Agents in the Treatment of

ER+ Aromatase Inbitor-Resistant Metastatic Breast Cancer:

M-THOR Inhibitors

Valero, M.D.,

Professor of Medicine and Deputy Chairman Department of Breast Medical Oncology

The University ot Texas MD Anderson Cancer Center Houston, Texas

• Paciente de 63 años sin antecedentes patológicos de interes.

Fumadora de 20 cig/día

• Abril de 2010. Se diagnostica un carcinoma ductal infiltrante de

CSE mama derecha, grado II, RE 100%, RP 90%, HER2-.

• Se realiza tumerectomía+ BSGC seguida de vaciamiento axilar

• AP. Carcinoma ductal infiltrante de 2,6 cm. de diámetro y

afectación de 2/15 ganglios axilares disecados.

•Quimioterapia adyuvante con antraciclinas y taxanos, RT.

Locorreegional y letrozol adyuvante.

•Junio de 2013 la paciente comienza a presentar dolor lumbar de

características mecánicas.

• Octubre de 2013 se diagnostican metástasis ganglionares a nivel

de FSCD, metástasis liticoblásticas a nivel de pelvis y columna

lumbar y 2 nodulos en pulmón izquierdo de 2 cm. De diametro

máximo. ECOG 1

• Se biopsia la FSCD. AP. Carcinoma ductal infiltrante , grado II, RE

80%, RP 50%, HER2-

Caso clínico

• Current endocrine strategies limited by resistance

– In MBC: 30% to 50% initially respond; all eventually acquire resistance

The Estrogen Receptor as a Target

Normanno, et al. Endocrine-Related Cancer. 2005;12:721-747; Johnston, et al. Cancer. 2008:112:710-717.

De Novo Resistance

Lack of ER expression

Alternative pathways driving cell

Acquired Resistance

ER expression and function

ER loss (40% to 50% at time of progression on therapy)

Role of GF receptors – ↑ GF signaling (eg, ↑ levels of EGFR / HER2 or ↑ activation)

Downstream intracellular signaling

Review of Trials of Hormone Therapy in Advanced Breast Cancer After

Progression on Prior Non-Steroidal Aromatase Inhibitor

Timeline of Approval of New Agents for

Hormone Receptor Positive MBC

1970 1980 1990 1995 2000 2005 2010 2012

Tamoxifen (1977)

Letrozole (1997)

Toremifene (1997)

Anastrozole (1995)

Exemestane (1999)

Fulvestrant (2002)

Drugs@FDA. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm Accessed May 24, 2012

Everolimus (2012)

Selected Trials of Hormonal Therapy Including Everolimus After Progression on

Prior AI* Trial N

EFECT Fulvestrant (250) vs exemestane

693

CONFIRM Fulvestrant (500) vs fulvestrant (250)

736

SoFEA Fulvestrant + anastrozole vs fulvestrant (250) vs exemestane

750

TAMRAD Tamoxifen + everolimus

110

BOLERO-2 Exemestane + everolimus

725

Fulvestrant 250

Fulvestrant 500

Everolimus Combinations

*Non-steroidal aromatase inhibitor.

FULVESTRANT 500 mg IM day 1, 250 mg day 14, 28,

monthly

EXEMESTANE 25 mg QD

EFECT: Fulvestrant (250, loading) vs Exemestane

Chia S, et al. J Clin Oncol 2008;26(10):1664-1670

N = 693

PMW with

advanced HR+

BC after failure of

NSAI therapy

Primary

TTP

Secondary

ORR, CBR,

DOR, TTR, OS,

tolerability

FUL n = 351

EXE n = 342

P-value

TTP (mo) 3.7 3.7 0.653

ORR (%) 7.4 6.7 0.736

Fulvestrant (250 loading) similar to exemestane

FULVESTRANT 500 mg IM on day 1, 14, 28, monthly

FULVESTERANT 250 mg IM monthly

CONFIRM: Fulvestrant 250 vs 500 mg

N = 736

PMW with

advanced HR+

BC after failure of

prior endocrine

therapy

Primary

PFS

Secondary

ORR, CBR,

DoCB, OS, Qol

Bachelot T, et al. J Clin Oncol 2012. Epub 1-7; DiLeo et al. J Clin Oncol 2010;28:4594-4600

FUL 500 n = 362

FUL 250 n = 374

P-value

PFS (mo) 6.5 5.5 0.004

ORR (%) 9.1 10.2 0.795

CBR (%) 45.6 39.6 0.100

FULVESTRANT 500 mg loading dose on day 1, then

250 mg monthly + ANASTROZOLE 1 mg/daily

EXEMESTANE 25 mg/daily

SoFEA: Fulvestrant (250, loading) With or Without Anastrozole vs Exemestane

No significant differences were observed in PFS, ORR, CBR, or OS

Johnston S et al. EBCC-8. 2012

N = 723

Post menopausal

women with

advanced HR+

BC following

progression on

NSAI

Primary

PFS

Secondary

ORR, CBR,

OS, tolerability

FULVESTRANT 500 mg loading dose on day 1, then

250 mg monthly + Placebo daily

FUL 500 n = 231

FUL + ANA n = 243

EXE

PFS (mo) 4.8 4.4 3.4

SOS RAS

RAF

Basal transcription machinery p160

ERE ER target gene transcription

ER CBP P

P P P

ER

P

Akt P

MAPK P

Cytoplasm

Nucleus

ER

PI3-K P

P

P

P P

P

MEK P

Plasma membrane

HER2-1

IGFR-1

Estrogen

mTOR

Strategies to Overcome Resistance in HR+ Breast Cancer

DiCosimo & Baselga. Nature Clin Prac Oncol. 2009.

TAMRAD Schema Randomized Phase II (n=111) Metastatic patients with prior exposure to AI

• 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 • Primary end point: CBR (CR+ PR+ SD for 6 months)

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

A : Tamoxifen, 20 mg/d (TAM)

Randomization

Bachelot T, et al. J Clin Oncol 2012. Epub 1-7

TAMRAD: CBR at 6 months

Tamoxifen + RAD001

Tamoxifen

Bachelot T, et al. J Clin Oncol 2012. Epub 1-7

Time to Progression

HR = 0.54; 95% CI (0.36-0.81) Exploratory log-rank: P = 0.0026

TAM: 4.5 mo. TAM + RAD: 8.6 mo.

Month

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

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

Pro

bab

ility

of

Surv

ival

TAM

TAM + RAD

Patients at risk

TAM + RAD: n =

TAM : n =

54

57

45

44

39

30

34

24

28

22

25

13

19

11

12

6

7

1

1

0

0

0

26

16

16

7

9

2

1

0

HR = 0.45; 95% CI (0.24-0.81) Exploratory log-rank: P = 0.0019

Month

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 6 12 18 24 30 36 P

rob

abili

ty o

f Su

rviv

al

TAM

TAM + RAD

TAM + RAD: n =

TAM : n =

54

57

53

55

51

53

49

50

49

44

45

38

38

30

26

22

14

9

6

4

0

0

Patients at risk

3 9 15 21 27 33

Overall Survival

Bachelot T, et al. J Clin Oncol 2012. Epub 1-7

2

1

Everolimus 10 mg/day + Exemestane 25 mg/day

(N = 485)

Placebo + Exemestane 25 mg/day

(N = 239)

BOLERO-2 Schema

Stratification:

1. Sensitivity to prior hormonal therapy

2. Presence of visceral disease

No cross-over

N = 724

• Postmenopausal

• ER+ HER2- MBC

• Recurrence or progression to letrozole or anastrozole

PFS

OS ORR

Bone Markers Safety QOL PK

2:1

Baselga et al. ESMO 2011; Hortobagyi G et al. SABCS 2011, Baselga et al NEJM 2012.

BOLERO-2: Overall Response Rate and

Clinical Benefit Rate by Local Assessment

9.5%

33.4%

0.4%

18.0%

0

5

10

15

20

25

30

35

40

Response Clinical Benefit

Everolimus + Exemestane

Placebo + Exemestane

P < 0.0001

P < 0.0001

Baselga J, et al. N Engl J Med 2012;366(6):520-9.

BOLERO -2: Primary Endpoint, PFS (18-Month Follow-up, Central)

Number of patients still at risk

485

239

427

179

359

114

292

76

239

56

211

39

166

31

140

27

108

16

77

13

62

9

48

6

32

4

21

1

18

0

11

0

10

0

5

0

0

0

HR=0.38 (95% CI: 0.31-0.48) Log-rank P value: < .0001 Kaplan-Meier medians EVE 10 mg + EXE: 11.01 months PBO + EXE: 4.14 months

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108

EVE 10 mg + EXE (n/N=188/485)

PBO + EXE (n/N=132/239) 0

20

40

60

80

100

Pro

bab

ility

(%

) o

f Ev

en

t

Time (week)

EVE 10 mg + EXE

PBO + EXE

Piccart ASCO abstract 551.

BOLERO-2 PFS in Subgroups

Baselga et al. N Engl J Med 2012

<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: Most Common G3/4 AEs

Everolimus + Exemestane (N = 482), %

Placebo + Exemestane (N = 238), %

All Grades

Grade 3

Grade 4

All Grades

Grade 3

Grade 4

Stomatitis 56 8 0 11 1 0

Fatigue 33 3 <1 26 1 0

Dyspnea 18 4 0 9 1 <1

Anemia 16 5 <1 4 <1 <1

Hyperglycemia 13 4 <1 2 <1 0

AST 13 3 <1 6 1 0

Pneumonitis 12 3 0 0 0 0

Baselga J, et al. N Engl J Med 2012;366(6):520-9.

Time to definitive deterioration for EORTC QLQ-30 GHS, MID = 5%

EORTC QLQ-C30 GHS EVE + EXE PBO + EXE

TTD, months; MID = 5% Decrease from baseline

8.3 5.8

95% CI 7.0-9.7 4.2-7.2

P value (2-sided) .0084

TTD, months; MID = 10 points decrease

11.7 8.4

95% CI 9.7-13.1 6.6-12.5

P value (2-sided) .1017

BOLERO-2: HRQoL in Patients With HR+ ABC (18-Month Follow-Up)

Although the combination of EVE + EXE resulted in higher rates of grade 3/4 toxicity compared with PBO + EXE, analyses consistently show that time to definitive deterioration

in EORTC QLQ-C30 GHS was longer in EVE + EXE combination versus EXE monotherapy

HRQoL, health-related quality of life; EORTC QLQ-C30 GHS, European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 Global Health Scale; MID, minimal important difference; TTD, Time to definitive deterioration Beck JT, et al. ASCO; 2012. Abstract 539. 19

BOLERO-2 (39-mo): Final OS Analysis

20

One-sided P value was obtained from the log-rank test stratified by sensitivity to prior hormonal therapy and presence of visceral metastasis from IXRS®.

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System;

PBO, placebo.

232

109

248

113

266

120

279

130

292

145

311

153

330

162

347

170

373

182

399

194

414

201

429

211

448

220

471

232

485

239

EVE+EXE

PBO+EXE

No. at risk

HR = 0.89 (95% CI, 0.73-1.10)

Log-rank P = .14

Kaplan-Meier medians

EVE+EXE: 30.98 months

PBO+EXE: 26.55 months

Censoring times

11

5

23

8

39

18

58

28

91

41

118

56

154

77

196

98

216

102

0

0

1

1

• At 39 months’ median follow-up, 410 deaths had occurred (data cutoff date: 03 October 2013)

– 267 deaths (55%) in the EVE+EXE arm vs 143 deaths (60%) in the PBO+EXE arm

Presented at EBCC-9; 19–21 March 2014; Glasgow, Scotland. Abstract 1LBA.

BOLERO-2: Conclusions

• Adding everolimus to endocrine therapy improved response rate and PFS

(4.6-month benefit; P < .0001) in patients with HR+, HER2– advanced BC that

progressed after previous NSAI therapy

• Adding everolimus to endocrine therapy did not statistically improve overall

survival in second and third line therapy(31.0 months EVE+EXE vs 26.6

months PBO+EXE;

HR = 0.89; 95% CI, 0.73-1.10; P = .14)

• Everolimus adds some toxicity to endocrine therapy, mainly stomatitis,

fatigue, rash and diarrhea

• Ongoing translational research should further refine the benefit of mTOR

inhibition and related pathways in this treatment setting 21

MDACC Guidelines 2015

Post-menopausal

No Prior Tamoxifen or AI Prior Aromatase Inhibitor

Aromatase Inhibitor

Exemestane + Everolimus or Fulvestrant

Exemestane + Everolimus or Fulvestrant

Exemestane + Everolimus or Fulvestrant

Exemestane + Everolimus or Fulvestrant

Tamoxifen

Anastrozole + Fulvestrant

Exemestane + Everolimus

Tamoxifen

Prior Tamoxifen

Androgen, Megestrol/Highdose Estrogen