the evolution of endocrine therapy in advanced breast cancer: a...

The evolution of endocrine therapy in advanced breast cancer: a moving target?

Massimo Cristofanilli, M.D., F.A.C.P. Professor of Medicine

G. Morris Dorrance Jr. Endowed Chair in Medical Oncology Fox Chase Cancer Center, Philadelphia, PA

Medellin, Colombia, November 17, 2012

There is still a role for single agent endocrine therapy?

ENDOCRINE THERAPY FOR

METASTATIC BREAST CANCER

•  Response rate (RR) to first-line hormonal therapy (tamoxifen/AI) 21% to 33%1-2

•  RR to second-line hormonal therapies (exemestane or fulvestrant) 7%3

•  EFECT trial: Time to progression (TTP) for exemestane or fulvestrant 3.7 months3

•  Novel approaches to improve the efficacy of endocrine therapy urgently required

1. Nabholtz. JCO 2000; 2. Mouridsen JCO 2003; 3. Chia JCO 2008

Leary et al, Br J Cancer. 2006 September 18;95(6):661-666.

Outline

•  Combinations with GFR inhibitors: - Trastuzumab (TAnDEM) - Gefitinib (AZ225, 713) - AZD8931(MINT) - Lapatinib

•  Combinations with SERMs: - Fulvestrant

•  Combinations with rapamycin-analogs •  Combinations with HDACs inhibitors

Endocrine Therapy combined with growth factor receptor

inhibitors

The ErbB/HER receptor family

2 3 1 4

erbB1 EGFR HER1

erbB2 HER2

(no ligand)

erbB3 HER3

(kinase dead)

erbB4 HER4

NRG2

NRG1

Ligands

Receptors

TGFa

EGF

AR

EPR

HB-EGF

BTC

NRG4

NRG3

EPR

HB-EGF

BTC

NRG2

NRG1

Trial Regimen Population No. of patients

Median PFS, mo

Endocrine therapy alone

Endocrine therapy + anti-ErbB

TAnDEM 1

Phase III Anastrozole +/-

trastuzumab HER2+ 208 2.4 * 4.8 *

Osborne et al2

Randomized, placebo-controlled phase II

Tamoxifen +/- gefitinib

ITT

HER2+ subset

206†

37

8.8

5.8

10.9

6.7

Cristofanilli et al3

Randomized, placebo-controlled phase II

Anastrozole +/- gefitinib ITT 93 8.2 14.5

Clinical Evidence for Co-Targeting Growth Factor Receptors in ER+ MBC

*Increased slightly in exploratory analysis of centrally confirmed ER status, 3.8 vs 5.6 mo. †Stratum 1 of trial defined as never receiving tamoxifen or completed adjuvant tamoxifen > 1 year prior.

TAnDEM (Trastuzumab and Anastrozole Directed Against ER-Positive HER2-Positive Mammary Carcinoma) patient enrollment and study flow.

Kaufman B et al. JCO 2009;27:5529-5537

Kaplan-Meier curves showing estimated (A) progression-free survival (PFS) for the intent-to-treat (ITT) population, (B) PFS for patients with centrally confirmed hormone receptor–

positive tumors, (C) time to progression (TTP) for ITT population, (D) TTP for...

Kaufman B et al. JCO 2009;27:5529-5537

Gefitinib in ER+ postmenopausal breast cancer

Tamoxifen 20mg od

Iressa 250mg od

&

Tamoxifen 20mg od

Placebo

&

or

n = 206

12m post adjuvant therapy

Newly diagnosed

ER+ve advanced breast cancer

Osborne et al

Dec 2007

n = 93

ER+ve advanced breast cancer

Arimidex 1mg od

Iressa 250mg od

& Arimidex 1mg od

Placebo

&

Cristofanilli et al

June 2008

Tamoxifen + Iressa

Tamoxifen + Placebo

n=157

Time To Progression (Days)

HR 0.78 (0.52-1.15)

Arimidex + Iressa

Arimidex + Placebo

n=42

Time To Progression (Months)

HR 0.39 (0.16-0.97)

40%

Arimidex + Iressa

Arimidex + Placebo

n=93


HR 0.55 (0.32-0.94)

Data for endocrine therapy naïve patients only

Positive treatment effect for Iressa in

overall* population

Figure 11.3.1.4 : Kaplan-Meier Curves for Time to Progression - Stratum 1Intent-to-Treat Population

Time to progression is equivalent to progression free survival.

Treatment Group tamoxifen + gefitinib tamoxifen + placebo

proportio

n progres

sion-free

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

time (days)0 100 200 300 400 500 600 700 800 900 1000 1100

Tamoxifen + Iressa

Tamoxifen + Placebo

Stratum 1 n=206


HR 0.84 (0.59-1.19)

Treatment effect in endocrine therapy naïve

population only Interaction test

positive (p=0.07)

Osborne Study (225) San Antonio 07

Cristofanilli Study 713 ASCO 08

Gefitinib demonstrated POC in Endocrine Naïve ER+ve

Combined HR in endocrine therapy naïve pts = 0.7 * Overall population in stratum 1 of Osborne study

225

713

Endo naive

HR=0.78 N=157, e = 104

HR=0.39 N=42, e=23

Sensi;ve+resistant

HR=1.22 N=132, e=87

HR=0.74 N=45, e=29

Interac;on p (2-‐sided)

P=0.12

P=0.25

Osborne et al Study

Prior Endocrine Rx No Prior Endocrine Rx Interaction Test p = 0.43 (so 43% chance differences in subpopulations are by chance)

HR = 0.78

95% CI HR 0.52 – 1.15 p = 0.2

157 pts (77%) of 206 pts 49 pts (22%) of 206 pts HR = 1.47

95% CI HR 0.63 – 3.45 p = 0.37

J Clin Oncol 2009;15s(suppl; abstr 1014)

48%

52%

STRATUM 1: (endocrine naive or >12m post adj tam)

100%

Iressa/tam

placebo/tam

100%

placebo/tam

Iressa/tam

AZD8931 is equipotent vs erbB1, erbB2 and erbB3 in cells, unlike Iressa and Lapatinib

Differentiation of AZD8931

The MINT Study

D0102C00004

A Phase II, Randomised, Double-blind, Placebo-

controlled, Multi-centre Study to Assess the Efficacy

and Safety of AZD8931 In Combination with

Anastrozole, Compared to Anastrozole alone, in Post-

menopausal Women With Hormone Receptor-positive,

Endocrine Therapy-naive, Locally-advanced or Metastatic Breast Cancer (MINT)

First-Line Therapy With Lapatinib Combined with Letrozole vs Letrozole Alone for Postmenopausal Hormone Receptor Positive MBC: First

Results from the Phase III Double-Blind EGF30008 Trial

S. Johnston1, M. Pegram2, M. Press3, J. Pippen4, X. Pivot5, H. Gomez6,

A. Florance7, L. O’Rourke7, J. Maltzman7

•  Binds to intracellular ATP binding site of EGFR (ErbB-1) and HER2 (ErbB-2) preventing phosphorylation and activation

•  Blocks downstream signaling through homodimers and heterodimers of EGFR (ErbB-1) and HER2 (ErbB-2)

•  Dual blockade of signaling

1+2

Downstream signaling cascade

1+1 2+2

Geyer CE, ASCO 2006 Konecny GE et al., Cancer Res 2006 66(3):1630 Rusnak DW et al., Mol Cancer Ther 2001 1(2):85

Xia W et al., Oncogene 2002 21(41):6255

Lapatinib Mechanism of Action

Letrozole 2.5 mg daily + Lapatinib 1500 mg daily

Phase III, Randomized, Double-Blind Controlled Trial: Study Design

Patient Population •  ER+ and/or PgR+ •  Postmenopausal •  HER2+ , HER2-ve / Unknown •  Stage IIIb/IIIc/IV •  No prior treatment for MBC

Stratification •  Disease sites

•  Bone only / visceral or soft tissue

•  Interval since adjuvant tamoxifen therapy

•  < 6 mo / ≥ 6 mo or none

R A N D O M I Z E

N=1286 (including n=219 HER2+)

Letrozole 2.5 mg daily + Placebo

Endpoints

•  Primary –  Progression-free survival (PFS) as assessed by investigator

in patients with HR+, HER2+ MBC

•  Secondary –  PFS in HR+ ITT population (HER2+, HER2-ve/unknown) as

assessed by investigator –  Overall survival (OS) –  Overall response rate (ORR) –  Clinical benefit rate (CBR) –  Safety

Progression-Free Survival: HER2+ Population

Letrozole

(N = 108)

Letrozole + Lapatinib (N = 111)

Progressed or died 89 (82%) 88 (79%)

Median PFS, mo 3.0 8.2

Hazard ratio (95% CI) 0.71 (0.53, 0.96)

p-value 0.019

PFS: HER2-ve Patients (N=952) < 6 Mo Since D/C

of Tam

•  Median tam duration 2.8 y •  Median time since d/c 1 mo

Let (N=370)

Let + Lap (N=382)


Hazard ratio (95% CI), p-value

0.94 (0.79, 1.13); p=0.522

Let (N=104)

Let + Lap (N=96)


Hazard ratio (95% CI), p-value

0.78 (0.57, 1.07); p=0.117

≥ 6 Mo Since D/C of Tam (33%) or No Tam (67%)

• Median tam duration 5 y • Median time since d/c 3.5 y

Efficacy Summary

•  In postmenopausal women with HR+, HER2+ MBC the combination of letrozole and lapatinib showed: –  29% reduction in risk of disease progression (p=0.019), with an

improvement in median PFS from 3.0 to 8.2 months –  Significant improvement in clinical benefit rate

(29% to 48%; p=0.003)

•  In postmenopausal women with HR+, HER2- ve MBC: –  No significant treatment benefit on PFS [HR 0.90 (0.77, 1.05;

p=0.188)] –  23% reduction in risk of disease progression by preplanned Cox

analysis [adjusted treatment HR 0.77 (0.64, 0.94; p=0.010)] •  Prior tamoxifen exposure was a significant covariate •  Biomarker studies ongoing

Endocrine Therapy combined with SERMs

Combination anastrozole and fulvestrant in metastatic breast cancer

Mehta RS et al. N Engl J Med 2012;367:435-444.

Baseline Characteristics of the Patients and the Disease, According to Treatment Group.


Kaplan–Meier Curves for Progression-free Survival, According to Treatment Group.


Everolimus for postmenopausal women with advanced breast cancer:

updated results of the BOLERO-2 trial

G. N. Hortobagyi, M. Piccart, H. Rugo, H. Burris, M. Campone, S. Noguchi, M. Gnant, K. I. Pritchard, L. Vittori, P. Mukhopadhyay, T. Sahmoud, D. Lebwohl, J.

Baselga On behalf of the BOLERO-2 Investigators

Neoadjuvant (Ph II): Letrozole ± Everolimus

BC = breast cancer; ER+ = estrogen receptor-positive; RR = response rate. Baselga J et al. JCO. 2009;27:2630-2637

Primary endpoint: RR at 16 weeks (palpaFon)

270 postmenopausal women with ER+ early BC

Everolimus 10 mg/day + Letrozole 2.5 mg/day

Placebo + Letrozole 2.5 mg/day

Surgery

R A N D O M I Z E

•  Higher RR: 68% vs. 59% (P = 0.062) •  Greater antiproliferative response: È Ki67 by 57% vs. 30% (P < 0.01)

TAMRAD (Ph II): Tamoxifen ± Everolimus in Advanced BC

•  111 postmenopausal women with ER+ advanced BC previously treated with an AI were randomized in a phase II trial

AI = aromatase inhibitor; BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; TAM = tamoxifen. Bourgier C et al. ECCO/ESMO 2011 (Abstract #5005)

1.0

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34

Prob

abili

ty o

f Pro

gres

sion

TAM: 4.5 mos TAM + EVE: 8.6 mos

Months

HR = 0.54 Log-rank P = 0.002

BOLERO-2 (Ph III): Everolimus in Advanced BC

EVE 10 mg daily +

EXE 25 mg daily (n = 485)

Placebo +

EXE 25 mg daily (n = 239)

R

Endpoints •  Primary: PFS (local assessment) •  Secondary: OS, ORR, QOL, safety, bone markers, PK

2:1

N = 724 •  Postmenopausal ER+

•  Unresectable locally advanced or metastaFc BC

•  Recurrence or progression a]er letrozole or anastrozole

Stratification: Sensitivity to prior hormone therapy and presence of visceral metastases

Hortobagyi G et al. SABCS 2011 (Abstract #S3-7) 31 BC = breast cancer; ER+ = estrogen receptor-positive; EVE = everolimus; EXE = exemestane; ORR, overall response rate; OS = overall survival; PFS = progression-free survival; PK = pharmacokinetics; QOL = quality of life.

BOLERO-2: Baseline Characteristics Everolimus + Exemestane (n = 485), %

Placebo + Exemestane (n = 239), %

Median age (range), years 62 (34-93) 61 (28-90) Race

Caucasian 74 78 Asian 20 19

Performance status 0 60 59 Liver involvement 33 31 Lung involvement 29 33 Measurable diseasea 70 68

aAll other patients had ≥1 bone lesion.

32

BOLERO-2: Prior Therapy

Everolimus + Exemestane (n = 485), %


Sensitivity to prior hormonal therapy 84 84

Last treatment: LET/ ANA 74 75 Last treatment

Adjuvant 21 15 Metastatic 79 85

Prior tamoxifen 47 50 Prior fulvestrant 17 16 Prior chemotherapy for metastatic BC 26 26

Number of prior therapies: ≥3 54 53 33 Hortobagyi G et al. SABCS 2011 (Abstract #S3-7)

BOLERO-2 (12-month f/up): PFS Local

CI = confidence interval; EVE = everolimus; EXE = exemestane; HR = hazard ratio; PBO = placebo; PFS = progression-free survival.

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Time (weeks)

Prob

abili

ty (

%) o

f Eve

nt

HR = 0.44 (95% CI: 0.36-0.53) Log rank P value: <1 x 10-16 EVE + EXE: 7.4 months PBO + EXE: 3.2 months

EVE + EXE (E/N = 267/485) PBO + EXE (E/N = 190/239)

Everolimus Placebo

Number of patients still at risk

485 436 365 303 246 188 136 96 64 45 34 21 13 9 2 2 0 239 190 131 95 63 45 29 19 12 8 6 6 4 2 0 0 0

BOLERO-2 (12 mo f/up): PFS Central

CI = confidence interval; EVE = everolimus; EXE = exemestane; HR = hazard ratio; PBO = placebo; PFS = progression-free survival.

Everolimus Placebo

Number of patients still at risk

485 422 351 284 224 176 119 86 57 38 32 22 12 7 2 2 0 239 179 112 74 56 36 23 18 8 5 4 4 3 1 0 0 0

0

20

40

60

80

100

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96

Prob

abili

ty (%

) of E

vent

HR = 0.36 (95% CI: 0.28-0.45) Log rank P value: <1 x 10-16

EVE + EXE: 11.0 months PBO + EXE: 4.1 months

EVE + EXE (E/N = 155/485) PBO + EXE (E/N = 127/239)

Time (weeks)

BOLERO-2 (12 mo f/up): PFS in Subgroups

<65 (449) ≥65 (275)

YES (610) NO (114)

YES (406) NO (318)

0 (435) 1, 2 (274)

YES (493) NO (231)

1 (118) 2 (217) ≥3 (389)

YES (398) NO (326)

YES (523) NO (184)

0.0 0.2 0.4 0.6 0.8 1.0 1.2 Hazard Ratio

All (724) Age

Hormonal sensitivity

Visceral metastasis

Baseline ECOG PS

Prior chemotherapy

No. of prior therapies

Non-NSAI hormonal therapy

PgR status positive

Subgroups (N)

Favors Placebo + Exemestane Favors Everolimus + Exemestane

BOLERO-2 (12 mo f/up): Response and Clinical Benefit

12.0%

50.5%

1.3%

25.5%

0

10

20

30

40

50

60

Response Clinical Benefit

Everolimus + ExemestanePlacebo + Exemestane

P < 0.0001

P < 0.0001

Perc

ent

BOLERO-2 (12 mo f/up): Most Common Adverse Events

Everolimus + Exemestane (n = 482), %


All Grades Grade 3 Grade 4

All Grades

Grade 3

Grade 4

Stomatitis 59 8 0 11 <1 0

Rash 39 1 0 6 0 0

Fatigue 36 4 <1 27 1 0

Diarrhea 33 2 <1 19 <1 0

Appetite decreased 30 1 0 12 <1 0

Nausea 29 <1 <1 28 1 0

Non-infectious Pneumonitis* 15 3 0 0 0 0

Hyperglycemia* 14 5 <1 2 <1 0

BOLERO-2 (12 mo f/up): Summary • Addition of everolimus to exemestane

prolongs PFS in patients with ER+ HER2- breast cancer refractory to nonsteroidal aromatase inhibitors – Local: median 7.4 vs. 3.2 months,

HR = 0.44, P < 1 x 10-16

– Central: median 11.0 vs. 4.1 months, HR = 0.36, P < 1 x 10-16

• Benefit is observed in all subgroups 39 ER+ = estrogen receptor-positive; HER2- = human epidermal growth factor receptor 2-negative; HR = hazard ratio; PFS = progression-free survival.

Hortobagyi G et al. SABCS 2011 (Abstract #S3-7)

BOLERO-2 (12 mo f/up): Conclusion

• Everolimus is the first agent to significantly enhance the efficacy of hormonal therapy in patients with ER+, HER2- breast cancer

• The addition of everolimus in advanced breast cancer could represent a paradigm shift in the management of this patient population

• Everolimus was approved by the FDA 40 BC = breast cancer; ER+ = estrogen receptor-positive.

Hortobagyi G et al. SABCS 2011 (Abstract #S3-7)

Endocrine therapy combined with HDACs inhibitors

CMAJ 2006;174(3):341-‐8

E P I G E N E T I C S A S A T H E R A P E U T I C

T A R G E T I N B R E A S T C A N C E R

ENCORE 301: ADVERSE EVENTS Adverse Event1

AROM+ ENT (N=63) AROM + PBO (N=66)

Any G3 G4 Any G3 G4 Fatigue 29 ( 46%) 7 11% 1 2% 17 ( 26%) 2 3% -

Nausea 25 ( 40%) 3 5% - 10 ( 15%) 1 2% -

Neutropenia2, 3 16 ( 25%) 7 11% 1 2% 0 ( 0%) - -

Oedema peripheral 13 ( 21%) - - 3 ( 5%) - -

Vomiting 13 ( 21%) 3 5% - 3 ( 5%) - -

Anemia2 12 ( 19%) 1 2% - 8 ( 12%) 1 2% 1 2%

Dyspnoea 12 ( 19%) 2 3% - 7 ( 11%) - -

Weight decreased 11 ( 17%) - - 12 ( 18%) - -

Thrombocytopenia2 11 ( 17%) - - 4 ( 6%) - 1 2%

Diarrhoea 10 ( 16%) - - 8 ( 12%) 1 2% -

Pain 10 ( 16%) 1 2% - 4 ( 6%) 1 2% -

Back pain 9 ( 14%) - - 11 ( 17%) 1 2% -

Arthralgia 7 ( 11%) 1 2% - 11 ( 17%) - -

Constipation 6 ( 10%) - - 10 ( 15%) 1 2% -

45 Courtesy of P Ordentlich

E N C O R E 3 0 1 : R E S U LT S ( P F S )

Courtesy of P Ordentlich

E N C O R E R E S U L T S ( O S ) : F E B

2 0 1 2

Courtesy of P Ordentlich

Intent-to-treat population

Exemestane + En;nostat: median OS 28.1 months

Exemestane + Placebo: median OS 19.8 months

Hazard Ra;o 0.59 (95% CI: 0.36, 0.97) P=0.04 (2-‐sided) ; P=0.02 (1-‐sided)

Median Follow-‐up for OS = 25 months

28.1 months

19.8 months Improvement in OS

has stayed consistent with > 2 yr median

follow up

A C E T Y L AT I O N A S A P O T E N T I A L B I O M A R K E R O F R E S P O N S E

(#events/#at risk)

EE HA-

EE HA+

EE HA-: median PFS 2.76 months

EE HA+: median PFS 8.55 months

Hazard ratio 0.317 (95% CI: 0.127, 0.787)

7/14 3/7 2/3 0/1 0/1 0/1 0/1 0/1 1/1

1/13 1/12 2/11 2/8 3/5 0/2 0/0 0/0 0/0

Prog

ress

ion

Prob

abilit

y

0.00

0.25

0.50

0.75

1.00

Months

0 2 4 6 8 10 12 14 16 18

Aromasin® + En;nostat HA+ : median PFS 8.5 months (N=13) Aromasin® + En;nostat HA-‐ : median PFS 2.8 months (N=14) Hazard ra;o 0.32 (95% CI: 0.13, 0.79)

(#events/#at risk)

EE HA-

EE HA+

EE HA-: median PFS 2.76 months

EE HA+: median PFS 8.55 months

Hazard ratio 0.317 (95% CI: 0.127, 0.787)

7/14 3/7 2/3 0/1 0/1 0/1 0/1 0/1 1/1

1/13 1/12 2/11 2/8 3/5 0/2 0/0 0/0 0/0

Progression Probability

0.00

0.25

0.50

0.75

1.00

Months

0 2 4 6 8 10 12 14 16 18

Potential to benefit may be determined by blood test within 1st two weeks of treatment

Kaplan-Meier Estimates of PFS by Acetylation (n=27)

8.5 months

2.8 months

Eligible:

Advanced breast cancer

ER/PR+, HER2-‐

Progression/no progression on prior non-‐steroidal AI

Exemestane plus En;nostat

Exemestane plus Placebo

FES-‐PET and FDG-‐PET: baseline (at selected sites)

Blood sampling: baseline, 2 wks

Treatment un;l Progression/Intolerance: Exemestane 25mg daily po AND En;nostat/Placebo 5mg po weekly.

E2112-‐ Proposed Schema RANDOMIZE

N≈ 600

ELIGIBILITY •  Postmenopausal men/women •  Histologically confirmed invasive breast cancer •  Locally advanced or metastatic •  ER/PR-positive (>1% staining), HER2-negative •  Measurable or evaluable disease •  1st line: no prior endocrine therapy in the metastatic setting

OR prior adjuvant non-steroidal AI use allowed but completed ≥ 12 months prior to enrollment

•  Refractory: intolerance/disease progression after non-steroidal AI use in the metastatic setting OR prior adjuvant non-steroidal AI use allowed but completed ≤ 12 months prior to enrollment

•  Prior everolimus permitted, but not exemestane •  One prior chemo permitted in metastatic setting •  ECOG 0-1 and adequate organ function

Conclusions •  The management of hormone-receptor positive

MBC has significantly evolved in the last few years: - Newly diagnosed HER2+-> Combination with T or L - Newly diagnosed HER2 - AI/SERM - Refractory disease AI/Everolimus - EGFR-targeting agents?

•  Future directions - HDACs, IGFRs in MBC - Everolimus in adjuvant setting

There is still a role for single agent endocrine therapy?

NO

the evolution of endocrine therapy in advanced breast cancer: a...

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