Avances en el tratamiento del cáncer de mama metastásico hormono-sensible

Antonio González Martín

Servicio Oncología Médica

MD Anderson Cancer Center, Madrid·España

VI Simposium Bases Biológicas del Cáncer y Terapia Personalizada

Salamanca 22 de mayo de 2014

• La expresión del RE predice la respuesta a terapia endocrina (tamoxifeno, inhibidores de aromatasa, fulvestran). – Descubierto en 19601

– Primer biomarcador predictivo en oncología.

• La respuesta se ve limitada por una resistencia primaria y adquirida a la terapia endocrina.

Tratamiento de paciente metastásica con perfil Luminal

1. McGuire WL. Hormone receptors: their role in predicting prognosis and response to endocrine therapy. Semin Oncol 1978;5:428–33.

Resistencia primaria y adquirida a hormonoterapia

Resistencia Secundaria

7%

23%

3%

17%

30%

20%

Letrozol n=453

Tamoxifeno n=454

Mouridsen et al. J Clin Oncol 2003

70% 80%

Res

po

nse

Rat

e

4

Unmet Medical Needs in ER+ Nonsteroidal AI-Refractory Advanced or Metastatic Breast Cancer

EFECT Study

• Suboptimal efficacy with current treatments

– The response seen with exemestane reinforces the notion of incomplete resistance between the steroidal and nonsteroidal AIs

• New, effective agents that target outside the ER pathway are needed

1. Chia et al. J Clin Oncol. 2008;26:1664-1670.

Efficacy Measure Fulvestrant 250

n = 351 Exemestane

n = 342

ORR 7.4% 6.7%

Median TTP 3.7 months 3.7 months

Median duration of clinical benefit

9.3 months 8.3 months

Clinical benefit rate 32.2% 31.5%

5

Unmet Medical Needs in ER+ Nonsteroidal AI-Refractory Advanced or Metastatic Breast Cancer

CONFIRM Study

1. Di Leo. SABCS 2012

Efficacy Measure n= 736

Fulvestrant 500 Fulvestrant 250

ORR 9.1% 10.2%

Clinical benefit rate 45.6% 39.6%

Median PFS (months) 6.5 months

5.5 months

HR, 0.80; 95% CI, 0.68–0.94; P 0 .006

Median OS (months) 26.4 months 22.3 months

HR, 0.81; 95% CI, 0.69, 0.96; P 0 .016

Mecanismos de Resistencia a Hormonoterapia

• Pérdida del Receptor de Estrógeno (RE)

• Mutación de RE

• Activación cruzada del RE y vías de señalización de

factores de crecimiento (“cross-talk”)

• Sobre-expresión de receptor de andrógeno (AR)

RAS

RTKs

AKT PDK1

PIP3

TORC2

AMPK

TSC1/2

PTEN

TORC1

S6K

S6

4EBP1

eIF4E-F-G

PI3K

p85 p110

LKB1

There are several p110 isozymes (a, b, g, d), each with its own p85 subunit

The PI3K pathway

Mechanisms of activation include amplification/ mutation of oncogenes, mutations in PIK3CA and AKT, and loss of tumor suppressors PTEN and LKB1

Comprehensive molecular portraits of human breast tumours

The Cancer Genome Atlas Network*

Nature, 4 October 2012

Luminal A 45%

Luminal B 29%

HER-2 39%

Basal 9%

All 36%

Crosstalk between ER and mTOR Signaling

• mTORC1 activates ER in a ligand-independent fashion1

• Estradiol suppresses apoptosis induced by PI3K/mTOR blockade2

• Hyperactivation of the PI3K/mTOR pathway is observed in endocrine-resistant breast cancer cells3

• mTOR is a rational target to enhance the efficacy of hormonal therapy

1. Yamnik, RL. J Biol Chem 2009; 284(10):6361-6369.

2. Crowder, RJ. Cancer Res 2009;69:3955-62.

3. Miller, TW. J Clin Invest 2010; 120(7):2406-2413. 10

Neoadjuvant (Ph 2): Adding Everolimus to Letrozole Improved Response Rates

Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; Ph, phase; RR , response rate; vs, versus. Baselga J, et al. J Clin Oncol. 2009;27(16):2630-2637.

Primary endpoint: RR at 16 weeks (palpation)

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: Ki67 by 57% vs 30% (P < 0.01)

BOLERO-2 (Ph 3): 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 metastatic BC

• Recurrence or progression after letrozole or anastrozole

• Refractory to letrozol/anastrozol

• Previous endocrine therapy and one chemotherapy allowed

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

Abbreviations: BC, breast cancer; ER+, estrogen receptor-positive; EVE, everolimus; EXE, exemestane; ORR, overall response rate; OS, overall survival; PFS, progression-free survival; Ph, phase; PK, pharmacokinetics; QOL, quality of life. Baselga J, et al. N Engl J Med. 2012;366(6):520-529.38

Baselga et al. N Engl J Med 2011

BOLERO-2: Patient Demographics, Baseline Disease Characteristics

Characteristic EVE + EXE

(n = 485) % PBO + EXE (n = 239) %

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

Race

White 74 78

Asian 20 19

Black 3 1

Other 3 2

ECOG performance status 0 60 59

Visceral disease 56 56

Measurable disease* 70 68

Metastatic site

Lung 29 33

Liver 33 30

Bone 76 77

*All other patients had ≥1 mainly lytic bone lesion. ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; PBO, placebo. Baselga J, et al. N Engl J Med. 2012;366(6):520-529. 39

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

0

20

40

60

80

100

Time (week)

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120

485 436 366 304 257 221 185 158 124 91 66 50 35 24 22 13 10 8 2 1 0

239 190 132 96 67 50 39 30 21 15 10 8 5 3 1 1 1 0 0 0 0

Censoring times

EVE 10 mg + EXE (n/N = 310/485)

PBO + EXE (n/N = 200/239)

HR = 0.45 (95% CI: 0.38-0.54)

Log-rank P value: < .0001

Kaplan-Meier medians

EVE 10 mg + EXE: 7.8 months

PBO + EXE: 3.2 months

Pro

ba

bil

ity (

%)

of

Eve

nt

PFS Based on Local Assessment at 18-mo

Follow-up in BOLERO-2 Confirms Earlier Reports

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

Piccart M, et al. ASCO 2012; abstract 559 (poster). 41

EVE 10 mg + EXE

PBO + EXE

Number of patients still at risk

HR = 0.38 (95% CI: 0.31-0.48)

Log-rank P value: < .0001

Kaplan-Meier medians

EVE 10 mg + EXE: 11.0 months

PBO + EXE: 4.1 months

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

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

Censoring times

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

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

20

40

60

80

100

Pro

ba

bil

ity (

%)

of

Eve

nt

Time (week)

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

Piccart M, et al. ASCO 2012; abstract 559 (poster).

PFS Based on Central Review at 18-mo Follow-up in

BOLERO-2 Confirms Earlier Reports and Local Assessment

42

Análisis de subgrupos y análisis exploratorios

43

BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent

in All Subgroups by Local and Central Review

• The effect of EVE+EXE treatment was consistent among prospectively

defined subgroups by local investigator and central review

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Hazard Ratio and 95% CI

0.38 11.00 4.10

0.32 11.33 3.94

0.50 10.84 4.17

0.41 13.86 4.17

0.38 9.40 4.11

0.33 13.83 4.14

0.36 5.72 1.61

0.39 22.18 4.21

0.37 10.91 3.94

724

449

275

137

275

274

38

106

618

N

All

Local Central

Age group

< 65

≥ 65

Region

Asia

Europe

North America

Other

Japanese patients

Japan

Non-Japan

Median PFS, mo

HR EVE+EXE PBO+EXE

0.45 7.8 3.2

0.38 8.31 2.92

0.59 6.83 4.01

0.60 8.48 4.14

0.45 7.16 2.83

0.38 8.41 2.96

0.40 4.53 1.48

0.58 8.54 4.17

0.42 7.16 2.83

Favors EVE+EXE

0.42 13.86 4.17

0.38 10.91 4.14

0.15 NA 1.45

0.39 12.45 4.21

0.35 10.91 2.79

0.43 13.14 4.14

0.37 11.01 4.11

0.27 16.59 5.82

0.46 8.31 2.89

0.43 9.56 4.07

0.19 19.52 6.51

143

547

34

435

274

184

523

318

406

573

151

Race

Asian

Caucasian

Other

Baseline ECOG performance status

0

1, 2

PgR status

Negative

Positive

Presence of visceral metastasis No

Yes

Bone only lesions at baseline

No

Yes

0.62 8.48 4.14

0.42 7.36 2.96

0.25 6.93 1.41

0.48 8.25 4.11

0.39 6.93 2.76

0.51 6.93 2.83

0.41 8.08 3.32

0.41 9.86 4.21

0.47 6.83 2.76

0.48 6.90 2.83

0.33 12.88 5.29

Favors PBO+EXE

N

Median PFS, mo

HR EVE+EXE PBO+EXE

0 0.2 0.4 0.6 0.8 1 1.2 1.4

Hazard Ratio and 95% CI

Favors EVE+EXE Favors PBO+EXE

Abbreviations: EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival. 44

0.40 10.91 4.14

0.37 11.04 4.14

0.39 10.91 4.11

0.38 15.01 6.80

0.38 10.91 4.11

0.39 17.97 7.00

0.38 11.01 4.11

0.24 11.10 6.80

114

610

620

104

653

71

691

33

Sensitivity to prior hormonal therapy

No

Yes

Only received prior adjuvant therapy*

No

Yes

Only received prior adjuvant hormonal

therapy with chemotherapy*

No

Yes

Only received prior adjuvant hormonal

therapy without chemotherapy*

No

Yes

0.55 6.83 2.83

0.43 8.05 3.94

0.46 7.00 2.96

0.40 11.70 4.17

0.46 7.06 2.96

0.40 12.29 4.17

0.45 7.59 3.19

0.37 11.10 4.12

Subgroup analysis of PFS by local investigator review (yellow) and central review (blue).

*Does not include patients who received neoadjuvant therapy.

Abbreviations: CI, confidence interval; ECOG, Eastern Cooperative Oncology Group; EVE, everolimus; EXE, exemestane; HR, hazard ratio; NSAI, nonsteroidal aromatase inhibitor; PBO,

placebo; PFS, progression-free survival ; PgR, progesterone receptor.

0 0.2 0.4 0.6 0.8 1 1.2 1.4 Hazard Ratio and 95% CI

0.38 11.00 4.10

0.24 19.52 6.51

0.53 8.28 4.17

0.35 8.48 2.83

0.44 10.58 5.55

0.35 11.27 4.07

0.35 13.83 4.21

0.42 7.13 2.83

0.46 9.95 4.21

0.32 12.02 3.32

724

219

232

271

231

493

538

186

326

398

N

All

Number of organs involved

1

2

Prior chemotherapy

No

Yes

Prior chemotherapy

for metastatic disease

No

Yes

Prior use of hormonal therapy

other than NSAI

No

Yes

Median PFS, mo

HR EVE+EXE PBO+EXE

0.45 7.8 3.2

0.40 11.50 4.37

0.52 6.70 3.45

0.41 6.93 2.56

0.53 6.97 3.45

0.41 8.18 3.19

0.46 8.31 4.07

0.38 6.11 2.69

0.52 7.00 4.11

0.39 8.11 2.76

Favors EVE+EXE Favors PBO+EXE

≥ 3

Local Central N

Median PFS, mo

HR EVE+EXE PBO+EXE

0 0.2 0.4 0.6 0.8 1 1.2 1.4 Hazard Ratio and 95% CI

Favors EVE+EXE Favors PBO+EXE

BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent

in All Subgroups by Local and Central Review

45

BOLERO-2 (18-mo f/up): PFS Benefits Were

Comparable in Elderly vs Younger Patients

Abbreviations: CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo; PFS, progression-free survival; wk, weeks.

Pritchard, KI, et al. ASCO 2012; abstract 551 (poster). 46

BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable In Patients

With (A) Visceral Metastases, (B) Without Visceral Metastases, and

(C) With Bone-Only Metastases

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

Reprinted from Campone M, et al. Eur J Cancer. 2013 June 1 Epub.

0

20

40

60

Pro

bab

ility

of

Even

t, %

Pro

bab

ility

of

Even

t, %

80

100

Time, wk Time, wk

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114

EVE+EXE

PBO+EXE

Patients at risk

271 240 192 157 128 107 88 72 52 38 25 22 16 12 11 7 5 4 1 0

135 108 66 44 32 23 18 14 11 8 4 4 3 1 0 0 0 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 96 102 108 114 120

EVE+EXE

PBO+EXE

Patients at risk

214 196 174 147 129 114 97 86 72 53 41 28 19 12 11 6 5 4 1 1 0

104 82 66 52 35 27 21 16 10 7 6 4 2 2 1 1 1 0 0 0 0

A B C HR=0.47 (95% CI, 0.37-0.60)

Kaplan-Meier medians

EVE+EXE: 6.83 mo

PBO+EXE: 2.76 mo

HR=0.41 (95% CI, 0.31-0.55)

Kaplan-Meier medians

EVE+EXE: 9.86 mo

PBO+EXE: 4.21 mo

Censoring times

EVE+EXE (n/N=122/214)

PBO+EXE (n/N=84/104)

Censoring times

EVE+EXE (n/N=188/271)

PBO+EXE (n/N=116/135) 0

20

40

60

80

100

Time, wk

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

EVE+EXE

PBO+EXE

Patients at risk

105 95 88 75 72 65 53 47 41 30 20 13 7 6 5 3 2 1 0

46 35 30 24 19 14 12 10 5 3 1 1 1 0 0 0 0 0 0

EVE+EXE (n/N=48/105)

PBO+EXE (n/N=33/46)

Censoring Times

EVE+EXE: 12.88 mo

Kaplan-Meier medians

PBO+EXE: 5.29 mo

HR=0.33 (95% CI, 0.21-0.53)

Pro

gres

sio

n-F

ree

Surv

ival

, %

47

BOLERO-2 (18-mo f/up): PFS Benefits Were Comparable

In Patients With Visceral Mets Regardless of ECOG PS

• Among patients with visceral involvement at baseline and ECOG

PS = 0, median PFS was 6.83 months for EVE+EXE treated patients

and 2.76 months for PBO+EXE treated patients

• Among patients with visceral involvement at baseline and ECOG

PS ≥ 1, EVE+EXE extended the median PFS (6.77 months)

compared with PBO+EXE (1.45 months)

Everolimus + Exemestane Placebo + Exemestane

Pts Events %

Median

PFS,

mo Pts Events %

Median

PFS,

mo Hazard Ratio

(95%Cl)

Pts with visceral

disease at baseline 271 188 69.4 6.83 135 116 85.9 2.76 0.47 (0.37,

0.60)

ECOG PS = 0 167 114 68.3 6.83 84 70 83.3 2.79 0.54 (0.40,

0.73)

ECOG PS ≥ 1 100 71 71 6.77 48 43 89.6 1.45 0.35 (0.23,

0.52)

Abbreviations; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; Mets, metastases;

PFS, progression-free survival.

Campone M, et al. Eur J Cancer. 2013 June 1 Epub. 48

BOLERO-2 (18-mo f/up): Response Rates & Clinical

Benefit Were Significantly Higher in the Everolimus Arm

12,6%

51,3%

1,7%

26,4%

0

10

20

30

40

50

60

Response Clinical Benefit

Everolimus + Exemestane

Placebo + Exemestane

P < 0.0001

Pe

rce

nt

Piccart M, et al. ASCO 2012; abstract 559 (poster).

P < 0.0001

49

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

a Includes patients who also had prior neoadjuvant therapy.

Piccart M, et al. SABCS 2012; poster P6-04-02.

BOLERO-2 (18-mo f/up): Everolimus Improved PFS in

Patients Progressing After Adjuvant Therapya

Subgroup

EVE+EXE

(N = 100)

PBO+EXE

(N = 37)

Any adjuvant therapya 100 37

Adjuvant endocrine therapy onlya 26 9

Adjuvant endocrine therapy + chemotherapya 74 28

0

20

40

60

Pro

bab

ility

of

Eve

nt,

% 80

100

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

EVE+EXE PBO+EXE

Patients at risk

Kaplan-Meier medians EVE+EXE: 11.50 mo PBO+EXE: 4.07 mo

HR = 0.39 (95% CI, 0.25-0.62)

Censoring times EVE+EXE (n/N = 56/100) PBO+EXE (n/N = 30/37)

100 93 86 76 66 57 50 43 41 28 21 17 10 9 9 5 4 3 0 37 33 22 17 11 10 8 7 7 4 3 2 2 2 1 1 1 0 0

• EVE+EXE

improved PFS in

pts who received

adjuvant

endocrine

therapy ±

chemotherapy

• These data

support the

efficacy of EVE

+EXE as first-

line therapy in

the advanced

setting

50

Progression-free survival

BC, breast cancer; CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; PBO, placebo.

Campone M, et al, ASCO 2013 abstract 557 (poster)

BOLERO-2 (18-mo f/up): Everolimus Improved PFS in Patients Who Received Prior Chemotherapy for Advanced BC

51

0

20

40

60

80

100

0 6 12

EVE+EXE

PBO+EXE

Censoring times

HR = 0.38 (95% CI, 0.27-0.53)

Kaplan-Meier medians

EVE+EXE = 6.1 mo

PBO+EXE = 2.7 mo

Time, wk

Pat

ien

ts W

ith

ou

t An

Eve

nt,

%

Conclusion

• Demonstrated the efficacy of EVE+EXE in patients who received chemotherapy for advanced BC before

BOLERO-2 study entry or in patients who recurred during or after adjuvant endocrine therapy, consistent

with the overall population

Local Assessment Central Assessment

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

HR = 0.42 (95% CI, 0.27-0.65)

Kaplan-Meier medians

EVE+EXE = 7.1 mo

PBO+EXE = 2.8 mo

EVE+EXE

PBO+EXE

Censoring times

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

Time, wk

0

20

40

60

80

100

Pat

ien

ts W

ith

ou

t An

Eve

nt,

%

BOLERO-2: Safety

EVE + EXE (n = 482), % PBO + EXE (n = 238), %

Grade Grade

AE (Preferred Term)

All 1 2 3 4 All 1 2 3 4

Stomatitis 59 29 22 8 0 12 9 2 <1 0

Rash 39 29 9 1 0 7 5 2 0 0

Fatigue 37 18 14 4 <1 27 16 10 1 0

Diarrhoea 34 26 6 2 <1 19 14 4 <1 0

Nausea 31 21 9 <1 <1 29 21 7 1 0

Decreased appetite 31 19 10 1 0 13 8 4 1 0

Weight decreased 28 10 16 2 0 7 3 5 0 0

Cough 26 21 4 1 0 12 8 3 0 0

Pneumonitis* 16 7 6 3 0 0 0 0 0 0

Hyperglycaemia* 14 4 5 5 <1 2 1 1 <1 0

AE, adverse event; EVE, everolimus; EXE, exemestane; PBO, placebo. *Incidence <25%, but AE of special interest. Piccart M, et al. Presented at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium. Poster P6-04-02. 52

BOLERO-2 (18-mo f/up): Adding Everolimus to

Exemestane Maintained QOLa

Abbreviations: EORTC, QLQ-C30 European Organization for Research and Treatment of Cancer Core Cancer Quality of Life Questionnaire;

EVE, everolimus; EXE, exemestane; PBO, placebo; QOL, quality of life. a QOL evaluated using the EORTC-QLQ-30 Global Health Scale with 5% change from baseline. b Not statistically significant. Note that these statistical tests were not adjusted for multiple analyses, and should be interpreted with caution.

Burris H, et al. Cancer. 2013;119:1908-1915.

Log-rank P value = .0084b

EVE + EXE: 8.3 months

PBO + EXE: 5.8 months

100

90

80

70

60

50

40

30

20

10

0

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

485

239

EVE + EXE

PBO + EXE

427

201

305

116

245

83

198

62

176

49

145

36

119

27

99

19

71

16

52

7

43

6

29

3

18

1

13

0

9

0

8

0

Patients still at risk n

Pro

bab

ility

of

Eve

nt,

%

Censoring times

EVE + EXE (n = 485) PBO + EXE (n = 239)

Time to Deterioration in QOL, wk

Time to Deterioration for EORTC QLQ-30 GHS

5% change from baseline

53

BOLERO-2 (39-Month) Final OS Analysis

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®. CI, confidence interval; EVE, everolimus; EXE, exemestane; HR, hazard ratio; IXRS®, Interactive Voice and Web Response System; PBO, placebo. Piccart M, et al. Presented at EBCC-9; 19-21 March 2014; Glasgow, Scotland. Abstract 1LBA. 54

New from EBCC 2014; median line and

box/4.4 mo added

4.4-month difference

At 39 months’ median follow-up, 410 deaths had occurred

• 55% of patients (n = 267) in the EVE + EXE arm • 60% of patients (n = 143) in the PBO + EXE arm

Median OS was 4.4 months longer for EVE + EXE vs PBO + EXE

BOLERO-2 (18-mo f/up): Summary

• Addition of everolimus to exemestane prolongs PFS in patients

with ER+ HER2- breast cancer refractory to initial nonsteroidal

aromatase inhibitors1

– Local Assessment: Median 7.8 vs 3.2 months (HR = 0.45, P

< .0001)

– Central Assessment: Median 11.0 vs 4.1 months

(HR = 0.38, P < .0001)

– Benefit is observed in all subgroups

• Adverse events were consistent with previous experience with

everolimus1

• Time to deterioration of QOL was significantly longer with the

addition of everolimus to exemestane2

Abbreviations: ER+, estrogen receptor-positive; HER2-, human epidermal growth factor receptor 2-negative; HR, hazard ratio;

PFS, progression-free survival; QOL, quality of life; vs, versus.

1. Piccart M, et al. ASCO 2012; abstract 559 (poster); 2. Beck JT, et al. ASCO 2012; abstract 539 (poster). 55

Biomarker Analysis: Objective and Methods

• 3,230 exons of 182 oncogenes and tumor suppressor genes were

sequenced using next generation sequencing (NGS) on 309 FFPE

archival tissue samples

• Statistical methods

– KM curves and summary descriptive statistics calculated for each

genetic alteration. No hypothesis tests were conducted

– Hazard ratios (95% CI) from a Cox Proportional Hazards model was

computed to assess differences in PFS across EVE and EXE arms

for each genetic alteration defined subgroup (Alt and WT)

– Multi-gene model adjusted for covariates significantly imbalanced

across treatment arms in Alt or WT sub-groups

56

Abbreviations: Alt, genetically altered; CI, confidence interval; EVE, everolimus;

EXE, exemestane; KM, Kaplan-Meier; PFS, progression-free survival; WT, wild type.

NGS Population Is Representative of the

Trial Population

• No major baseline

clinical and

demographic

differences observed

between ITT and NGS

populations

• Clinical efficacies are

comparable between

the populations

Population N (% ITT) N Events (%) PFS (months)

Median (95%CI) HR (95%CI)

ITT—EVE 485 293 (60.4%) 7.8 (6.9-8.5) 0.45 (0.38–0.54)

ITT—PBO 239 197 (82.4%) 3.2 (2.8-4.1)

NGS—EVE 157 (32.4%) 94 (59.9%) 7.0 (6.2-9.6) 0.40 (0.28–0.55)

NGS—PBO 70 (29.3%) 59 (84.3%) 2.6 (1.7-4.2)

0 200 400 600 800

0.0

0.2

0.4

0.6

0.8

1.0

Time, days

Pro

bab

ilit

y o

f

Pro

gre

ss

ion

-Fre

e S

urv

ival

EVE.ITT

EVE.NGS

PBO.ITT

PBO.NGS

ITT = 724

NGS = 227

57

Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; ITT, intent to treat; NGS, next

generation sequencing ; PBO, placebo; PFS, progression-free survival.

1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 1 0 0 0 1 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 1 1 1 1 1 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 1 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 1 0 1 1 0 1 0 0 0 0 0 0 0 0 0 1 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 1 0 0 0 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 1 0 0 1 1 1 1 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 1 1 1 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0

1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 1 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0

1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 0 0 0 0 0 0

0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0 0 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 1 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 1 0 0

1 0 0 0 0 1 0 0 0 1 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0

0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 1

Frequency of Genetic Alterations in

Key Pathways

Mutation type

Missense NS_FS_Splice_Indel Amplification Loss

Gene %

PIK3CA 47.6

CCND1 31.3

TP53 23.3

FGFR1 18.1

MCL1 15.9

MYC 14.1

CDH1 10.1

MDM4 10.1

GNAS 7.5

ARID1A 6.2

PTEN 5.7

AKT1 5.7

MAP2K4 5.3

MDM2 4.4

RUNX1 4.4

ESR1 4.0

Tumor samples

58

Impact on Treatment by Genetic Status The Most Frequently Altered Single Genes and Pathways

Positive treatment effect in favor

of everolimus across the various

genetic marker subgroups

Pathway composition

• PI3K: PIK3CA, PTEN, AKT (PIK3CA Alt:

47.6%, total alteration: 55.5%)

• Cell Cycle: CCND1, CDK4, CDK6,

CDKN2A, CDKN2B, (CCND1 Alt: 31.3%,

total alteration: 35.7%)

• p53: TP53, MDM2, MDM4 (TP53 Alt:

23.3%, total alteration: 36.1%)

• FGFR1/2: FGFR1, FGFR2 (FGFR1 Alt:

18.1%, total alteration: 21.1%)

log10 (hazard)

-0.6 -0.4 -0.2 0.0

WT : PI3K

Alt : PI3K

WT : PIK3CA

Alt : PIK3CA

WT : Cell Cycle

Alt : Cell Cycle

WT : CCND1

Alt : CCND1

WT : p53

Alt : p53

WT : TP53

Alt : TP53

WT : FGFR1/2

Alt: FGFR1/2

WT : FGFR1

Alt : FGFR1

EVE+EXE better

Genetically altered (Alt)

Wild Type (WT)

HR of NGS population

59

Patients With No or Single Genetic Alteration in

PIK3CA/PTEN/CCND1 or FGFR1/2 Derive Greater PFS Benefit

With EVE

60

Subgroup Definition Size, %

WT No alteration in PIK3CA AND PTEN AND FGFR1/2 AND CCND1 Minimal

27% 76%

Single Single alteration only in PIK3CA OR PTEN OR FGFR1/2 OR CCND1 49%

Multiple Two or more alterations in PIK3CA OR PTEN OR FGFR1/2 OR

CCND1 genes Multiple 24% 24%

Subgroup N Events (%) Median

PFS (d) HR* (95%CI)

EVE: WT 43 19 (44%) 356 0.24

(0.11 - 0.54) PBO: WT 18 14 (78%) 203

EVE: Single 76 48 (63%) 214 0.26

(0.16 - 0.43) PBO: Single 35 31 (89%) 77

EVE: multiple 38 27 (71%) 138 0.78

(0.39 - 1.54) PBO: multiple 17 14 (82%) 128

*HR adjusted with imbalanced covariates

Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo;

PFS, progression-free survival; WT, wild type.

Greater PFS Benefit With EVE in Patients With Minimal

Alterations in PIK3CA/PTEN/CCND1 or FGFR1/2

61

0 100 200 300 400 500 600 700

Time, days

0.0

0.2

0.4

0.6

0.8

1.0 EVE.PI3K/FGFR/CCND1_.WT/single

EVE.PI3K/FGFR/CCND1_.multiple

PBO.PI3K/FGFR/CCND1_.WT/single

PBO.PI3K/FGFR/CCND1_.multiple

HR (95% CI):

0.27 (0.18 - 0.41)

Pro

ba

bil

ity o

f

Pro

gre

ss

ion

-Fre

e S

urv

iva

l

Abbreviations: CI, confidence interval; EVE, everolimus; HR, hazard ratio; PBO, placebo; PFS,

progression-free survival; WT, wild type.

Conclusiones Biomarcadores BOLERO-2

• El análisis exploratorio retrospectivo sugiere que:

– Ninguna de las 4 alteraciones más frecuentes encontradas tiene un valor predictivo si se consideran de forma individual.

– El mayor beneficio se observa en pacientes WT o con una única alteración de PI3KCA/PTEN/CCND1/FGFR 1-2 (76% población NGS)

• Este análisis requiere una validación, pero ayudan a diseñar nuevos ensayos clínicos para pacientes con cáncer de mama avanzado HER2-/RE+.

62

Futuro

• ¿Cambia BOLERO-2 el paradigma del tratamiento de las pacientes post-menopausicas RE+/HER2- resistentes a IA no esteroideo?

• ¿Cuál es el futuro en la inhibición de la vía de PI3K-Akt-mTORC más allá de everolimus?

• Nuevas dianas más allá de la vía PI3K-Akt-mTORC

CMM

Selección del Tratamiento Sistémico

• RE+ y/o RP +

• ILE prolongado

• Respuesta previa a HT en Enf. Avanzada

• RE- y RP-

• ILE Corto

• Enfermedad Visceral Rápidamente Progresiva

• Resistente a HT previa en Enf. Avanzada

HORMONOTERAPIA

QUIMIOTERAPIA

Bevacizumab

HER2 positivo

Trastuzumab, Lapatinib

Soporte

Bifosfonatos (Mts Óseas)

Cortesía Dr. César Rodríguez, Salamanca

Everolimus/Exe

Bolero-6

EVE 10 mg daily +

EXE 25 mg dail

EVE 10 mg/day R

Endpoints • Primary: PFS (local assessment)

• Secondary: OS, ORR, CBR, Safety

1:1:1

• Postmenopausal ER+

• Unresectable locally advanced or metastatic BC

• Recurrence or progression after letrozole or anastrozole

• Refractory to letrozol/anastrozol

• Previous endocrine therapy and one chemotherapy allowed

Stratification: presence of visceral metastases

Capecitabine

PI3K inhibitors

Drug Source Target(s)

BYL719 Novartis PI3Kα

GDC-0032 Genentech PI3Kα

MLN-1117 Millenium PI3Kα

CAL-101 Calistoga PI3Kd

XL-147 Exelixis/Sanofi Pan-PI3K

BKM120 Novartis Pan-PI3K

GDC-0941 Genentech Pan-PI3K

PKI-587 Pfizer Pan-PI3K

Co-primary

• PFS (full)

• PFS (PI3K +)

Co-key secondary

• Overall Survival

(full & PI3K+)

Secondary

• Safety (all)

• PK

• QOL (full &

PI3K+)

Exploratory

• Biomarkers

BKM120 (buparlisib)100 mg p.o. daily Faslodex i.m. on Days 1 & 15 of cycle 1 and Day 1 of every cycle

Placebo p.o. daily Faslodex i.m. on Days 1 & 15 of cycle 1 and Day 1 of every cycle

BELLE-2: ER+ HER2- 2nd/3rd line (AI resistant)

BELLE-3: ER+ HER2- 3rd/4th line (AI and mTORi resistant)

BKM120 (buparlisib)100 mg p.o. daily Faslodex i.m. on Days 1 & 15 of cycle 1 and Day 1 of every cycle

Placebo p.o. daily Faslodex i.m. on Days 1 & 15 of cycle 1 and Day 1 of every cycle

R 1:1 N = 842

(334 PI3K+*)

BKM120 in ER+ Breast Cancer Pivotal Trials Stratification by PI3K status and co-primaries

R 2:1 N = 615

(246 PI3K+*)

* PI3K+ is PI3K activation = PI3KCA mutation or PTEN mutation or PTEN loss of expression

Key Features

• Early safety look

• Interim futility 2013

PD 0332991 (CDK4/6 inhibitor) + Letrozole vs Letrozole: Study Design

• 2-part, randomized phase II study

PD 0332991 125 mg QD + Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Postmenopausal women

with ER-positive, HER2-negative

advanced breast cancer

(N = 66)

Stratified by disease site (visceral, bone only, or other); Disease-Free Interval (>12 vs ≤12 mo from end

of adjuvant to recurrence or de novo advanced disease)

PD 0332991 125 mg QD + Letrozole 2.5 mg QD

Letrozole 2.5 mg QD

Postmenopausal women

with ER-positive, HER2-negative

advanced breast cancer, CCND1 amp,

and/or p16 loss (N = 99)

Part 1 Part 2

All patients continued assigned treatment until disease progression, withdrawal of consent, or unacceptable toxicity with follow-up tumor assessment every 2 mos

Finn RS, et al. SABCS 2012. Abstract S1-6.

Stratified by disease site (visceral, bone only, or other); Disease-Free Interval (>12 vs ≤12 mo from end of

adjuvant to recurrence or de novo advanced disease)

70

TRIO-18 (PALOMA 1) Final results:Letrozole

palbociclib (CDK4/6 inhibitor)

71

TRIO-18 (PALOMA 1) Evaluación inicial de

SG:Letrozole palbociclib (CDK4/6 inhibitor)

Conclusiones

• El conocimiento de los mecanismos de resistencia a la terapia endocrina marca el desarrollo de nuevas estrategias de tratamiento.

• La inhibición de mTOR con everolimus + exemestano es una nueva opción para pacientes resistentes a IA no esteroideo.

• Las dianas más prometedoras son la vía de PI3K-Akt-mTORC, y el ciclo celular (inhibidores de CDK4/6)

Muchas Gracias