FULVESTRANT prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I.

Presentazione sul tema: "FULVESTRANT prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I."— Transcript della presentazione:

1 FULVESTRANT prof. Giuseppe Naso ONCOLOGIA MEDICA POLICLINICO UMBERTO I

2 ER – a ER - b ER +

3 ER- ER + Androstenedione Testosterone Estrone Estradiolo
Aromatase inhibitors Aromatase (Ovary, Fat, Liver, Breast) Tamoxifen Er-a Er-b ER- cells ER + cells

4 PTEN HER-2 APOPTOSYS MAP ER PHOSPHORYLATION Anti-apoptotic response
PI3K RAS AKT (PKB) MAP ER PHOSPHORYLATION (SERINE 167-activation and ER indipendent pathway) Cellular proliferation Anti-apoptotic response ER-a / b APOPTOSYS PTEN

5 ER + Tumor cell Androstenedione Testosterone Aromatase inhibitors
Estrone Estradiolo Aromatase inhibitors Aromatase (Ovary, Fat, Liver, Breast) Tamoxifen Er-a Er-b ? ER + cells Tumor cell

6 Meccanismo d’azione di Estradiolo e Tam
a confronto AF1 ERE ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE ESTRADIOLO ER ERE AF2 Nella mammella 98% attività trascrizionale P stimola la trascrizione di PgR AF1 nella mammella 2% attività trascrizionale

7 Pgr Trascrizione AF (in assenza di HER-2)

8 Meccanismo d’azione di Estradiolo e Tam
a confronto AF1 ERE ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE ESTRADIOLO ER ERE AF2 Agonista ERE ATTIVAZIONE PARZIALE DELLA TRASCRIZIONE (solo AF1) AF1 TAMOXIFEN ER AF2 Antagonista

9 The EGFR (ErbB) family and ligands
TGFa Amphiregulin b-cellulin HB-EGF Epiregulin NRG2 NRG3 Heregulins b-cellulin Heregulins Cysteine-rich domains 100 44 82 33 36 59 24 48 79 28 Her 2: Recettore di membrana ad attività tirosinochinasi appartenente alla famiglia di EGFR. Condivide con gli altri membri della famiglia dei recettori tirosin-chinasi di tipo I, la struttura generale in cui si riconoscono una parte esterna glicosilata, un singolo elemento idrofobico ad alfa elica che attraversa la membrana cellulare e una parte intracitoplasmatica contenente un sito di fosforilazione con funzione di regolazione negativa. Rispetto agli altri membri della famiglia non è stato identificato alcun ligando che interagisca direttamente con erbB-2. Tyrosine kinase domain C-terminus ErbB-1 Her1 EGFR ErbB-2 Her2 neu ErbB-3 Her3 ErbB-4 Her4

10

11 HER hierarchy

12 Bivalence of EGF-like ligands

13 HER2-promoted recycling of HER1
cbl

14 Relative potency of HER dimers

15 La cascata delle chinasi della via ras
ras-GDP ras-GTP Tyrosine Kinase SOS raf GRB2 forma inattiva Forma attivata ATP MEK ATP MAPK MAP ATP fos myc jun

16 Hormone-dependent growth
La cascata delle chinasi della via ras ras-GDP ras-GTP Tyrosine Kinase SOS raf GRB2 forma inattiva Forma attivata ATP MEK ATP MAPK AKT MAP ATP COREPRESSORE fos myc jun AF1 MAP COATTIVATORE ATP Hormone-dependent growth

17 Pgr Trascrizione AF (in assenza di HER-2) Pgr Trascrizione AF (in prezsenza di HER-2)

18 Es A.I. FASLODEX AF1 ERE ATTIVAZIONE COMPLETA DELLA TRASCRIZIONE
ESTRADIOLO ER ERE AF2 AF1 A.I. FASLODEX Es BLOCCO COMPLETO DELLA TRASCRIZIONE ER AF2

19 Chemical Structures OH Estradiol HO OH (CH2)9SO(CH2)3CF2CF3 ‘Faslodex’
(fulvestrant) HO 7 Tamoxifen O NMe2 Raloxifene HO S OH O N Fulvestrant (‘Faslodex’) has a steroidal structure similar to that of the naturally occurring hormone estradiol, differing by the addition of a long side-chain at the 7-a position, which is responsible for its antagonistic properties This steroidal structure of fulvestrant is markedly different from that of two typical SERMs (Selective Estrogen Receptor Modulators), tamoxifen and raloxifene

20 ER: Interazione con Fulvestrant
La struttura di Fulvestrant è molto simile a quella dell’estradiolo ma con una catena laterale. Questa struttura è responsabile: dell’innovativo meccanismo d’azione di una più elevata affinità per il recettore rispetto al TAM. Quando Fulvestrant si lega al recettore questo cambia leggermente la sua conformazione, ma entrambi AF1 e AF2 rimangono inattivi ANTIESTROGENO SENZA ALCUN EFFETTO AGONISTA

21 ER: Interazione con Fulvestrant
Viene accelerata la degradazione e quindi la perdita della maggior parte dei recettori. EFFETTO DOWN REGULATOR Dei pochi dimeri che si formano alcuni riescono a passare nel nucleo e a legarsi al DNA, ma non essendoci il reclutamento dei coattivatori, l’attività dell’RNA polimearsi 2 è completamente bloccata e di conseguenza nessun gene verrà trascritto.

22 SELETTIVITÀ LEGAME 3H-ESTRADIOLO/RE ESTRADIOLO VS FULVESTRANT VS TAM
100 90 80 70 E2 60 Percentuale di inibizione Fulvestrant 50 Tam 40 30 20 10 1 5 10 50 100 300 1000 3000 10000 Concentrazione (nM)

23 Mean tumour volume (mm3)
Effects of Estrogen Withdrawal, Tamoxifen and ‘Faslodex’ (fulvestrant) on MCF-7 Tumour Growth 200 400 600 Mean tumour volume (mm3) 100 300 –Estradiol Tamoxifen Fulvestrant 800 1000 1200 Days Estrogen withdrawal MCF-7 tumours transplanted into female nude mice were stimulated to grow by estradiol. This growth was suppressed when estradiol was withdrawn, but eventually tumours showed estrogen-independent growth Addition of tamoxifen suppressed the growth for longer than withdrawal of estradiol alone, but eventually tumours also became resistant to tamoxifen and growth continued Treatment with fulvestrant suppressed the growth for twice as long as treatment with tamoxifen Some, but not all, cells developed resistance Adapted from: Osborne CK et al. J Natl Cancer Inst 1995; 87: 746–750.

24 Mean tumour volume (mm3)
Effect of ‘Faslodex’ (fulvestrant) on Tamoxifen-stimulated Tumour Growth 200 400 20 40 60 80 100 120 Tamoxifen Tamoxifen + fulvestrant Fulvestrant 300 500 Days Mean tumour volume (mm3) MCF-7 tumour cells, which developed tamoxifen resistance (I.e. grew despite continued use of tamoxifen), were transplanted into castrated female nude mice Further treatment with tamoxifen stimulated tumour growth The stimulatory effect of tamoxifen in these tumours was inhibited by the addition of fulvestrant Treatment with fulvestrant alone did not stimulate tumour growth Fulvestrant lacks the stimulatory effect of tamoxifen in this model This demonstrates lack of cross-resistance with tamoxifen Adapted from: Osborne CK et al. Cancer Chemother Pharmacol 1994; 34: 89–95.

25 Summary of Preclinical Data for ‘Faslodex’ (fulvestrant): The First of a New Type of Antitumour Agent Downregulates estrogen receptors in breast cancer cells No estrogenic activity Completely blocks estrogen action Greater efficacy than tamoxifen in breast cancer models Effective in tamoxifen-resistant breast cancer models A summary of key actions of fulvestrant, an Estrogen Receptor Downregulator

26 Post-treatment Mean ER H-scores
20 40 60 80 100 120 Mean ± 1SEM p=0.0006 NS p=0.024 p=0.026 Overall treatment effect p=0.0003 Placebo (n=29) 50mg Fulvestrant (n=31) 125mg (n=32) 250mg Tamoxifen (n=25) All doses of fulvestrant produced a significantly lower mean ER H-score (histology score) than placebo, which was dose-dependent The mean ER H-score was also reduced after treatment with tamoxifen The reduction seen with the 250mg dose of fulvestrant, currently being investigated in the Phase III clinical trial programme, was significantly greater than that seen with tamoxifen This is further evidence of the downregulation of the estrogen receptor produced by fulvestrant NS = not significant Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.

27 Post-treatment Mean PgR H-scores
20 40 60 80 100 NS p=0.003 p=0.0002 p=0.0001 Placebo (n=28) 50mg Fulvestrant (n=29) 125mg 250mg Tamoxifen (n=21) Mean ± 1SEM Overall treatment effect p=0.0001 Three different doses of fulvestrant each produced a lower mean PgR H-score compared with placebo This was significant for the higher two doses Tamoxifen produced an increase in PgR H-score The difference between tamoxifen and fulvestrant was significant for all doses As PgR expression is under the control of the ER, this is evidence of both the partial agonist activity of tamoxifen and the lack of estrogen agonist activity of fulvestrant NS = not significant Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.

28 Fulvestrant 250mg vs placebo Fulvestrant 250mg vs tamoxifen
Antitumour Effects of Single Doses of ‘Faslodex’ (fulvestrant) in Postmenopausal Patients with Primary Breast Cancer Fulvestrant 250mg vs placebo Fulvestrant 250mg vs tamoxifen Post-treatment mean ER H-scores p= p=0.024 Post-treatment mean PgR H-scores p= p=0.0001 Post-treatment mean Ki67 values p= NS Post-treatment mean apoptotic index values NS NS The table summarises the statistical analyses of the data from the 250mg single dose of fulvestrant, which is that being used in ongoing clinical trials The reduction in ER expression was statistically significant for fulvestrant compared with placebo (p=0.0001) and tamoxifen (p=0.024) For PgR H-scores, fulvestrant produced a statistically significant reduction compared with placebo (p=0.0002) and tamoxifen (p=0.0001). Tamoxifen increased PgR H-scores Fulvestrant significantly reduced Ki67 values, a measure of cell proliferative activity, compared with placebo (p=0.0002). There were no statistically significant differences in Ki67 values between fulvestrant and tamoxifen NS = not significant Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.

29 ‘Faslodex’ (fulvestrant): Phase I Clinical Summary
Phase I: Dose-dependent reduction in ER and PgR, greater than tamoxifen and reduction in Ki67 index Antiestrogenic and therapeutic effects demonstrated in breast cancer ER downregulation demonstrated in clinical tumour samples Summary of clinical findings of fulvestrant monthly injection from the Phase II study and the single-dose study on tumour markers Robertson JFR et al. Breast 1997; 6; 186–189. Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.

30 Potential Clinical Advantages of ‘Faslodex’ (fulvestrant) — Under Investigation in Ongoing Clinical Trial Programme Higher tumour response rate and/or longer duration of response Lack of cross-resistance with tamoxifen Lack of tumour flare No agonist activity on endometrium Lack of CNS effects related to estradiol antagonism Reduced risk of thromboembolic disease A summary of potential clinical benefits of fulvestrant (under investigation in the ongoing clinical trial programme)

31 ‘Faslodex’ (fulvestrant): Clinical Development Programme: Phase II

32 ‘Faslodex’ (fulvestrant): Phase II Study in Advanced Breast Cancer
Monthly injection (250mg i.m.) Nineteen postmenopausal women Relapsed following previous response to tamoxifen for advanced breast cancer or >2 years’ adjuvant therapy Phase II study in advanced breast cancer A study of patients with advanced breast cancer resistant to tamoxifen who were treated with monthly injections of fulvestrant Howell A et al. Lancet 1995; 345: 29–30.

33 69% of patients achieved OR (= CR+PR) or SD ³24 weeks
‘Faslodex’ (fulvestrant): Phase II Results Clinical Efficacy — Response Rate n % Complete response (CR) 0 0 Partial response (PR) 7 37 Stable disease (SD) 6 32 Progression 6 31 Total } 69 Response rates showing that patients with advanced breast cancer respond to fulvestrant after failure of treatment with tamoxifen 37% of patients achieved a partial response In total, 69% of patients achieved clinical benefit (objective response + stable disease) following treatment with fulvestrant 69% of patients achieved OR (= CR+PR) or SD ³24 weeks Howell A et al. Lancet 1995; 345: 29–30.

34 ‘Faslodex’ (fulvestrant): Summary of Tolerability from the Phase II Study
No reports of hot flushes or vaginal dryness (n=19) No change in endometrial thickness in five patients assessed No apparent effect on prolactin, SHBG, cholesterol (HDL, LDL) or triglycerides Initial rise in LH/FSH — due to tamoxifen withdrawal? No deaths, withdrawals or drug-related serious AEs Summary of tolerability information on fulvestrant monthly injection from the Phase II study Howell A et al. Lancet 1995; 345: 29–30. Howell A et al. Br J Cancer 1996; 74: 300–308.

35 ‘Faslodex’ (fulvestrant): Phase II Clinical Summary
Antiestrogenic effects demonstrated in breast cancer Therapeutic effects demonstrated in advanced breast cancer Lack of cross-resistance with tamoxifen confirmed High response rates and long DoRs in tamoxifen failures (n=19) No major local or systemic safety issues in patients ER downregulation demonstrated in clinical breast tumour samples Median survival for fulvestrant-treated patients in second-line advanced breast cancer = 54 months1 Summary of clinical findings of fulvestrant monthly injection from the Phase II study and the single-dose study on tumour markers 1. Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.

36 Phase III Trials 0020 and 0021: prospective combined analysis
Fulvestrant in postmenopausal women with tamoxifen-resistant advanced breast cancer Phase III Trials 0020 and 0021: prospective combined analysis

37 Fulvestrant: disegni dello studio
Donne in postmenopausa con carcinoma mammario avanzato precedentemente trattate con endocrinoterapia per carcinoma mammario precoce o avanzato Studi 0020 e 0021: reclutamento tra maggio 1997 e agosto 1999 Studio 0020: internazionale, randomizzato 1:1, aperto, a gruppi paralleli Studio 0021: nordamericano, randomizzato 1:1, in doppio cieco,, a gruppi paralleli Anastrozolo 1 mg in monosomministrazione orale giornaliera Studio 0020: (n=229) Studio 0021: (n=194) Fulvestrant 250 mg i.m. depot mensile Studio 0020: 1 x 5 ml (n=222) Studio 0021: 2 x 2,5 ml (n=206) Analisi combinata

38 Proportion not progressed Time to progression (months)
Tempo alla progressione: Studi EU – USA ANALISI COMBINATA Robertson ,Cancer, 2003 1,0 Median TTP: Fulvestrant 5,5 months Anastrozolo 4,1 months 0,9 0,8 Hazard Ratio (95%CI): (0.82–1.10); p=0.48 0,7 0,6 Proportion not progressed 0,5 0,4 Fulvestrant 250 mg 0,3 Anastrozolo 1 mg 0,2 0,1 0,0 6 12 18 24 30 36 Time to progression (months)

39 Fulvestrant vs Anastrozole durata della risposta (analisi combinata)
1,0 Durata Mediana: Fulvestrant 16,7 months Anastrozole 13,7 months 0,9 0,8 0,7 Fulvestrant 250 mg Anastrozole 1 mg 0,6 Risposta 0,5 0,4 0,3 0,2 0,1 0,0 6 12 18 24 30 36 Duration of Response (months) Robertson JFR et al. Cancer 2003; 98:

40 Fulvestrant: analisi prospettica combinata. Miglior risposta obiettiva
Numero di pazienti (%) Fulvestrant (n=428) Anastrozole (n=423) Risposta completa (CR) Risposta parziale (PR) Risposta obiettiva (CR+PR) 20 (4,7) 11 (2,6) 62 (14,5) 59 (13,9) 82 (19,2) 70 (16,5)* Malattia stabile ³24 settimane Beneficio clinico (CR+PR+SD ³24 settimane) 104 (24,3) 103 (24,3) 186 (43,5) 173 (40,9) *Odds ratio (95,14% CI): 1,21 (0,84–1,74); p=0,31 Robertson JFR et al. Cancer 2003; 98: 229–238.

41 (a) without visceral metastases (a) without visceral metastases
DURATA RISPOSTA OBIETTIVA IN BASE ALLA PRESENZA/ASSENZA DI METASTASI VISCERALI: STUDI EU - USA (a) without visceral metastases (a) without visceral metastases (a) without visceral metastases (a) senza metastasi viscerali, (b) con metastasi viscerali (c) con metastasi solo viscerali Mauriac, Eur J Cancer, 2003

42 TOLLERABILITÀ STUDI EU - USA
Numero di eventi avversi (%) Fulvestrant (n=423) Anastrozolo (n=423) p value Vampate di calore (21,0) (20,6) ,91 Disturbi gastrointestinali (46,3) (43,7) ,53 Aumento di peso (0,9) (1,7) ,35 Vaginiti (2,6) (1,9) ,51 Eventi tromboembolici (3,5) (4,0) ,68 Dolori articolari (5,4) (10,6) ,0036 Infezioni tratto urinario (7,3) (4,3) ,062

43 SECONDA LINEA DI TRATTAMENTO: OPPORTUNITA’ TERAPEUTICHE

44 EFFICACIA DELLA TERAPIA ENDOCRINA DOPO PROGRESSIONE DA AI NON STEROIDEI
Exemestane (n=105) CB 20%1 AI ns CB = clinical benefit CB 43%2 Exemestane (n=30) 1 Lønning PE et al. J Clin Oncol 2000; 18: 2234–2244 2 Carlini et al. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 171P

45 STUDIO DI FASE II DEL NORTH CENTRAL CANCER TREATMENT GROUP
Criteri di eligibilità Donne con ca mammario in post menopausa con ER e/o PgR + Progressione da AI Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409

46 CARATTERISTICHE DELLE PAZIENTI
Età mediana Precedente chemio. Solo adiuvante adiuvante + ABC solo ABC Precedente AI adiuvante ABC Precedente tamoxifen solo adiuvante adiuvante + ABC ABC n (%) (29–89) (27) (18) (14) (1) (99) (44) (4) (25) 68 1 76 Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409

47 PRECEDENTE TRATTAMENTO
EFFICACIA PRECEDENTE TRATTAMENTO Totale (n=77) AI (n=21) AI + tamoxifene (n=56) PR SD 6 months CB rate 10% (13)* 15% (19) 32% 5% (24)* 6% (29) 52% 5% (9)* 9% (16) 25% * Durata mediana di 10 mesi (range 2-20 mesi) Sopravvivenza mediana: 21 mesi 1-anno survival rate: 70.4% (95% CI 60.5–82.0) Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409

48 TOLLERABILITA’* n=76 % Fatigue 25 Vampate di calore 17 Nausea 13
Anoressia Artralgia Alopecia % 25 17 13 11 8 Buona tollerabilità. * all NCI-CTC grado 1-3 Ingle JN et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S38, abs 409

49 STUDIO DI FASE II: GRUPPO SVIZZERO PER LA RICERCA CLINICA (SAKK)
Criteri di elegibilità Donne con ca mammario in post menopausa che sono progredite dopo 12 settimane da AI Perey L et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S236, abs 6048

50 STUDIO DI FASE II: GRUPPO SVIZZERO PER LA RICERCA CLINICA (SAKK) EFFICACIA
Risposte parziali Malattia stabile 24 weeks Clinical benefit n (%) 1 (1) 18 (27) 28% 7% dei pazienti sta ancora ricevendo fulvestrant (durata mediana del trattamento 9.3 mesi [6.7–39.8 mesi]) Perey L et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S236, abs 6048

51 STUDIO DI FASE II: GRUPPO SVIZZERO PER LA RICERCA CLINICA (SAKK) TOLLERABILITA’
12 (17.9) 6 (9.0) 3 (4.5) 1 (1.5) Vampate di calore Fatigue Perdita di appetito Nausea Solo 1 paziente ha interrotto il trattamento (1.5%) a causa di eventi avversi Solo 2 pazienti (3.0%) hanno grado 3 : reazione al sito di iniezione (n=1), vampate di calore (n=1) Perey L et al. Breast Cancer Res Treat 2004; 88 (Suppl 1): S236, abs 6048

52 EFFICACIA DELLA TERAPIA ENDOCRINA DOPO PROGRESSIONE DA FULVESTRANT
AI ns (n=46) CB 41%1 Fulvestrant CB = clinical benefit AI ns (n=22) CB 50%2 1 Vergote I et al, Breast Cancer Res Treat 2003; 79: 207–211. 2 Howell A, Robertson J. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 173P.

53 CONCLUSIONE Fulvestrant è efficace nelle pazienti resistenti al tamoxifene Fulvestrant o Exemestane sono efficaci in pazienti che progrediscono da inibitori dell’aromatasi non steroidei Pazienti che rispondono a Fulvestrant risultano essere sensibili ad una successiva terapia endocrina