Il trattamento della malattia metastatica ormonoresponsiva: una visione d insieme. Sapienza Università di Roma

(1)

ONCOLOGIA:

ESPERIENZE

CLINICHE

A CONFRONTO.

IL CARCINOMA

MAMMARIO

METASTATICO

CHIETI

12 NOVEMBRE 2013

SALA FONDAZIONE D’ANNUNZIO CENTRO SCIENZE

DELL’INVECCHIAMENTO CE.S.I. Via Colle dell’Ara 66100 - Chieti

Giuseppe Naso MD

Associate Professor of Medical Oncology Head of Translational Oncology

Clinical Head of Breast Unit

Sapienza Università di Roma

Il trattamento della malattia metastatica ormonoresponsiva: una visione d’insieme

(2)

Breast Cancer Epidemiology

Italy

~ 47,000 New EBC/year

~ 15,000 New MBC

(3)

Months 60 48 36 24 12 0 C umulat iv e surv iv a l 0.8 0.6 0.4 0.2 0.0 1995–2000 1990–1994 1985–1989 1980–1984 1974–1979

Giordano S, et al. Cancer 2004

Ca Mammario Metastatico

(4)

Median Overall

Survival after

relapse

TNBC

9-12 months

ER pos.ve

24-36

months

Andre F et al. JCO 2004;22:3302-3308

Hormone Receptor positive metastatic Breast

Cancer: a different disease

(5)

No Response

Diagnosis of metastatic breast cancer Determination of sites and extent of disease

Assessment of HER2, hormonal receptor status, disease-free interval, age, and menopausal status

No life-threatening disease Hormone-responsive

Hormone-unresponsive, or Life-threatening disease 1st-line hormonal therapy 1st-line chemotherapy

Response _No _Response

2nd-line hormonal therapy

2nd-line chemotherapy Progression

Progression

3rd-line hormonal therapy Response

No Response

3rd-line chemotherapy

Supportive care

(6)

(7)

(8)



Symptomatic/ poor PS

Palliation



Elderly/indolent disease/poor PS

Improve TTP & QoL



Amenable to locoregional control Increase response rate



Young/good PS visceral mts

Prolong survival

Characteristics

Treatment

Objectives

(9)

(10)

(11)

(12)

Tamoxifene

(SERM)

(13)

Trattamento della malattia

metastatica

Tamoxifen 1269 Yes Yes 32

Oophorectomy 3380 Yes 33

Progestins 3479 Yes Yes 31

A.I. 1153 Yes 32

LH-RH analogs 293 Yes 40

Estrogens 1683 Yes 26

Androgens 2250 Yes Yes 21

Adrenalectomy 3739 Yes Yes 32

Hypophysectomy 1174 Yes Yes 36

(16-52) (21-41) (9-67) (16-43) (32-45) (15-38) (10-38) (23-46) (22-58) Number of patients Effective in Pre-MP Post-MP Response rate (%) (range)

(14)

(15)

Selective Estrogen Receptor Modulators

• First generation

– Toremifene, Droloxifene, Idoxifene

• Second /Third generation

– Raloxifene, Arzoxifene, EM-800, etc.

Status: Advantage over Tam not

shown

(16)

(17)

Aromatase Inhibitors Versus Tamoxifen as First-Line

Therapy in Metastatic Breast Cancer

Patients

No. OR, _% Benefit Clin. % TTP mo ER unknown % Nabholtz*

J Clin Oncol 18:3758, 2000 ANA

170 vs

182 21 vs 17 59p 0.0098 vs 46

11 vs 6

p 0.005 11 vs 11

Bonneterre*

J Clin Oncol 18:3748, 2000 ANA

340 vs 328 32 vs 32 56 vs 55 8 vs 8 56 vs 54 Mouridsen^ J Clin Oncol 21:2101, 2003; LET 453 vs ₄₅₄ 30 vs 20 49 vs 38 p 0.004 9 vs 6 p <0.0001 34 vs 33 Paridaens^

J Clin Oncol 2008 EXE

182 vs

189 46 vs 31 66 vs 49 10p 0.028 vs 6 15 vs 11

(18)

0 10 20 30 40 50 60 70 0 10 20 30 40 50 60 70 OR Rate (%) Benefit (%) Clinical AN = anastrazole TX = Tamoxifene TTP (month) (month) TTF Pts = 353 (171 vs 182) Pts = 668 (340 vs 328)

*

* OR Rate

(%) Benefit (%) Clinical (month) TTP (month) TTF

Bonneterre et al, J Clin Oncol 2000 Nabholtz et al, J Clin Oncol 2000

Anastrozole versus Tamoxifen

60% pts included no previous Adjv ET

20% pts included previous Tam Adjv

10% pts included previous Tam Adjv

70% pts included no previous Adjv ET

Exclusion Criteria: Adjv Tam received within 12 months before study entry

(19)

Letrozole/Exemestane vs Tamoxifene

OR Rate (%) Clinical _Benefit (%)

*

EX = exemestane TX = tamoxifene TTP (month) (month) TTF

*

_*

Pts = 907

OR Rate (%) Clinical _Benefit (%) TTP (month)

Pts = 371

LE = letrozole

*

Paridaens et al, JCO2008 Mouridsen et al, J Clin Oncol 2001

80% pts included no previous Adjv ET

20% pts included previous Adjv Tam

(20)

(21)

17ESTRADIOLO AF1 AF2

TAMOXIFENE

ERE ERE ATTIVAZIONE PARZIALE DELLA TRASCRIZIONE (solo AF1) ANTAGONISTA AGONISTA

INIBITORI DELLE

AROMATASI

BLOCCO COMPLETO DELLA TRASCRIZIONE, PERSISTENZA DELLA

VIA RECETTORIALE ESTROGENICA

FULVESTRANT

TRASCRIZIONE, ABOLIZIONE DEL BLOCCO COMPLETO DELLA SEGNALE MITOGENICO

ESTROGENO-MEDIATO RE AF1 AF2 ERE ERE RE AF1 AF2 RE ERE ERE

DIFFERENTE MECCANISMO D’AZIONE:

SERM, IA, SERD

17ESTRADIOLO

AF1

AF2

(22)

0 10 20 30 40 50 60 70 80 90 100 1 5 10 50 100 300 1000 3000 10000

Concentrazione (nM)

Per

centu

ae d

i inib

izi

on

e

E2 Faslodex Tam

SELETTIVITA

’

DEL LEGAME 3H-ESTRADIOLO/RE

(23)

(24)

(25)

PK model of plasma fulvestrant

0 5 10 15 20 25 30 35 0 28 56 84 112 140 168 196 224 252 280 Time (days) Pl a s m a c o n c e n tra tio n o f fu lv e s tra n t (n g /m L )

Standard Dose Regimen Loading Dose Regimen High Dose Regimen

Auc=8

(26)

Approved Dose

(AD)

250 mg 250 mg 250 mg

Day 0 Day 28 Monthly

Loading Dose

(LD)

500 mg 250 mg 250 mg 250 mg

Day 0 Day 14 Day 28

High Dose

(HD)

500 mg 500 mg 500 mg _{500 mg} Day 0 Monthly Monthly Day 14 Day 28

(27)

(28)

CONFIRM: Effect of Fulvestrant 500 mg vs

250 mg on Survival in Postmenopausal Women

• Baseline characteristics appeared well balanced between treatment arms

– Subsequent therapies were well balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one third receiving other hormonal therapy

Outcome

Timing of

Analysis

Fulvestrant

500 mg

Fulvestrant

250 mg

HR (95% CI)

Median PFS

First*

6.5 mos

5.5 mos

0.80

‡

_(0.68-0.94)

Median OS

First*

25.1 mos

22.8 mos

0.84

§

_(0.69-1.03)

Median OS

Final

†

_{26.4 mos}

_{22.3 mos}

_0.81

¶

_(0.69-0.96)

*First analysis was performed at 50% maturity.

†_{Final analysis was performed at 75% maturity.} ‡ _{P = .006}

§_{P = .001}

¶_{P = .016}

(29)

(30)

FIRST: Study Design

• Randomized, open-label phase II trial

–

Primary endpoint: CBR, defined as CR, PR, or SD

for ≥ 24 wks

Postmenopausal women with previously untreated hormone receptor– positive advanced breast cancer (N = 205)

Fulvestrant 500 mg by intramuscular injection Days 0, 14, 28, and every 28 days thereafter

(n = 102)

Anastrozole 1 mg/day orally (n = 103) Until disease progression or other event requiring discontinuation Robertson JFR, et al.

(31)

FIRST Trial: efficacy Analysis

Primary EndPoint: Clinical Benefit Rate

CBRs of 72.5% and 67.0%, respectively

(32)

Robertson et al. Br Cancer Res Treatm 2012;136: 503

Median TTP: 23.4 vs 13.1 months 34 % reduction in risk of progression

An impressive results!

(secondary endpoint)

PHASE III TRIAL

FALCON

(33)

(34)

(35)

(36)

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

Aromatase Inhibitor + CDK4/6 Inhibitor

Improves PFS in ER+ MBC

0 0.2 0.4 0.6 0.8 1.0 0 6 10 12 14 Mos 16 20 22 28 PD 991 + LET (n = 84) 21 (25) 26.1 (12.7-26.1) PF S Prob abil it y Pts at Risk, n PD 991 + LET LET 84 81 75 57 60 38 53 29 43 22 35 17 25 11 3 1 1 1 24 26 18 8 2 4 0.3 0.5 0.7 0.9 0.1 LET (n = 81) 40 (49) 7.5 (5.6-12.6) 18 6 15 5 14 4 9 3 5 3 Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value 0.37 (0.21-0.63) < .001

An impressive results!

(Waiting for a phase III)

(37)

(38)

FACT: Phase III, Open-Label, Multicenter Trial

of Combined Fulvestrant and Anastrozole

Therapy

Fulvestrant im LD, 500 mg day 0, 250 mg days 14 and 28

then 250 mg monthly +

Anastrozole po, 1 mg daily

ER+ and/or PR+, at first relapse: After/during TAM > 12 mo After/during CT After/during AI >12 mo Postmenopausal or premenopausal rendered post-menopausal by adjuvant LHRH analogue*

R

*In these cases, the LHRH analog must be continued throughout the study period

N= 514

Bergh J et al. SABCS 2009;Abstract 23. Anastrozole po, 1 mg daily

(39)

11,4 months 12,4 months

(40)

mOS 37,8 months mOS 38,2 months

(41)

FACT: Efficacy

F + A (n=258) A (n=256) HR (95% CI) p-value

Best objective response1

Complete response (CR) Partial response (PR)

Stable disease (SD) ≥ 24 weeks

1.6% 14.3% 39.1% 1.6% 13.3% 40.2% —

Median time to progression

(months)

10.8

10.2

0.99 (0.81, 1.20) p = 0.91 Overall survival (months)

37.8

38.2

1.00 (0.76, 1.32) p = 1.00

(42)

Postmenopausal women with ER+ MBC: Previous TAM Previous AIs or CT > 12 months (N = 707) Anastrozole 1 mg/day PO + Fulvestrant LD 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg every 28 days (n = 355) Anastrozole 1 mg/day PO (n = 352)

Treatment until disease progression Stratified by previous adjuvant tamoxifen Women with progression encouraged to cross over to receive fulvestrant

Mehta RS, et al. SABCS 2011. Abstract S1-1.

SWOG S0226: Study Design



Primary endpoint: PFS

(43)

(44)

(45)

(46)

(47)

(48)

(49)

FACT

SWOG

Previous AdjEsTx

_69%

_40%

ORR%

_31,8

_NR

TTP mo

_10.8

₁₅

No previous adjuvant tamoxifen - _{(n = 414)}17.0 Previous adjuvant tamoxifen - _{(n = 280)}13.5

OS mo

_37.8

_47.7

No previous adjuvant tamoxifen - _{(n = 414)}47.7 Previous adjuvant tamoxifen - (n = 280) 49.6 Diagnosis of MBC 7% <1yr 39% Visceral disease 50% 50%

(50)

(51)

Cross-talk between different signal transduction

pathways is the best studied cause of resistance

Johnston S R Clin Cancer Res 2010;16:1979-1987

(52)

(53)

LTED

(54)

(55)

56

mTOR Inhibition Combines Effectively With

Hormonal Therapy in BC

4-HT, 4-hydroxytamoxifen.

Yamnik RL et al. J Biol Chem. 2009;284(10):6361-6369; Johnston SR. Clin Cancer Res. 2005;11(2 Pt 2):889S-899S.

Interaction between mTOR and ER

a

S6K1 mTOR Growth factors ERα P Ser167 Transcription ER-Responsive Element E

Cell proliferation

*P < 0.05, 2-tailed paired Student t test.

C el l proli fer ation ( absorbance 540 nm ) MDA-MB- 231 MCF7 ZR-75-1 T47D 0.7 0.6 0.5 0.4 0.3 0.2 0.1 0 * * Control Rapamycin 0.1μM 4-HT 0.1μM 4-HT+ rapamycin

(56)

Co-Targeting

mTOR and HR in HR+/HER2-ve ABC

TAMRAD1

( prior AI)

BOLERO 22,3

(prior Let or Ana)

TAM TAM + everolimus EXA + placebo EXA + everolimus 57 54 239 485 CBR % 42.1 61.1 p 0.045 25.5 50.5 p < 0.0001 Median PFS (m) 4.5 8.6 HR 0.54 p 0.002 4.1 11 HR 0.44 p<1x10-16 Median OS (m) 24 NR HR 0.45 p 0.007 NR NR

(57)

Postmenopausal women with ER-positive advanced breast

cancer who progressed on previous nonsteroidal AI therapy* (N = 724) Exemestane 25 mg/day + Everolimus 10 mg/day (n = 485) Exemestane 25 mg/day + Placebo (n = 239)

Treatment until disease progression or unacceptable toxicity Randomized 2:1; stratified by sensitivity to

previous hormonal therapy, presence of visceral metastases

*> 50% of patients in each arm with ≥ 3 previous therapies

BOLERO-2: Study Design

• Primary endpoint: PFS (investigator assessment)

• Secondary endpoints: OS, ORR, clinical benefit rate, safety, bone markers, PK

(58)

BOLERO-2: ORR and CBR by Local Assessment

• Significantly improved ORR and CBR in the everolimus +

exemestane group compared with the placebo + exemestane group

Everolimus + exemestane Placebo + exemestane p<0.0001

p<0.0001

7.1-months median follow-up 12.5-months median follow-up

p<0.0001 p<0.0001 ORR CBR ORR CBR Re spo n se rate by l oca l asse ssmen t (% )

(59)

BOLERO-2: PFS Central Assessment

• Significantly improved PFS for everolimus + exemestane group compared with the placebo + exemestane group

7.1-months median follow-up

HR=0.36, 95% CI (0.27–0.47) Log-rank p=3.3x10–15

Everolimus + exemestane: 10.6 months

Placebo + exemestane: 4.1 months

12.5-months median follow-up

HR=0.36 (95% CI: 0.28–0.45) p<1x10–16

Everolimus + exemestane: 11.0 months

Placebo + exemestane: 4.1 months

Time (weeks) Pr oba bi lity of e ven t ( %) Pr oba bi lity of e ven t ( %)

(60)

(61)

(62)

HDAC Inhibitors Mechanism of Action



HDAC inhibitors relax the structure of DNA making it more

accessible to RNA polymerases

40. Pathiraja TN, et al. J Mam Gland Biol Neoplasia. 2010;15:35-47.

Closed chromatin = genes off

Histone acetyltransferases (HATs) Histone deacetylases (HDACs) Open chromatin = genes on HDAC inhibitors AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC AC