurrent cancer should be biopsied at least once

Amir et al, Locatelli et al, Karlsson et al PASCO 2010

Principle 2: Patients achieving stable disease do just as well as patients whose tumors respond

0

100

0 1 2 3 4

Years From Randomization

80

60

40

20

At 2-Year Risk Deaths Estimate

CR or PR 33 10 85%

Stable 24 wk78 23 86%

Other 152 118 35%

Robertson JF, et al. Breast Cancer Res Treat. 1999;58:157-162.

Sur

viva

l (%

)

Clinical Benefit = CR + PR + Stable 24 wks

R E S I S T A N C E

40% 30% 25% 15%

Principle 3: If it works the first-time….

1st Line

2nd Line

3rd

Line 4th

Line

Endocrine therapy

Bottom-line

Endocrine therapy works and should be given first-line to patients with hormone-responsive MBC Chemotherapy only indicated for: life-threatening visceral mets or when endocrine therapy options fail and/or exhausted

Use of 21-gene recurrence score in MBC

Objective – To determine whether the 21-gene Recurrence Score®

provides clinically meaningful information in patients with de novo stage IV breast cancer enrolled in TBCRC 013.

Eligibility – Metastatic breast cancer with intact primary*

– Tissue from primary tumor and metastatic lesion

– 110 pts (86%) with pre-treatment primary tumor samples suitable for 21-gene Recurrence Score® analysis

– Included patients with ER-negative and HER2-positive disease

King et al Proc ASCO 2013 * small number developed mets within 3-months of diagnosis

Time to 1st Progression by Risk Group

Median TTP, mos RS<18 RS18-30 RS≥31 Log rank, p

All pts (n=102) 32 (16-NR) 20 (15-NR) 15 (9-21) 0.046 ER+ (n=86) 32 (16-NR) 20 (15-NR) 15 (9-25) 0.034

ER+HER2- (n=70) 32 (16-NR) 20 (15-NR) 15 (9-26) 0.013

RS<18

RS 18-30

RS ≥31

months

% p

rogr

ess

ion

free

2yr Overall Survival by Risk Group

2 yr OS, % RS<18 RS18-30 RS ≥31 Log rank, p

All pts (n=102) 100 (78-100) 100 (78-100) 80 (69-93) 0.049

ER+ (n=86) 100 (78-100) 100 (78-100) 77 (64-94) 0.016

ER+HER2- (n=70) 100 (78-100) 100 (75-100) 69 (51-93) 0.001

RS<18

RS 18-30

RS ≥ 31

% a

live

wit

h d

isea

se

ER+ pts treated with 1st line endocrine tx high RS shorter TTP

ER positive (IHC) ER pos Her 2 neg

Median TTP, mos RS<18 RS18-30 RS ≥31 Log rank, p

ER+ (n=50) NR (18-NR) 22 (13-NR) 15 (8-NR) 0.009

ER+HER2- (n=49) NR (18-NR) 22 (13-NR) 15 (8-NR) 0.016

RS<18

RS 18-30

RS ≥31

% p

rogr

ess

ion

free

ER+ pts treated with 1st line chemotherapy No difference in TTP by RS

ER positive ER pos Her 2 neg

Median TTP, mos RS<18 RS18-30 RS ≥31 Log rank, p

ER+ (n=36) 10.5 (4-NR) 20 (12-NR) 16 (9-NR) 0.54

ER+HER2- (n=21) 10.5 (4-NR) 18 (12-NR) 13 (9-NR) 0.56

RS<18

RS 18-30

RS ≥ 31

% p

rogr

ess

ion

free

Endocrine Agents for Breast Cancer

• SERMs Tamoxifen Toremifene Raloxifene

• Estrogens Estradiol DES, EE2

• ER-Down Regulator Fulvestrant

• Aromatase Inhibitors Anastrozole Letrozole Exemestane

• Progestins Megestrol Acetate MPA

• Androgens Fluoxymesterone

Quick summary of older trials

Tamoxifen effective regardless of menopausal status and only agent approved for premenopausal patients (combination ovarian ablation + tamoxifen > tamoxifen alone)

All aromatase inhibitors > tamoxifen in first-line setting (9 to 11 months PFS AI vs 6 months TAM)

Non-steroidal AIs are cross-resistant Steroidal and non-steroidal are not cross-

resistant and can be used sequentially

Fulvestrant Equivalent to anastrozole in patients with

metastatic breast cancer previously treated with tamoxifen (FDA approved for antiestrogen treated MBC)

Equivalent to tamoxifen in first-line treatment of ER-positive MBC

Equivalent to exemestane in patients with MBC previously treated with non-steroidal AIs

Dose and schedule may have been sub-optimal in earlier trials

Howell et al JCO 2004, Gradishar JCO 2008

EFECT: Time to progression (ITT)

Proportion of patients progression-free

Months At risk: Fulvestrant Exemestane

3.7 3.7 Median (months)

HR = 0.963, 95% CI (0.819, 1.133), p=0.6531

Cox analysis, p=0.7021

Exemestane Fulvestrant

Fulvestrant*

Exemestane

0 3 6 9 12 15 18 21 24 27

0.0

0.2

0.4

0.6

0.8

1.0

351 195 96 50 25 12 4 2

342 190 98 41 21 12 8 6

0

1

0

0

Gradishar et al JCO 2008 *500mg D1 250mg D14, q28d

CONFIRM Phase III Trial of Fulvestrant in ER-Positive Advanced Breast Cancer: Efficacy

Di Leo et al. JCO2010

Fulvestrant

500 mg

(n = 362)

Fulvestrant

250 mg

(n = 374)

HR/OR (95%

CI) P Value

Median TTP 6.5 months 5.5 months 0.80 (0.68-0.94) .006

ORR 9% 10% 0.94 (0.57-1.55) NR

CBR 46% 40% 1.28 (0.95-1.71) NR

Median Duration

of Benefit 16.6 months 13.9 months NR NR

•57.5% of patients had received prior antiestrogens, and 42.5% had received prior AIs •Approximately one third had demonstrated no response to prior hormonotherapy

FIRST Study Design

Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3., JCO 2009

Endpoints at primary DCO Primary endpoint •Clinical benefit rate Secondary endpoints •Objective response rate •Time to progression •Duration of response •Duration of clinical benefit •Safety Exploratory endpoints •Best response to subsequent therapy

Randomization (1:1), open-label first-line ER+ postmenopausal patients

with advanced breast cancer (target, n = 200; actual, n = 205)

Fulvestrant 500 mg (500 mg IM on Days 0, 14, and 28, and every 28 days

thereafter)

Anastrozole 1 mg (1 mg PO daily)

Progression

Follow-up

Progression

Follow-up

DCO = data cut-off

FIRST: Efficacy Outcomes at Follow-Up Analysis

CI = confidence interval; TTF = time to treatment failure; TTP = time to progression

Outcome

Median, months

Hazard ratio (95% CI) P value

Fulvestrant (n = 102)

Anastrozole (n = 103)

TTP 23.4 13.1 0.66 (0.47-0.92) .01

TTF 17.6 12.7 0.73 (0.54-1.00) .05

TTP (adjusted for predefined covariates)

-- -- 0.64 (0.46-0.90) .01

Robertson JF, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-3.

SWOG S0226 Phase III Trial of Anastrozole +

Fulvestrant 250 vs Anastrozole Alone

Mehta et al NEJM 2012.

FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg

PO qday*

ANASTROZOLE 1 mg PO qday*

N = 707

Post menopausal women with HR+ advanced breast

cancer, untreated with

HR for advanced disease

Primary PFS

Secondary OS

FUL + ANA n = 355

ANA n = 352

HR P value

PFS (mo) 15.0 13.5 0.80 0.007

OS (mo) median 47.7 41.3 0.81 0.049

*Crossover to fulvestrant 500 mg allowed after progression

FACT: Phase III Study of Anastrozole +

Fulvestrant 250 vs Anastrozole Alone

Bergh et al. J Clin Oncol. 2012;30(16):1919-1925

FULVESTRANT 250 mg q4wk + ANASTROZOLE 1 mg PO

qday

ANASTROZOLE 1 mg PO qday

N = 514

Pre/Post menopausal

women with HR+ advanced breast

cancer, untreated with

HR for advanced disease

Primary TTP

Secondary TTF, ORR,

CBR, Safety, OS

FUL + ANA n = 256

ANA n = 254

HR P value

TTP (mo) 10.8 10.2 0.72 0.91

OS (mo) median 37.8 38.2 1.00

Sequencing: which order is best?

All we know from a series of phase 2 trials is that agents with different mechanisms of action can be sequencing successfully

The exception is using non-steroidal aromatase inhibitors – sequencing letrozole and anastrozole does not work

Unclear which order is best – EFECT trial suggests it may not matter

AI or Fulvestrant* probably good choices as 1st line therapy

* Fulvestrant not approved in 1st line setting

Mechanisms of hormone resistance

From Johnston CCR 2005

ER Target Gene Transcription

SOS

P P

P P

PI3-K

Akt

P P

RAS RAF

MEK

MAPK p90RSK

ER

P p160

Basal Transcription

Machinery CBP ER ER P P P

ERE

Plasma Membrane

Cytoplasm

Nucleus

E2

SERD

AI T

IGF1R EGFR/HER2

Increased signaling through PI3-K pathway

Increased upstream signaling through EGFR and/or IGF-IR and or VEGFR

VEGFR

Absence or undetectable target

HER2-positive breast cancers are intrinsically resistant to endocrine therapy

Transfection of ER-positive breast cancer cells with HER2 renders them resistant to tamoxifen

Retrospective analyses of trials in the ER-positive metastatic setting show a worse outcome for cancers that co-express HER2, compared to those that do not

Median progression free survival is less than 6 months for ER+ HER2+ MBC treated with aromatase inhibitors

Benz BRCT BRCT 1992, De Laurentiis J Clin Oncol 2005, Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009

LET LET LET ANAST ANAST

Prog

ress

ion

free s

urvi

val(

mon

ths)

HER2- HER2+/-

Outcome for patients with ER+ metastatic breast cancer based on HER2 status

Kaufman J Clin Oncol 2009, Johnston J Clin Oncol 2009, Bonneterre Cancer 2001, Moridisen J Clin Oncol 2003, Nahta BRCT 2012

Progression-free survival in patients with HR-positive, HER2-positive MBC

103 48 31 17 14 13 11 9 4 1 1 0 0 A + H

104 36 22 9 5 4 2 1 0 0 0 0 0 A

CI, confidence interval PFS = time from randomisation to date of progressive disease or death

Probability 1.0

0.8

0.6

0.4

0.2

0 5 10 15 20 25 30 35 40 45 50 55 60 Months

95% CI

3.7, 7.0 2.0, 4.6

p value

0.0016

Median PFS

4.8 months 2.4 months

Events

87 99

0.0

No. at risk

Kaufman et al JCO 2009

Johnston et al., JCO 2009

ITT HER2+ HER2-

let

(n=644)

let + lap

(n=642)

let

(n=108)

let + lap

(n=111)

let

(n=474)

let + lap

(n=478)

PFS (months) 10.8 11.9 3.0 8.2 13.4 13.7

HR 0.86; P =.026 HR 0.71; P =.019 HR 0.90; P =.188

ORR 28% 30% 15% 28% 32% 33%

P =.262 P =.021 P =.726

CBR 51% 56% 29% 48% 56% 58%

P =.096 P =.003 P =.761

OS (months) NR NR 32.3 33.3 NR NR

NR HR 0.74; P =.113 NR

Letrozole ± Lapatinib in HR-positive MBC

TAMRAD Study Design

Stratification: Primary or secondary hormone resistance

– Primary: Relapse during adjuvant AI; progression within 6 months of starting AI

treatment in metastatic setting

– Secondary: Late relapse (≥6 months) or prior response and subsequent

progression to metastatic AI treatment

No crossover planned

Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

• Randomized Phase II

• HR-positive MBC with prior exposure to aromatase inhibitors (AI)

A: Tamoxifen 20 mg/day (TAM)

B: Tamoxifen 20 mg/day + RAD001 10 mg/day (TAM + RAD)

R

TAMRAD: Time to Progression

TAM 4.5 mo. TAM + RAD 8.6 mo.

Hazard Ratio (HR) = 0.53 (95% CI: 0.35-0.81) Exploratory log-rank: P = .0026

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0 Pr

obab

ilit

y of

sur

viva

l

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 Months

Bachelot T, et al. Cancer Res. 2010;70(24 Suppl): Abstract S1-6.

Primary endpoint: Clinical benefit rate improved from 42% with TAM to 61% with TAM + RAD (p=.045 exploratory analysis)

Effects of mTORC1 Activation

Treilleux I. ASCO 2013. Abstract 510.

Markers of Treatment Response Everolimus Response in ER+ MBC

Treilleux I. ASCO 2013. Abstract 510.

TAM, tamoxifen; RAD, RAD-001 (everolimus)

Markers of Treatment Response Everolimus Response in ER+ MBC

Treilleux I. ASCO 2013. Abstract 510.

TAM, tamoxifen; RAD, RAD-001 (everolimus).

2 1

Everolimus 10 mg/day + Exemestane 25 mg/day

(N = 485)

Placebo + Exemestane 25 mg/day

(N = 239)

BOLERO-2: Trial Design

ABC: advanced breast cancer, NSAI: non steroidal aromatase inhibitors, HER2-: human epidermal growth factor receptor 2 – negative; PFS: progression-free survival; PK: pharmacokinetics

Stratification:

1. Sensitivity to prior hormonal therapy

2. Presence of visceral disease

No cross-over

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA.

34

N = 724

Postmenopausal ER+ HER2- ABC refractory to letrozole or anastrozole

PFS

OS ORR

Bone Markers Safety

PK

BOLERO-2: Addition of everolimus to exemestane improves PFS in HR+ MBC

Time (weeks)

HR = 0.36 (95% CI: 0.27–0.47)

EVE + EXE: 10.6 Months PBO + EXE: 4.1 Months

Log rank P value = 3.3 x 10 -15

0 12 6 18 24 30 36 48 60 42 54 72 66 78

80

60

40

20

100

0 Prob

abilit

y of

Eve

nt (

%)

Everolimus + Exemestane (E/N=114/485) Placebo + Exemestane (E/N=104/239)

Presented by J. Baselga at the 2011 European Multidisciplinary Cancer Congress (ECCO/ESMO), September 26, 2011. Abstract: 9LBA. Baselga et al ESMO 2011

Markers of Treatment Response Everolimus Response in BOLERO-2

Hortobagyi G. ASCO 2013. Abstract 509.

EVE, everolimus; PBO, placebo.

Phase 2 Trial of CDK 4/6 inhibitor PD0332991 in first-line metastatic

HR-positive breast cancer

ER-positive Her2-

negative MBC

N=66 Letrozole

PD 0332991 Letrozole

Part 1

ER-positive Her2-

negative MBC with

CCDN1 amp and/or loss

of p16

N=99

Letrozole

PD 0332991 Letrozole

Part 2

Stratification • Disease site (visceral vs bone-only vs other) • Disease-free interval (> 12 mths vs ≤ 12 mths from adjuvant to recurrence or de novo advanced disease

Primary Endpoint: PFS

Finn et al SABCS 2012

Most Common AEs

Adverse Event (n)

PD 0332991

Letrozole (n=83)

Letrozole

(n=77)

Grade 1/2 3 4 1/2 3 4

Neutropenia 19 46 5 3 1 0

Fatigue 29 2 2 21 1 0

Anemia 20 4 1 3 1 0

Nausea 19 2 0 10 1 0

Hot flashes 19 0 0 12 0 0

Alopecia 18 0 0 3 0 0

Arthralgias 18 0 0 14 1 0

Thrombocytopenia 11 1 0 0 0 0

Stomatitis 10 0 0 1 0 0

Finn et al SABCS 2012

Phase 3 trial of PD-0332991 (Palbociclib)

Primary endpoint: PFS

Finn RS. ASCO 2013. Abstract 652.

Summary other targeted agents in HR-positive MBC

Bevazicumab does not significantly improve TTP when added to letrozole in first-line setting (LEA trial)

Inhibition of IGF1R does not enhance activity of aromatase inhibition

Addition of HDAC inhibitor, Entinostat, to endocrine therapy improved overall survival (confirmatory ECOG trial planned)

Martin et al SABCS 2012, Robertson et al Lancet Onc 2013, Yardley et al J Clin Oncol 2013

HER2 trumps ER when both receptors are expressed…..

But is this true for all ER+ HER+ breast cancers?

T T T T T L L L L T/L T/L T/L T/L P T/P T/P

P P -> FEC FEC -> P D EC -> D

Perc

ent

PC

R

Pathologic complete response is consistently lower in ER+ HER2+ breast cancers compared to

ER- HER2+ breast cancers

Reviewed in Nahta and O’Regan BRCT 2012

PCR is prognostic in ER- cancer but not ER+ cancers that co-express HER2

von Mitchwitz et al SABCS 2011

ER-negative, HER2-positive ER-positive, HER2-positive

Why is this important?

We may (and probably are) over-treating a subgroup of ER+, HER2+ breast cancers in the adjuvant setting

This subgroup of patients with ER+, HER2+ breast cancers may suffer late recurrences (similar to what we see with luminal A cancers)

Can we identify this subgroup?

HER2+/HR-

HER2+/ER+

HER2+/ER+++

Perc

ent

PC

R

ER expression

Likelihood of PCR is inversely related to level of ER expression for HER2+ breast cancers

Bhargava Mod Path 2011, Nahta BRCT 2012

Prognostic ability of 70-gene signature in HER2+, ER+ cancers: untreated patients (n = 89)

Knauer et al BJC 2010

C40601: HER2+ Subtypes by Hormone Receptor (HR)

HR-negative HR-positive

Carey et al Proc ASCO 2013

ER ER

ERE

FOXO3a

PI3-K

AKT

HER2 HER1/2/3

FOXO3a

ER-regulated gene transcription

x

Ras

MEK

Erk1/2

Nucleus

Cytoplasm

Membrane

ER ER

ERE

FOXO3a

PI3-K

AKT

HER2 HER1/2/3

ER-regulated gene transcription

Ras

MEK

Erk1/2

Nucleus

Cytoplasm

Membrane

TKI x x

TRAST

HER2 signaling decreases ER activation and inhibition of HER2 increases ER-regulated gene transcription

Xia PNAS 2006, Valabrega Oncogene 2005

Clinical relevance of this cross-talk

Inhibition of HER2 without inhibition of ER may increase ER signaling allowing ER to act as an escape mechanism – This could contribute to the lower PCR seen in ER+

HER2+ breast cancers and have potential implications in the metastatic setting

– There may be a subset of ER+ HER2+ breast cancers where ER inhibition is critical (more important than chemotherapy)

Response to pre-operative trastuzumab and lapatinib ± letrozole (12 weeks)

0 10 20 30 40 50 60

pCR

(%

)

70

All ER+

ER -

40%

21% 28%

53%

56%

48%

All ER+

ER-

pCR pCR + npCR

Rinawi CCR 2013 npCR = < 1cm residual cancer in the breast

Andre F, et al. J Clin Oncol 22: 3302, 2004

Receptor positive

Receptor negative

We have made progress!