SECUENCIA TRATAMIENTO HORMONAL CMM · FALCON: PFS in patients with or without visceral disease Post...

SECUENCIA TRATAMIENTO HORMONAL CMM

ELECCIÓN DE IA + INH CDK COMO PRIMERA LINEA

PALOMA2/MONALEESA2 SUBGRUPOS

¿APLICABLE A TODAS LAS PACIENTES?¿EXISTEN OTRAS OPCIONES EN PRIMERA LINEA?

¿TIENE CABIDA FULVESTRANT EN ESTE LIO?

Opciones de HT: Fulvestrant

Fulvestrant28

Mecanismo de acción de Fulvestrant (No-agonista)29

HO (CH2)9SO(CH2)3CF2

CF3

7

OH

Fulvestrant

AF1

ER+Attenuated

dimerisationReduced nuclear

localisation of inactiveER to ERE

ERE RNAPOL II

NOTRANSCRIPCION(no división cel tumoral)

No coactivatorrecruitment

AF1 + AF2INACTIVE

F F FF

F

ACCELERATED RECEPTOR

DEGRADATION

Nicholson RI, Johnston SR. Endocrine therapy-current benefits and limitations. Breast Cancer Res Treat. 2005;93 Suppl 1:S3-10.

Wakeling AE. Similarities and distinctions in the mode of action of different classes of antioestrogens. Endocr-Relat Cancer 2000; 7: 17–28

HT: Hormonoterapia

4. DATOS CLÍNICOS

4.1 Indicaciones terapéuticas

Faslodex está indicado para el tratamiento de mujeres

posmenopáusicas con cáncer de mama localmente

avanzado o metastásico y con receptor de estrógeno positivo:

• no tratadas previamente con terapia endocrina, o

• cuya enfermedad ha recidivado durante o después del

tratamiento adyuvante antiestrogénico, o bien

cuya enfermedad ha progresado a un tratamiento

antiestrogénico.

http://ec.europa.eu/health/documents/community-register/html/h269.htm

http://ec.europa.eu/health/documents/community-register/html/h269.htm

http://www.ema.europa.eu/docs/en_GB/document_library/Minutes/2017/08/WC500232800.pdf

Faslodex (fulvestrant) receives EU approval for use in 1st-line hormone receptor-positive advanced breast cancer on 26th July 2017

FALCON: Phase III study design

• Randomised, double-blind, parallel-group, international, multicentre study

• Follow-up for disease progression and survival

• Randomisation of 450 patients was planned to achieve 306 progression events; if the true PFS HR was 0.69 this would provide 90% power for statistical significance at the 5% two-sided level (log-rank test)

• Stratification factors: prior chemotherapy for advanced disease (yes / no); measurable vs. non-measurable disease (at baseline); locally advanced vs. metastatic disease

• Subgroup analysis of PFS for pre-defined baseline covariates

aAssessed via RECIST 1.1, surgery / radiotherapy for disease worsening, or death; bInterim analysis at the time of PFS analysis EDoCB, expected duration of clinical benefit; EDoR, expected duration of response; FACT-B, Functional Assessment of Cancer Therapy – Breast; TOI, Trial Outcome Index

• Postmenopausal women• Locally advanced or

metastatic breast cancer• ER+ and / or PgR+• HER2-• Endocrine therapy-naïve

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

every 28 days)

+ placebo to anastrozole

Anastrozole 1 mg (daily PO)

+ placebo to fulvestrant

Primary endpoint: PFSa

Secondary endpoints1:1 • OSb

• ORR

• CBR

• DoR, EDoR

• DoCB,

EDoCB

• HRQoL

(FACT-B

total and

TOI)

• Safety

60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005

FALCON: Primary endpoint, PFS

A circle represents a censored observation

HR 0.797 (95% CI 0.637, 0.999); p=0.0486

Median PFS

Fulvestrant: 16.6 months

Anastrozole: 13.8 months

Number of patients at

risk:Fulvestrant

Anastrozole

230

232

187

194

171

162

150

139

124

120

110

102

96

84

81

60

63

45

44

31

24

22

11

10

2

0

0

0

Pro

port

ion o

f patients

aliv

e a

nd

pro

gre

ssio

n fre

e

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.00 3 6 9 12 15 18 21 24 27 30 3633 39

0.2

Fulvestrant (n=230)

Anastrozole (n=232)

60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005

FALCON: Forest plot for PFS by patient subgroup

Global interaction test p=0.106

NC, not calculable

All patientsBreast cancer type

Locally advancedMetastatic

Prior chemotherapy YesNo

Geographic regionUS and CanadaNon-US or CanadaAsiaNon-Asia

Measurable diseaseMeasurableNon-measurable

ER+ and PgR+ at baselineYesNo

Prior systemic estrogen containing HRTYesNo

Bisphosphonate use at baselineYesNo

Visceral diseaseYesNo

143 / 230 (62.2%)

11 / 28 (39.3%)132 / 202 (65.3%)

31 / 36 (86.1%)112 / 194 (57.7%)

16 / 25 (64.0%)127 / 205 (62.0%)

19 / 34 (55.9%)124 / 196 (63.3%)

124 / 193 (64.2%)19 / 37 (51.4%)

103 / 175 (58.9%)40 / 55 (72.7%)

3 / 3 (100.0%)140 / 227 (61.7%)

44 / 61 (72.1%)99 / 169 (58.6%)

92 / 135 (68.1%)51 / 95 (53.7%)

166 / 232 (71.6%)

14 / 32 (43.8%)152 / 200 (76.0%)

33 / 43 (76.7%)133 / 189 (70.4%)

19 / 24 (79.2%)147 / 208 (70.7%)

22 / 33 (66.7%)144 / 199 (72.4%)

143 / 196 (73.0%)23 / 36 (63.9%)

127 / 179 (70.9%)39 / 53 (73.6%)

3 / 5 (60.0%)163 / 227 (71.8%)

53 / 62 (85.5%)113 / 170 (66.5%)

87 / 119 (73.1%)79 / 113 (69.9%)

Number of patients with eventFulvestrant Anastrozole

0.25 0.5 1 1.5 2HR (95% CI)

0.797 (0.637, 0.999)

0.790 (0.360, 1.731) 0.784 (0.621, 0.991)

1.081 (0.659, 1.771) 0.752 (0.585, 0.967)

0.664 (0.338, 1.304) 0.811 (0.640, 1.029)0.811 (0.438, 1.501)0.791 (0.622, 1.005)

0.763 (0.599, 0.971) 0.985 (0.534, 1.818)

0.728 (0.561, 0.944) 1.041 (0.669, 1.621)

NC0.779 (0.622, 0.977)

0.685 (0.455, 1.032)0.820 (0.626, 1.073)

0.993 (0.740, 1.331) 0.592 (0.419, 0.837)

HR (95% CI)

60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cancer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005

FALCON: PFS in patients with or without visceral disease

Post hoc interaction test p<0.01

A circle represents a censored observation

Without visceral disease With visceral disease

HR 0.59 (95% CI 0.42, 0.84)

Median PFS Fulvestrant: 22.3 monthsAnastrozole: 13.8 monthsP

roport

ion o

f patients

aliv

e a

nd p

rogre

ssio

n-f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0.2P

roport

ion o

f patients

aliv

e a

nd p

rogre

ssio

n-f

ree

Time (months)

0.9

1.0

0.7

0.8

0.5

0.6

0.3

0.4

0.1

0.0

0 5 10 15 20 25 30 35 40

0.2

0 5 10 15 20 25 30 35 40

HR 0.99 (95% CI 0.74, 1.33)

Median PFS Fulvestrant: 13.8 monthsAnastrozole: 15.9 months

Fulvestrant (n=135)

Anastrozole (n=119)

Fulvestrant (n=95)

Anastrozole (n=113)

Adaptado de:60. Robertson JFR, et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast cáncer (FALCON): an international, randomised, double-blind, phase 3 trial. Lancet. 2016 Dec 17;388(10063):2997-3005

One size does not fit allPatient selection for the most appropriate therapy

• Numerous factors should be considered, such as:

• Disease free interval following adjuvant treatment

• Age

• Co-morbidities

• The extent of disease spread

• Tumour evolution

• Treatment decisions therefore need to be driven by patient and tumour characteristics

Mecanismos de resistencia a HT

37. Ma et al Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer.2015 May;15(5):261-75

Mecanismos de resistencia a Inhibidores de Aromatasa

Al resistance

ER pathway• Loss of ER

expression• ESR1 mutation, amplificationor translocation• Aberrant

expressionor mutation of ER co-regulators

Apoptosis and senescence•Mutation of TP53•Amplification of MDM2•↑BCL-2 and survivin•↑Telomerase

Cell cycle machinery• Loss of Rb, p16 and p18• Amplification of CCND1

Tumourmicroenvironment

• ECM: fibronectin, collagen

• Cellular components: TAM

(M1, M2), CAF, MSC, MDSC,TH2cell, B cell,

dendritic cell, NK cell, cytotoxic T cell, osteoclast, osteoblast and platelet

Growth factor receptor pathway

HER2, IGF1R and EGFR overexpression, mutation oramplification

Secondary messengers• PI3K pathway (e.g. mutationsin PI3KCA, PTEN and AKT1)• MAPK pathway

EMT and CSC• Notch, Hedgehog, WNT and TWIST1

• Tumour dormancy

=0.0002

Which group of patients are at risk for mutation?

Turner. ASCO 2016

What is the prevalence of mutation?

ESR1 mutations seem to be associated with resistance to AIs

SoFEA SoFEA: treatment less effective in mut vs wt

PALOMA-3: no difference between mut vs wtPALOMA-3

BOLERO-2 BOLERO-2: improved OS and PFS in wt vs mut*

Schiavon et al Schiavon et al: ESR1 mutations predict resistance to subsequent AI therapy**

*no statistical analysis carried out; **small sample size (n=45); mut = mutant; wt = wildtype[PALOMA-3] Turner N, presented at ASCO 2016 (abstract 512); [SoFEA] Fribbens et al. J Clin Oncol 2016; 34:2961–2968; [BOLERO-2] Chandarlapaty, presented at SABCS 2015 (abstract S2-07); Schiavon et al. Sci Transl Med 2015;7

Biomarker Clinical studies Findings (mutant/amplified/loss vs wildtype)

ESR1

Not all medications used in these studies are approved/marketed for use in Spain

Chandarlapaty S et al. SABCS 2015

Pronostic of ESR1 mutation and OS

Mutation N Median OS (m) HR

WT 385 32.1 1.4 (1.2-1.65)

MT 156 20.7 1.25 (1.02-1.54)

D538G 83 26.0 2.31 (1.34-3.97)

Y537S 42 20.0 1.77 (1.31-2-39)

Impact of ESR1 Mutation on EXE tratment

Chandarlapaty S et al. SABCS 2015

Impact of ESR1 mutation on EVE treatment

Chandarlapaty S et al. SABCS 2015

¿COMPROMETEMOS TRATAMIENTOS POSTERIORES?

25

▪ Postmenopausal women with ER+ MBC or LABC

▪ Patients who experienced relapse during or within 1 year of completion of adjuvant endocrine therapy

▪ Previous treatment with either an anti-oestrogen or an aromatase inhibitor as a first-line therapy for metastatic breast cancer if relapse occurred after more than 1 year from completion of adjuvant endocrine therapy

▪ Previous treatment with either an anti-oestrogen or an aromatase inhibitor as a first-line therapy if patients had de novo advanced disease

▪ Measurable disease as per RECIST, or without measurable disease but with bone lesions with a lytic or mixed component

▪ ER, oestrogen receptor; MBC, metastatic breast cancer; LABC, locally advanced breast cancer; RECIST, Response Evaluation Criteria In Solid Tumors

Key inclusion / exclusion criteria

Di Leo A et al. J Clin Oncol 2010; 28: 4594-4600

BOLERO-2: Prior Therapies Were Balanced

Between Treatment Arms

Therapy

Everolimus +

Exemestane

(N = 485), %

Placebo +

Exemestane

(N = 239), %

Sensitivity to prior hormonal therapy 84 84

Last treatment: LET/ ANA 74 75

Last treatment

Adjuvant 21 15

Metastatic 79 85

Prior tamoxifen 47 49

Prior fulvestrant 17 16

Prior chemotherapy for metastatic BC 26 26

Number of prior therapies: ≥ 3 54 53

Abbreviations: ANA, anastrozole; LET, letrozole.

Adapted from: Baselga J, et al. N Engl J Med. 2012;366(6):520-529.28

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

Subgroup categories in black font indicate prespecified analyses. Subgroup categories in green indicate retrospective analyses.

*Does not include patients who received neoadjuvant therapy.

Yardley D, et al. Adv Ther. 2013;30:870-884.

BOLERO-2 (18-mo f/up): PFS Benefits Were Consistent in All Subgroups by Local and Central Review (2/2)

0.40 10.91 4.14

0.37 11.04 4.14

114

610

Sensitivity to prior hormonal therapy

No

Yes

0.55 6.83 2.83

0.43 8.05 3.94

0 0.20.40.60.8 1 1.21.4Hazard 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

724

219

232

271

231

493

538

186

N

All

Number of organs involved

1

2

Prior chemotherapy

No

Yes

Prior chemotherapy

for metastatic disease

No

Yes

Median PFS, mo

HR EVE + EXEPBO + 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

Favors EVE + EXE Favors PBO + EXE

≥ 3

Local Central N

Median PFS, mo

HR EVE + EXEPBO + EXE

0 0.20.40.60.8 1 1.21.4Hazard Ratio and 95% CI

Favors EVE + EXE Favors PBO + EXE

Last therapy setting

Neo/adjuvant/prevention

Advanced/metastatic

0.32 15.24 4.21

0.40 10.84 4.11

0.39 11.50 4.07

0.47 6.93 2.96

0.46 9.95 4.21

0.32 12.02 3.32

326

398

Prior use of hormonal therapy

other than NSAI

No

Yes

0.52 7.00 4.11

0.39 8.11 2.76

538

186

137

587

Train of Trainers organized by AstraZeneca

Demographics and Baseline Characteristics PALOMA-3

aRelapsed after 24 months of adjuvant endocrine therapy or had clinical benefit to prior therapy in the advanced setting; bAny prior endocrine therapy anytime before study entry;

GnRH = gonatotropin-releasing hormone.

Characteristic Palbociclib + Fulvestrant

(n=347)

Placebo + Fulvestrant

(n=174)

Documented sensitivity to prior hormonal therapy,a %

Yes 79 78

No 21 22

Prior aromatase inhibitor +/- GnRH,b %

85 87

Prior tamoxifen +/-GnRH,b %

61 60

Disease stage at study entry, %

Recurrent locally advanced

14 14

Metastatic 85 84

Prior chemotherapy in metastatic setting, %

31 36

Prior lines of therapy in metastatic setting, %

0 24 26

1 38 40

2 26 25

≥3 12 9

Characteristic Palbociclib + Fulvestrant

(n=347)

Placebo + Fulvestrant

(n=174)Median age (range), years (range)

57 (30−88) 56 (29−80)

Receptor status, %

ER+ PR+ 69 64

ER+ PR– 26 28

ECOG performance status, %

0 60 66

1 40 34

Menopausal status,a %

Pre-/peri- 21 21

Post- 79 79

Visceral metastases,b %

59 60

Number of disease sites, %

1 32 35

2 29 29

3 39 36

61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19.

N=304(152 per treatment arm)

Fulvestrant HD (500 mg) + palbociclib (3w/4)

Letrozole + palbociclib (3w/4)

PD1:1

Stratification factors:

• Visceral disease

• Adjuvant AI

Postmenopausal MBC ER+/HER2–AI sensitivefirst-line ET

PD, progressive disease; R, randomisation. Llombart, et al. ASCO 2015.

Palbociclib and Fulvestrant Front-Line: PARSIFAL Design

R

Primary Objective:

• 1-year PFS Rates

• Odds Ratio: 70% vs. 85%

Train of Trainers organized by AstraZeneca

FULVESTRANT, SEGUNDA LINEA Y MÁS ALLÁ…

SECUENCIA TRATAMIENTO HORMONAL CMM

PALOMA-3 : FUL+Palbociclib.

61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19.

Primary Endpoint: PFS (Updated Analysis)

62. P4-22-06 Presented at the 39th Annual San Antonio Breast Cancer Symposium (SABCS); December 6–10, 2016; San Antonio, TX, USA

Confidential and Proprietary to AstraZeneca. Not for Distribution.

39

61. Turner NC, Ro J, André F, Loi S, Verma S, Iwata H, Harbeck N, Loibl S, Huang Bartlett C, Zhang K, Giorgetti C, Randolph S, Koehler M, Cristofanilli M; PALOMA3 Study Group.. Palbociclib in Hormone-Receptor-Positive Advanced Breast Cancer. N Engl J Med. 2015 Jul 16;373(3):209-19.

PALOMA-3 : FUL+Palbociclib

• MONARCH-2

Enferme

• MONARCH-2: Abemaciclib + fulvestrant tras PD a ttº endocrino

Enfermed

Abemaciclib 150 mg BID

(cont) + Fulvestrant 500 mg

Placebo BID (cont) +

Fulvestrant 500 mg

CMM RH+/HER2-,

Resistente a ttº

endocrino:

- Recaída en

neoadyuvancia o

dentro del primer año

ady

- Progresión a HT

No QT, < 1 línea HT,

ECOG PS 0/1

(N = 669)

Aleatorización 2:1

Sledge et al. JCO 2017 Jun 3.

doi: 10.1200/JCO.2017.73.7585. [Epub ahead of print]

• MONARCH-2: PFS

Enfermedad

Sledge et al. JCO 2017 Jun 3. doi: 10.1200/JCO.2017.73.7585.

• MONARCH-2: ORR

Enfermed

Presentado por Sledge en ASCO 2017, abstract 1000

SECUENCIA TRATAMIENTO HORMONAL CMM

EN CONCLUSIÓN…

Single AgentEndocrine Therapy

Chemotherapy

Disease activity

- Short DFI- visceral disease burden- Symptoms

Probability to respond to ET

- Resistance Type (I⁰/II⁰)- Intrinsic Subtype- Biomarkers ?

CDK4/6 inhibitors + Endocrine Therapy ?

“Low Risk” “Intermediate Risk” “High Risk”

Single agent ET * ET + CDK4/6 Chemo

(ET + CDK4/6) (Single agent ET) ET + CDK4/6(Chemo)

First line therapy: ET alone or ET + CDK4/6 or Chemotherapy

Visceral/non-visceral?

*ESR1 Mutation and choice of ET

La opción de fulvestrant en monoterapia en primera linea podría

considerarse en pacientes:

- Sin exposición previa a tratamiento hormonal

- Recidiva con ILE corto.

- Pacientes de bajo riesgo o con afectación no visceral

Es preciso disponer de los resultados de los estudios en marcha

para considerar la opción de fulvestrant en combinación en

primera linea.

Constituye la opción preferente en monoterapia o en

combinación tras progresión a una pauta que incluya un IA,