Overview

Fulvestrant (‘Faslodex’) First of a new type: 

Fulvestrant (‘Faslodex’) First of a new type

Chemical Structures: 

Chemical Structures

Mode of Action of Estradiol, Tamoxifen and Fulvestrant (‘Faslodex’): 

Adapted from: Wakeling AE. Endocr-Relat Cancer 2000; 7: 17–28. Mode of Action of Estradiol, Tamoxifen and Fulvestrant (‘Faslodex’) Tamoxifen AF1 ER + PARTIALLY INACTIVATED TRANSCRIPTION (reduced rate of tumour cell division) T T T AF1 AF1 ACTIVE AF2 INACTIVE

Fulvestrant (‘Faslodex’): Effects on the Estrogen Receptor (ER) Content of Human MCF-7 Cells: 

Reproduced courtesy of Professor R Nicholson, Tenovus Institute for Cancer Research, Cardiff, UK. Fulvestrant (‘Faslodex’): Effects on the Estrogen Receptor (ER) Content of Human MCF-7 Cells Control 4-hydroxy tamoxifen fulvestrant

Uterotrophic and Antiuterotrophic Effectin the Immature Rat: 

Uterotrophic and Antiuterotrophic Effect in the Immature Rat Adapted from: Wakeling A et al. Cancer Res 1991; 51: 3867–3873. Adapted from: Wakeling A, Bowler J. Endocrinology 1987; 112: R7–R10.

Effects of Estrogen Withdrawal, Tamoxifen andFulvestrant (‘Faslodex’) on MCF-7 Tumour Growth: 

Adapted from: Osborne CK et al. J Natl Cancer Inst 1995; 87: 746–750. Effects of Estrogen Withdrawal, Tamoxifen and Fulvestrant (‘Faslodex’) on MCF-7 Tumour Growth

Effect of Fulvestrant (‘Faslodex’) on Tamoxifen-stimulated Tumour Growth: 

Adapted from: Osborne CK et al. Cancer Chemother Pharmacol 1994; 34: 89–95. Effect of Fulvestrant (‘Faslodex’) on Tamoxifen-stimulated Tumour Growth

Summary of Preclinical Data for Fulvestrant (‘Faslodex’): The First of a new type of Antitumour Agents : 

Summary of Preclinical Data for Fulvestrant (‘Faslodex’): The First of a new type of Antitumour Agents 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

Post-treatment Mean ER H-scores: 

Post-treatment Mean ER H-scores Robertson JFR et al. Cancer Res 2001; 61: 6739–6746. NS = not significant

Comparison of Fulvestrant (‘Faslodex’) with Tamoxifen: ER — Pre- and Post-treatment: 

Tamoxifen: pre-treatment Tamoxifen: post-treatment Fulvestrant: pre-treatment Fulvestrant: post-treatment Comparison of Fulvestrant (‘Faslodex’) with Tamoxifen: ER — Pre- and Post-treatment Robertson JFR et al. Cancer Res 2001; 61: 6739–6746.

Fulvestrant (‘Faslodex’): Phase I and II Clinical Data Summary: 

Fulvestrant (‘Faslodex’): Phase I and II Clinical Data Summary Phase I: Dose-dependent reduction in ER and PgR, greater than tamoxifen and reduction in Ki67 index Phase II clinical data obtained from 19 patients with hormone-sensitive advanced breast cancer who had progressed on tamoxifen Antiestrogenic and therapeutic effects demonstrated in breast cancer ER downregulation demonstrated in clinical tumour samples Lack of cross-resistance with tamoxifen confirmed Clinical benefit rate 69% and durable responses (median 26 months) in tamoxifen failure No major local or systemic safety issues in patients Median survival for fulvestrant-treated patients in second-line advanced breast cancer = 54 months Robertson JFR et al. Breast 1997; 6; 186–189. Robertson JFR et al. Breast Cancer Res Treat 2001; 69: 289, Abstr 451.

Fulvestrant (‘Faslodex’): Trial Designs : 

Fulvestrant (‘Faslodex’): Trial Designs Postmenopausal women with advanced breast cancer receiving prior endocrine treatment for early or advanced breast cancer Trial 0020: International, randomised 1:1, open, parallel-group Trial 0021: North American, randomised 1:1, double-blind, double-dummy, parallel-group Anastrozole 1mg daily, orally Trial 0020: (n=229) Trial 0021: (n=194) Fulvestrant 250mg i.m. once monthly Trial 0020: 1 x 5ml (n=222) Trial 0021: 2 x 2.5ml (n=206) Analysis after 340 events (progression or death prior to progression) Trials 0020 and 0021: Recruitment between May 1997 and August 1999

Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Patient Characteristics: 

Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Patient Characteristics Mean age (years)/range Mean weight (kg)/range Hormone receptor status (%) ER and/or PgR+ ER/PgR unknown ER/PgR– Prior treatment (%) Cytotoxic chemotherapy Endocrine therapy for advanced disease Adjuvant endocrine therapy Fulvestrant (n=428) 63 (33–89) 63 (33–94) 70 (37–127) 70 (40–134) 80 83 15 12 5 5 52 52 55 53 57 56 Anastrozole (n=423) Robertson JFR, et al. Cancer 2003; 98: 229–238.

Fulvestrant (‘Faslodex’): Trials 0020 and 0021 — Time to Progression: 

Fulvestrant (‘Faslodex’): Trials 0020 and 0021 — Time to Progression Median TTP: Fulvestrant 5.5 months (n=222) Anastrozole 5.1 months (n=229) Osborne CK et al. J Clin Oncol 2002; 20: 3386–3395. Howell A et al. J Clin Oncol 2002; 20: 3396–3403. 0020 0021

Fulvestrant (‘Faslodex’): Prospective Combined Analysis (Trials 0020 and 0021) — Time to Progression: 

Fulvestrant (‘Faslodex’): Prospective Combined Analysis (Trials 0020 and 0021) — Time to Progression Robertson JFR et al. Cancer 2003; 98: 229–238. Hazard ratio (95.14% CI): 0.95 (0.82–1.10); p=0.48 Median TTP: Fulvestrant 5.5 months Anastrozole 4.1 months

Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Best Objective Response: 

Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Best Objective Response 20 (4.7) 11 (2.6) 62 (14.5) 59 (13.9) 82 (19.2) 70 (16.5)* Complete response (CR) Partial response (PR) Objective response (CR+PR) Stable disease ³24 weeks Clinical benefit (CR + PR + SD ³24 weeks) 104 (24.3) 103 (24.3) 186 (43.5) 173 (40.9) Number of patients (%) Anastrozole (n=423) Fulvestrant (n=428) *Odds ratio (95.14% CI): 1.21 (0.84–1.74); p=0.31 Robertson JFR et al. Cancer 2003; 98: 229–238.

Fulvestrant (‘Faslodex’): Kaplan–Meier Estimates for DoR from Onset of Responseto Disease Progression(all randomised patients): 

Fulvestrant (‘Faslodex’): Kaplan–Meier Estimates for DoR from Onset of Response to Disease Progression (all randomised patients) Ratio of average response durations = 1.30; 95%CI 1.13–1.50; p<0.01 Robertson JFR et al. Cancer 2003; 98: 229–238.

Median Duration of Objective Response in Patients without or with Visceral Metastases: 

Median Duration of Objective Response in Patients without or with Visceral Metastases Mauriac L et al. Eur J Cancer 2003; 39: 1228–1233.

Overall Response Rates to Endocrine Therapy (AIs or Megestrol Acetate) after Progression on Fulvestrant (‘Faslodex’) — Trials 0020 and 0021: 

Overall Response Rates to Endocrine Therapy (AIs or Megestrol Acetate) after Progression on Fulvestrant (‘Faslodex’) — Trials 0020 and 0021 Vergote I et al. Breast Cancer Res Treat 2003; In press. Howell A, Robertson J. Ann Oncol 2002; 13 (Suppl 5): 48, Abstr 173P. Trial 0025 data show responses to subsequent endocrine therapy post-fulvestrant similar to those post-tamoxifen

Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Tolerability: Predefined Adverse Events: 

Hot flushes 89 (21.0) 87 (20.6) 0.91 GI disturbances 196 (46.3) 185 (43.7) 0.53 Weight gain 4 (0.9) 7 (1.7) 0.35 Vaginitis 11 (2.6) 8 (1.9) 0.51 Thromboembolic disease 15 (3.5) 17 (4.0) 0.68 Joint disorders 23 (5.4) 45 (10.6) 0.0036 Urinary tract infection 31 (7.3) 18 (4.3) 0.062 Withdrawn due to AE 12 (2.8) 8 (1.9) Number of adverse events (%) Anastrozole (n=423) Fulvestrant (n=423) p value Robertson JFR et al. Cancer 2003; 98: 229–238. Fulvestrant (‘Faslodex’): Prospective Combined Analysis — Tolerability: Predefined Adverse Events

Injection Site Adverse Events Encounteredwith 5ml Injection: 

Injection Site Adverse Events Encountered with 5ml Injection Fulvestrant (n=219) Patients with injection site adverse events (AEs) 16 (7.3%) Patients withdrawing due to an injection site AE 1 (0.5%) Injections associated with an AE 20/1898 (1.1%) Howell A et al. J Clin Oncol 2002; 20: 3396–3403.

Fulvestrant (‘Faslodex’): Benefits of Injection: 

Fulvestrant (‘Faslodex’): Benefits of Injection Assurance that patients are receiving medication Compliance issues have been observed with oral endocrine therapies1 Many patients have co-morbidities — ‘Faslodex’ injection means one less tablet to remember! Fosters regular contact between patients and healthcare professionals Allows management issues to be discussed regularly Simple injection procedure For some patients, the possibility of home administration by a nurse 1. Jones S et al. J Clin Oncol 1999; 17: 3418–3425.

Fulvestrant (‘Faslodex’): Phase III Summary in the Second-line Treatment of Advanced Breast Cancer: 

Fulvestrant (‘Faslodex’): Phase III Summary in the Second-line Treatment of Advanced Breast Cancer Fulvestrant (‘Faslodex’): The first of a new type of breast cancer treatment agents Effective in tamoxifen-resistant advanced breast cancer At least as effective as anastrozole in disease that has progressed during antiestrogen therapy Longer duration of response than anastrozole Lower incidence of joint disorders than anastrozole Survival data compare well with the non-steroidal and steroidal aromatase inhibitors in the second-line advanced breast cancer setting Well tolerated — with low numbers of withdrawals due to adverse events Given as a once-monthly injection, which offers the potential for excellent compliance and convenience

Trial 0025: Fulvestrant (‘Faslodex’) vs Tamoxifen as First-line Treatment for Advanced Disease — Design: 

Primary endpoint — Time to progression Secondary endpoints — Tumour response — Duration of response — Time to treatment failure — Time to death — Tolerability/QoL Trial 0025: Fulvestrant (‘Faslodex’) vs Tamoxifen as First-line Treatment for Advanced Disease — Design Fulvestrant 250mg i.m. once monthly Tamoxifen 20mg/day Postmenopausal patients with advanced breast cancer* and ER+/PgR+ or ER/PgR-unknown tumours A double-blind, randomised, multinational, multicenter, parallel-group, comparative trial * no prior endocrine treatment (exception of adjuvant tamoxifen stopped ³12 months prior to randomisation) Robertson JFR et al. Ann Oncol 2002; 13 (Suppl 5): 46, Abstr 164O.

Trial 0025: Time to Progression, Objective Response and Clinical Benefit Rates — Predefined, Prospective Analyses: 

Trial 0025: Time to Progression, Objective Response and Clinical Benefit Rates — Predefined, Prospective Analyses All patients n (% total population) 313 (100) 274 (100) Median TTP (months) 6.8 8.3 0.0876 Objective response (%) 31.6 33.9 0.45 Clinical benefit (%) 54.3 62.0 0.03 ER+ and/or PgR+ n (% total population) 247 (78.9) 212 (77.4) Median TTP (months) 8.2 8.3 0.3882 Objective response (%) 33.2 31.1 0.64 Clinical benefit (%) 57.1 62.7 0.22 Endpoint Fulvestrant Tamoxifen p value Robertson JFR et al. Cancer 2003; 98: 229–238.

Trial 0025: Time to Progression, Objective Response and Clinical Benefit Rates — Retrospective Analysis : 

Trial 0025: Time to Progression, Objective Response and Clinical Benefit Rates — Retrospective Analysis ER+ and PgR+ n (% total population) 131 (41.9) 114 (41.6) Median TTP (months) 11.4 8.5 0.3061 Objective response (%) 44.3 29.8 0.02 Clinical benefit (%) 67.9 60.5 0.23 Endpoint Fulvestrant Tamoxifen p value

Phase III Summary: Fulvestrant (‘Faslodex’) in the First-line Treatment of Advanced Breast Cancer: 

Phase III Summary: Fulvestrant (‘Faslodex’) in the First-line Treatment of Advanced Breast Cancer Unequivocal evidence of fulvestrant efficacy Response rate 32% Clinical benefit rate 54% Median duration of response from randomisation 17.3 mths Fulvestrant has similar efficacy to tamoxifen in the hormone receptor-positive population Suggestion of possible superiority for fulvestrant in a retrospective analysis of ER+ and PgR+ tumours In the first-line setting, the most appropriate patient population requires further definition

Phase III Summary: Fulvestrant (‘Faslodex’) vs Anastrozole — Overall Conclusions : 

Phase III Summary: Fulvestrant (‘Faslodex’) vs Anastrozole — Overall Conclusions Fulvestrant (‘Faslodex’) represents the first of a new type of drugs that bind, block and degrade ER No known agonist action Fulvestrant is the only antiestrogen to have demonstrated a clinical benefit rate in over 40% of patients whose disease had progressed after previous tamoxifen therapy Fulvestrant vs a third-generation aromatase inhibitor: At least as effective — demonstrated trends in favour of fulvestrant over anastrozole for all major efficacy endpoints Longer duration of response Responsiveness to subsequent endocrine therapy may be retained after response and subsequent progression on fulvestrant