`
`Review
`
`European
`Journal of
`Cancer
`
`www.ejconline.com
`
`Endocrine treatment options for advanced breast cancer — the role of
`fulvestrant
`
`J.F.R. Robertson **, S.E. Come ”, S.E. Jones °, L. Beex “4, M. Kaufmann *, A. Makris z
`J.W.R. Nortier ®, K. Possinger *, L.-E. Rutqvist ?
`
`* Unit of Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NGS IPB, UK
`> Beth Israel Deaconess Medical Center, Boston, MA, USA
`° Charles A. Sammons Cancer Center, Dallas, TX, USA
`4 University Medical Centre Nijmegen, Nijmegen, The Netherlands
`* Goethe University, Frankfurt, Germany
`® Academic Oncology Unit, Mount Vernon Hospital, Middlesex, UK
`® Leiden University Medical Center, Leiden, The Netherlands
`» Humboldt University Berlin, Berlin, Germany
`' Karolinska Institute, Stockholm, Sweden
`
`Received 28 April 2004; accepted 20 July 2004
`Available online 11 November 2004
`
`
`
`Abstract
`
`For many years, tamoxifen has been the ‘gold standard’ amongst anti-oestrogen therapies for breast cancer. However, the
`selective aromatase inhibitors (Als), anastrozole, letrozole and exemestane, have demonstrated advantages over tamoxifen as
`first-line treatments for advanced disease. Anastrozole is also more effective as an adjuvant treatment in early, operable breast
`cancer and is being increasingly used in the adjuvant setting. Generally, the selective oestrogen receptor modulators (SERMs),
`such as toremifene, droloxifene, idoxifene, raloxifene, and arzoxifene, show minimal activity in tamoxifen-resistant disease and
`show no superiority over tamoxifen as first-line treatments. In addition to these agents, other treatment options for advanced
`disease include high-dose oestrogens and progestins. Response rates for high-dose oestrogens and tamoxifen are similar, but
`the use of oestrogens is limited by their toxicity profile. Consequently,
`there is a need for new endocrine treatment options
`for breast cancer, particularly for use in disease that is resistant to tamoxifen or Als. Fulvestrant (‘Faslodex’) is a new type
`of steroidal oestrogen receptor (ER) antagonist that downregulates cellular levels of the ER and progesterone receptor and
`has no agonist activity. This paper reviews the key efficacy and tolerability data for fulvestrant in postmenopausal women in
`the context of other endocrine therapies and explores the potential role of fulvestrant within the sequencing of endocrine ther-
`apies for advanced breast cancer.
`© 2004 Published by Elsevier Ltd.
`
`Keywords: Advanced breast cancer; Treatment; Fulvestrant; Faslodex; Postmenopausal
`
`1. Introduction
`
`Fulvestrant (‘Faslodex’) is a new type of endocrine
`agent, an oestrogen receptor (ER) antagonist that has
`a
`Corresponding author. Tel.: +44 115 969 1169x46859; fax: +44
`115 840 2618
`Robertson).
`
`address:
`
`john.robertson@nottingham.acuk
`
`no agonist effects. It downregulates cellular levels of
`the ER,resulting in the decreased expression of the pro-
`gesterone receptor (PgR). This paper reviews key effi-
`cacy and tolerability data for fulvestrant in the context
`of other endocrine therapies and explores the potential
`rae
`’
`role of fulvestrant within the sequence of endocrine
`agents used for treating postmenopausal women with
`advanced breast cancer,
`
`(J.F.R.
`
`0959-8049/$ - see front matter © 2004 Published by Elsevier Ltd.
`doi: 10.1016/.ejca.2004.07.035
`
`AstraZeneca Exhibit 2073 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLCv. AstraZeneca AB IPR2017-01910
`
`
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`J.F.R. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`347
`
`2. SERMs, oestrogens and ER downregulators
`
`3. Activity versus tamoxifen and in tamoxifen-resistant
`disease
`
`3.1. SERMs
`
`triphenylethylene
`a non-steroidal
`Tamoxifen is
`agent that has been the ‘gold standard’ selective oes-
`trogen receptor modulator
`(SERM) amongst anti-
`toremifene is
`Several studies have confirmed that
`oestrogen therapies since the 1970s. Tamoxifen is an
`cross-resistant with tamoxifen in advanced disease [9-
`oestrogen antagonist
`in breast
`tissue, but acts as
`11]. Both these agents display similar efficacy and toler-
`an oestrogen agonist in the bones and endometrium.
`ability in the advanced [12,13] and adjuvantsettings[14].
`This spares bone mineral density and serum choles-
`Efficacy results for the structurally related, droloxifene
`terol levels from the full effects of oestrogen depriva-
`[15-17] and idoxifene [18,19], have both been disap-
`tion [1,2], but is also associated with undesirable side
`effects such as an increased risk of endometrial cancer
`pointing when either compared directly with tamoxifen
`or when used in tamoxifen-resistant disease; the devel-
`and thromboembolic events [3]. The selective aroma-
`opment of these agents has now ceased.
`tase inhibitors (AIs), anastrozole,
`[4,5]
`letrozole [6,7]
`The second-generation, ‘fixed ring’ SERM arzoxifene
`and exemestane [8], have since been shown to have
`has also shown poorefficacy in tamoxifen-resistant dis-
`advantages over tamoxifen as first-line treatments for
`ease [20]. Furthermore, a randomised Phase III trial of
`advanced disease, but a review of these data is beyond
`arzoxifene versus tamoxifen was terminated early be-
`the scope of this paper,
`cause of a lack of efficacy (Buzdar A, data not shown).
`Several new anti-oestrogens have been developed
`Raloxifene also shows low efficacy in tamoxifen-resist-
`since tamoxifen, some with similar mechanisms of ac-
`ant disease [21], but has shown promise in breast cancer
`tion to tamoxifen and some that are very different.
`prevention [22,23] and is currently being tested in this
`First-generation SERMs, such as toremifene, droloxif-
`setting in the STAR (Study of Tamoxifen and Raloxif-
`ene and idoxifene, are tamoxifen analogues based on
`ene) trial [24]. ERA-923 is a second-generation SERM
`the non-steroidal
`triphenylethylene
`structure. The
`
`
`
`
`structurally and_third-generationdistinct second- that is currently in development for the treatment of
`SERMs (raloxifene, arzoxifene, EM-800 and ERA-
`tamoxifen-refractory metastatic breast cancer, but no
`efficacy data for this agent are available to date. In sum-
`923) are also non-steroidal, but are ‘fixed-ring’ benzo-
`thiophene derivatives, yet appear to retain some oes-
`mary, the SERMs as a group have thus far shown no
`trogen agonist
`activity.
`In
`contrast,
`fulvestrant,
`superiority over tamoxifen as first-line advanced breast
`which has a steroidal structure closely resembling oest-
`cancer treatments and minimal activity in tamoxifen-re-
`sistant disease.
`radiol,
`is a new ER antagonist that has no agonist
`activity. Fig.
`| shows the chemical structures of oest-
`radiol, fulvestrant, tamoxifen and raloxifene. Anti-oes-
`trogens are generally compared on the basis of their
`activity in tamoxifen-resistant disease, their ability to
`delay the development of resistance and their side-ef-
`fect profiles.
`
`Oestradiol
`
`Fulvestrant
`
`OH
`
`HO
`
`af
`
`HO
`
`(CH)gSO(CHs)3CF,CF,
`
`Tamoxifen
`
`NMe:
`
`Raloxifene
`
`
`ow
`
`Fig. 1. Chemical structures of oestradiol, fulvestrant, tamoxifen and
`raloxifene.
`
`3.2. High-dose oestrogens
`
`Prior to the introduction of tamoxifen, high-dose
`oestrogens — such as diethylstilboestrol (DES) or ethi-
`nyl oestradiol — were generally considered the endo-
`crine treatment of choice for postmenopausal women
`with breast cancer [25]. Subsequently, the use of oes-
`trogens declined, but
`recent
`trial data have shown
`these drugs to have similar efficacy to tamoxifen [26]
`and to produce responses, even in those who havere-
`ceived extensive prior endocrine therapy [27]. However,
`the use of these agents is limited by their toxicity
`profile.
`
`4. Fulvestrant — a novel oestrogen antagonist that
`downregulates cellular levels of ER
`
`4.1. Biological effects
`
`Fulvestrant blocks the trophic actions of oestrogen
`without exerting any partial agonist effects. Fulvestrant
`entered clinical development after preclinical studies
`suggested it was active in tamoxifen-resistant breast
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`AstraZeneca Exhibit 2073 p. 2
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`348
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`JER. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`cancer [28-30]. Fulvestrant acts by competing with oest-
`radiol for binding to the ER and has a higher affinity for
`the ER than tamoxifen [31]. Fulvestrant downregulates
`expression of ER and decreased activity of the ER path-
`way results in reduced expression of the PgR and re-
`duced proliferative and cell turnover indices both im
`vitro [32-35] and in the clinical setting [36,37].
`In the presence of fulvestrant, ER is rapidly depleted,
`producing a loss of functional response to oestrogens
`after relatively short periods of time in im vitro studies.
`This is in contrast with the increases in ER levels seen
`on either oestrogen withdrawal or tamoxifen treatment
`[32]. The effects of three different fulvestrant doses and
`one dose of tamoxifen on cellular ER, PgR and Ki67
`levels were investigated in a study of postmenopausal
`women with primary breast cancer. Patients received
`either a single intramuscular (i.m.) injection of fulves-
`trant 50, 125 or 250 mg, or oral tamoxifen 20 mg, daily
`for 14-21 days, prior to surgery of curative intent. Fig. 2
`demonstrates the dose-dependent reductions in ER and
`
`PgRlevels with fulvestrant treatment. Reductions in ER
`levels were statistically significant for all fulvestrant
`doses compared with placebo and for the 250 mg dose
`compared with tamoxifen. There werestatistically sig-
`nificant reductions in PgR levels with fulvestrant 125
`and 250 mg compared with placebo. In contrast, tam-
`oxifen treatment produced significant increases in PgR
`levels compared with placebo, probably as a result of
`its oestrogen agonist activity. All doses of fulvestrant
`significantly reduced the Ki67 labelling index, but there
`were no significant differences compared with tamoxifen
`[36].
`
`4.2. Clinical efficacy
`
`(a)
`
`Mean+1SEM
`
`(b)
`
`=
`WY
`Wi
`*o]
`=
`8
`=
`
`120
`
`100
`
`80
`
`60
`
`40
`
`69
`
`40
`
`20
`
`0
`
`NS
`
`d
`1
`
`=
`
`a
`
`
`i
`
`,
`
`
`
`Placebo
`(n=28)
`
`50mg
`125mg
`250mg
`Fulvestrant Fulvestrant Fulvestrant
`(n=29)
`(n=29)
`(n=29)
`Overall treatment effect P=0.0001
`
`Tamoxifen
`(n=21)
`
`(a) oestrogen
`Fig. 2. Post-treatment mean H-scores for cellular:
`levels. Figure
`receptor (ER) and (b) progesterone receptor (PgR)
`reproduced with the permission of Cancer Research [36]. SEM,
`standard error of the mean; NS, non-significant.
`
`AstraZeneca Exhibit 2073 p. 3
`
`20
`
`
`
`
`
`
`
`C]
`A,
`
`4.2.1. Fulvestrant versus anastrozole
`Two large Phase III trials (Trial 0021: North Ameri-
`can; Trial 0020: Rest of World [Europe, South Africa,
`Australia]) have compared the efficacy and tolerability
`of fulvestrant with anastrozole, in postmenopausal wo-
`men with advanced breast cancer who had progressed
`on prior endocrine treatment (mainly tamoxifen). Pa-
`tients were randomised to receive either fulvestrant 250
`mg, by monthly i.m. injection or a daily oral dose of
`anastrozole 1 mg andcontinued treatment until disease
`progression or withdrawal.
`In the North American trial, 400 patients received
`double-blind, randomised treatment with either fulves-
`trant (as 22.5 ml
`i.m.
`injections) (7 = 206) or oral
`anastrozole (a = 194) and were followed for a median
`of 16.8 months. Fulvestrant was found to be as effective
`as anastrozole in terms of time to progression (TTP)
`(Hazard Ratio (HR): 0.92; 95% Confidence Interval
`(CI) 0.74-1.14; P = 0.43); median TTP was 5.4 months
`Placebo 250mg_Tamoxifen50mg 125mg
`
`
`
`with fulvestrant and 3.4 months with anastrozole.
`(n=29)
`Fulvestrant Fulvestrant Fulvestrant
`(n=25)
`(n=31)
`(n=32)
`(n=32)
`Objective response (OR) rates were 17.5% for both
`Overall treatment effect P=0,0003
`treatments and clinical benefit
`(complete response
`(CR) + partial
`response
`(PR)+stable
`disease
`P=0.0001
`(SD) = 24 weeks; CB) rates were 42.2% and 36.1% for
`-—————_pa0001
`100
`P=0.0001
`fulvestrant and anastrozole, respectively. Median dura-
`re|
`80
`___ P=0,0002
`tion of response (DOR; from randomisation to progres-
`P=0,003
`sion) was 19.0 months for fulvestrant compared with
`10.8 months for anastrozole. An analysis using all rand-
`omised patients, defined for responders as the time from
`onset of response to disease progression and for non-re-
`sponders as zero, showed that mean DOR wassignifi-
`cantly
`greater
`for
`fulvestrant
`compared with
`anastrozole;
`the ratio of average response durations
`being 1.35 (95% CI 1.10-1.67; P< 0,01) [38].
`In the Rest of World (open) trial, 451 patients were
`randomised to receive either fulvestrant as a single 5
`ml
`im.
`injection (#=222) or
`anastrozole orally
`(n= 229) and were followed for a median of 14.4
`months. Again, fulvestrant was shown to beat least as
`effective as anastrozole in terms of TTP (HR: 0.98;
`95% CI 0.80-1.21; P= 0.84); median TTP was 5.5
`
`
`
`J.F.R. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`349
`
`Table 1
`Response to subsequent therapy in patients who derived CB from
`fulvestrant
`
`
`Number of patients
`
`CR PR SD 2 24weeks
`PD Total
`Patients who derived. CB from first-line fulvestrant
`Anastrozole
`1
`0
`8
`Letrozole
`0
`1
`0
`Fadrozole
`0
`0
`1
`Tamoxifen
`0
`1
`e
`Megestrol acetate
`0
`0
`1
`Medroxyprogesterone
`0
`0
`0
`acetate
`
`16
`5
`1
`10
`1
`a
`
`7
`4
`0
`2
`0
`2
`
`
`
`
`
`
`
`Patients who derived. CB from second-line fulvestrant
`«4637
`23
`Anastrozole
`0
`1
`13
`8
`3
`Letrozole
`0
`2
`3
`1
`I
`Formestane
`0
`0
`0
`Megestrol acetate 8 0 1 S a
`Table adapted from[44] and [42], with the permission of Breast Cancer
`Research and Treatment.
`CR, complete response; PR, partial response; SD, stable disease; PD,
`disease progression; CB, Clinical benefit.
`
`
`
`
`
`months for fulvestrant and 5.1 months for anastrozole.
`ORrates were 20.7%for fulvestrant and 15.7% for anas-
`trozole (odds ratio: 1.38; 95% CI 0.84-2,29; P = 0.20).
`CB rates were 44.6%for fulvestrant and 45.0%for anas-
`trozole and the median DOR was 15.0 months and 14.5
`months for fulvestrant and anastrozole, respectively. In
`addition, mean DOR using all randomised patients was
`significantly greaterfor fulvestrant compared with anas-
`trozole, the ratio of average response durations being
`1.27 (95% CI 1.05-1.55; P = 0,01) [38].
`The two Phase III trials were prospectively designed
`to be evaluated both individually and using combined
`data. A combined analysis of all patients included in
`both second-line Phase III trials demonstrated a signifi-
`cant 30% increase in mean DORin patients treated with
`fulvestrant (ratio of average response durations: 1,30;
`95% CI 1.13-1.50; P < 0.01; Fig. 3) [40]. In addition
`to confirming the efficacy of fulvestrant that was ob-
`served in the individual trials, retrospective analyses of
`these combined data also showed fulvestrant had stmilar
`efficacy (in terms of OR rate, CB rate and DOR) to
`anastrozole in the subgroup of patients with visceral
`metastases. The median DOR in patients with visceral
`metastases was 17.5 months in the fulvestrant group
`compared with 11.7 months in the anastrozole group.
`Notably, in the subgroup of patients with visceral meta-
`stases only, seven of 69 (10%) fulvestrant-treated pa-
`tients achieved a CR, compared with one of 86 (1%)
`anastrozole-treated patients [41].
`The data from these two trials reiterate that fulves-
`trant is a novel agent with levels of activity in tamoxi-
`fen-resistant disease that distinguish it from SERMs
`and other anti-oestrogens. Furthermore,
`fulvestrant
`was at least as effective as anastrozole in this setting.
`In addition, retrospective analysis evaluating combined
`questionnaire data from the twotrials showed that pa-
`tients can retain sensitivity to other endocrine agents
`(anastrozole,
`letrozole, and megestrol acetate) after
`receiving second-line fulvestrant (Table 1) [42].
`
`
`
`Duration of response (months)
`
`Fig. 3. Kaplan—Meierestimates for duration of response from onset of
`response to disease progression (combined analysis of all randomised
`patients included in Phase III trials). Copyright © 2003 American
`Cancer Society. Reprinted by permission of Wiley - Liss, Inc., a
`subsidrary of John Wiley & Sons, Inc. [40].
`
`AstraZeneca Exhibit 2073 p. 4
`
`4.2.2. Fulvestrant versus tamoxifen
`Fulvestrant and tamoxifen have been compared as
`first-line treatments in a trial including postmenopausal
`women with advanced breast cancer. Approximately,
`20-25% of patients in this trial had previously received
`adjuvant tamoxifen, but no patients received prior endo-
`crine therapy for advanced disease. In this study, the
`median TTP was 6.8 months in the fulvestrant group
`and 8.3 months in the tamoxifen group. The between-
`treatment difference was non-significant
`(HR: 1.18;
`95% CI 0.98-1.44; P= 0.088), but the upper limit of
`the 95% CI (1.44) did not satisfy the pre-defined crite-
`rion for non-inferiority (<1.25) of fulvestrant compared
`with tamoxifen. OR rates for fulvestrant and tamoxifen
`were similar (31.6% versus 33.9%; P= 0.45), but more
`tamoxifen-treated patients overall achieved CB (62.0%
`versus 54.3%; P = 0.03) [43]. Median DOR (from rand-
`omisation to progression) was 17.3 and 19.8 months
`for fulvestrant and tamoxifen, respectively [43]. In the
`prospectively defined subgroup of patients with ER-pos-
`Fulvestrant 250 mg
`itive and/or PgR-positive tumours, median TTP was
`O804442reiitii Anastrozole 1 mg
`similar for the fulvestrant and tamoxifen treatment
`0.25
`groups (8.2 months versus 8,3 months; HR: 1.10; 95%
`0.20
`CI 0.89-1.36; P = 0.39) [43].
`0.15
`Subsequent exploratory analyses of response by hor-
`0.10
`mone receptor status showed that in the subgroup ofpa-
`tients with tumours expressing both ER and PgR 44.3%
`of fulvestrant-treated patients and 29.8% of patients
`treated with tamoxifen experienced an OR (P =0.02)
`[43]. However, the authors note that these data wereret-
`rospectively derived and therefore should be interpreted
`with caution in terms oftheir clinical significance. Fur-
`ther confirmatory data are required. In addition, pa-
`tients who responded to first-line treatment with
`
`0.35
`
`
`
`Proportionresponding
`
`0.05
`0.00
`
`
`
`350
`
`JER. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`fulvestrant may retain sensitivity to subsequent endo-
`crine therapy with a variety of agents, including anas-
`trozole, letrozole, fadrozole, tamoxifen, and megestrol
`acetate (Table 1)
`[44]. This is similar to the findings
`noted above where tumours appeared to retain sensitiv-
`ity to other endocrine agents following second-line treat-
`ment with fulvestrant [42]. It therefore appears that the
`use of fulvestrant does not per se lead to end-stage hor-
`mone insensitivity.
`
`4.3. Tolerability
`
`In the second-line trials, both fulvestrant and anas-
`trozole were well tolerated, with few patients in either
`group withdrawing due to treatment-related adverse
`events (0.9% and 1.2% of the fulvestrant- and anastroz-
`ole-treated patients, respectively). Overall, the incidence
`and severity of events (generally mild to moderate)
`were similar between groups; the most common events
`in both groups included hot flushes, nausea, asthenia,
`pain, headache and pharyngitis. The incidence of
`events considered important with endocrine therapy
`such as weight gain, thromboembolic events and vagi-
`nitis was low for both fulvestrant and anastrozole
`[38,39].
`The use of placebo injections in the North American
`trial indicated that fulvestrant was well tolerated locally
`and that injection-site reactions were related to the injec-
`tion itself, as 27%of patients receiving fulvestrant com-
`pared with 23% of those receiving placebo reported
`injection-site reactions
`[38]. Overall, 86 fulvestrant
`courses (4.6%) of the total 1879 and 71 placebo courses
`(4.4%) of the total 1624 resulted in an injection-site reac-
`tion. This is supported by the clinical experience of phy-
`sicians administering the 2 x 2.5 ml fulvestrant regimen
`in the US. Here, nursing guidelines have previously sug-
`gested that, for adults, im. injections into large muscles
`such as the gluteus medias, should not usually exceed 4
`ml [45], therefore in the trial it was decided to use 2 x 2.5
`mil im. injections, one into each buttock, rather than a
`single 5 ml injection [38]. The pharmacokinetics of these
`two regimens have previously been shown to be similar
`[46]. Moreover, since the 2.5 ml injections were so well
`tolerated, most US institutions now prefer to administer
`fulvestrant as a single 5 ml i.m. injection, thereby reduc-
`ing the numberofinjections given to the patient (Astra-
`Zeneca, data on file).
`tamoxifen comparative
`In the fulvestrant versus
`study, both treatments were well tolerated with no sta-
`tistically significant differences in the incidence of pro-
`spectively defined adverse events of gastrointestinal
`disturbances, hot flushes, vaginitis and thromboembolic
`disease. However, the incidence of hot flushes was lower
`in the fulvestrant group than in the tamoxifen group and
`the difference approached statistical significance (17.7%
`versus 24.7%; P = 0.0501) [43].
`
`5. Fulvestrant — the US experience
`
`In April 2002, the US Food and Drug Administra-
`tion (FDA) granted approval for fulvestrant to be used
`for the treatment of hormone receptor-positive meta-
`static breast cancer in postmenopausal women with dis-
`ease progression following anti-oestrogen therapy. The
`use of fulvestrant as second-line therapy is increasing,
`although the drug continues to be used in patients
`who have progressed on both tamoxifen and an AI.
`Data from the two Phase III studies of fulvestrant versus
`anastrozole suggest that fulvestrant is as effective as an
`AI in the second-line setting and that DOR may,in fact,
`be longer with fulvestrant treatment [38,39].
`In the US, there appears to be a general underutilisa-
`tion of hormonal therapy and a lack of differentiation
`between fulvestrant and other hormonal agents such as
`anastrozole. At several oncology meetings in the US,
`surveys of treatment practice amongst US oncologists
`suggest that US physicians often favour chemotherapy
`in situations where European clinicians prefer further
`endocrine treatment. Furthermore, US physicians may
`utilise endocrine treatment for a shorter duration and
`switch to chemotherapy earlier than their European
`counterparts (Jones SE, data not shown).
`The personal experiences of the US physicians in-
`volved in the US Phase III fulvestrant verstus anastrozole
`tnal are in agreement with the formal DOR analysis,
`which suggest that, on average, fulvestrant-treated pa-
`tients respond for approximately 30% longer than those
`treated with anastrozole [40]. One investigator had 27 pa-
`tients included in the Phase III UStrial, of these, five
`have had responses of >3 years (two for >4 years), four
`of these patients have now relapsed and have been un-
`blinded and all had been receiving fulvestrant and one
`is currently continuing double-blind treatment (Jones
`SE, data not shown), A second investigator had 16 pa-
`tients entered in the sametrial; four of these patients
`(25%) had CB for 20-44 months three of whom were
`foundto be receiving fulvestrant after unblinding (Come
`SE, Personal Communication) (Table 2). This empha-
`sises the fact that there appears to be a population of pa-
`tients who have an extremely long DORwith fulvestrant.
`Furthermore, personal experiences from these physicians
`have shown that parenteral dosing can also be beneficial
`over oral dosing for some patients, particularly those
`demonstrating poor compliance with oral therapies.
`
`6. Sequencing of endocrine treatments
`
`Because of the toxicity associated with chemotherapy,
`it would be advantageous in appropriate patients to ex-
`tend the endocrine treatment window,
`thus deferring
`the initiation of more toxic treatments that are associated
`with acute and more severeside effects. Endocrine treat-
`
`AstraZeneca Exhibit 2073 p. 5
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`J.F.R. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`351
`
`Table 2
`Case studies from the US phase II fulvestrant versus anastrozole trial (Come SE, Personal Communication)
`
`Patient characteristics Efficacy results
`Case study 1
`e 55 years old
`e ER-positive infiltrating lobular carcinoma
`e Developed metastases to the colon during adjuvant tamoxifen treatment
`
`e SD of 7 months duration on anastrozole (after code-break)
`
`e SD of 20 months duration on fulvestrant
`
`Case study 2
`e 59 years old
`e ER-positive/PgR-positive tumour
`e Metastases to liver, bone, skin, and lymph nodes
`
`e SD of 39 months duration on fulvestrant
`e SD of 7 months duration on anastrozole (after code-break)
`
`Case study 3
`e 64 years old
`e ER-positive tumour
`
`¢ CR of 44 months on fulvestrant*
`e Still receiving fulvestrant outside oftrial setting and still in CR
`(currently of 55 months duration)
`
`e Skin metastases (following first-line tamoxifen treatment)
`
`ER, oestrogen receptor; PgR, progesterone receptor; SD, stable disease; CR, complete response.
`* Patient withdrew from the trial whilst experiencing a CR (at that time of 44 months duration) to receive off-study treatment with fulvestrant
`closer to home.
`
`ment should generally continue as long as the patient re-
`mains hormonesensitive (1.e., achieving CB with hor-
`mone treatment)
`and when the patient becomes
`hormoneresistant, chemotherapy treatment should then
`be initiated. For the past 20 years, the most commonly
`used first-line or adjuvant endocrine treatment for ad-
`vanced breast cancer has been tamoxifen. However, the
`
`non-steroidal Als are now used routinely in the advanced
`setting and are also starting to be used as adjuvanttreat-
`ment following the recently reported results from the
`‘Arimidex’, Tamoxifen, Alone or
`in Combination
`(ATAC)trial [47].
`Two schema of treatment options following adjuvant
`or first-line tamoxifen treatment (Fig. 4(a)) or adjuvant
`
`(a)
`
`Adjuvant or 1™-line TAM
`
`
`y
`
`Disease
`recurrence
`
`>12 months
`disease-free
`after TAM
`
`(b)
`
`Adjuvant ANA
`
`v
`
`Y
`
`Disease
`recurrence
`on ANA
`
`>12 months
`disease-free
`after ANA
`
`-
`
`on TAM
`my y ANAILET
`r--TAMmeet
`
`v
`
`TAM
`
`TAM
`
`+ vy 4
`4
`yy
`rr
`
`EXE ANA/LET=FUL r-ANAVLET~1 FUL FUL
`
`
`FUL--1ee
`+ yy yt
`dy
`:
`+ yy ty vy
`+
`+
`‘
`
`EXE
`
`FUL
`
`EXE
`
`EXE FUL
`
`EXE ANA/LET
`
`MA
`
`EXE
`
` ANA/LET
`
`MA
`
`MA EXE
`!
`1
`
`EXE
`!
`1
`
`1
`
`EXE
`
`FUL
`
`EXE
`1
`!
`
`¥ vy
`MA
`MA
`
`v
`MA
`
`TAM, tamoxifen; ANA, anastrozole; LET, letrozole; FUL, fulvestrant; EXE, exemestane;
`MA, megestrol acetate
`
`— Treatmentoption (no re-challenge)
`--p Treatment option (with re-challenge)
`
`Fig. 4. Treatment options flow charts for patients previously treated with: (a) adjuvant or first-line tamoxifen; (b) adjuvant anastrozole.
`
`AstraZeneca Exhibit 2073 p. 6
`
`
`
`B52
`
`JER. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`anastrozole treatment (Fig. 4(b)) are proposed. These
`suggestions have been based on data from randomised
`clinical
`trials where available, or otherwise, on non-
`randomised data or the authors’ personal experiences.
`
`6.1. Treatment options following adjuvant or first-line
`tamoxifen
`
`If a patient experiences disease recurrence on adju-
`vant or progressive disease on first-line tamoxifen treat-
`ment(Fig. 4(a)), there is sufficient evidence to show that
`fulvestrant is comparable to anastrozole in these pa-
`tients [38,39], and the longer DOR with fulvestrant
`treatment may suggest an advantage for fulvestrant in
`this setting [40]. At the current time, despite these data,
`the wealth of clinical experience with Als may mean that
`these agents could be the most comfortable treatment
`choice for many physicians,
`There is evidence to suggest that patients receiving
`fulvestrant may retain sensitivity to tamoxifen and
`non-steroidal Als [42,44]. Fulvestrant or exemestane
`(a steroidal AI) could be considered following sec-
`ond-line treatment with a non-steroidal AI. Preliminary
`data from a small Phase II study suggests that fulves-
`trant is effective in this setting [48], although more data
`are available to support the reverse sequence (fulves-
`trant followed by an AI), High-dose oestrogens could
`also be used following AI failure [27]. However,
`the
`toxicities of this type of treatment may limit the use
`of this option. Data from a large Phase III trial
`is
`needed to clarify the optimal choice of sequenceat this
`point.
`Exemestane has shown activity in women with ad-
`vanced breast cancer previously treated with non-ste-
`roidal AIs
`such as aminoglutethimide, anastrozole
`and letrozole [49]. Exemestane has shown superioreffi-
`cacy and tolerability over megestrol acetate, after tam-
`oxifen
`failure,
`in
`postmenopausal women with
`advanced breast cancer [50], and therefore this agent
`is now chosen ahead of megestrol acetate in most situ-
`ations. Further data regarding the sequencing of Als
`was presented in 2002 at the annual meeting of the
`American Society of Clinical Oncology. Bertelli and
`colleagues [51] investigated whether patients who had
`previously received exemestane could still benefit from
`treatment with anastrozole or letrozole after exemes-
`tane failure and vice versa. One PR, two SD and one
`disease progression (PD) were observed amongst
`the
`first
`five patients receiving non-steroidal Als after
`exemestane. Responses to exemestane after treatment
`with non-steroidal Als were similar to those observed
`in previous studies, being 3 PR, 3 SD, and 4 PD in
`the first 17 evaluable patients. Although preliminary,
`these data suggest that there is some evidence for a
`lack of cross-resistance between steroidal and non-ste-
`roidal Als [51]. The Evaluation of Faslodex (fulves-
`
`trant) versus Exemestane Clinical Trial (EFECT) will
`compare the efficacy of fulvestrant and exemestane in
`postmenopausal women with advanced breast cancer
`who have progressed after prior non-steroidal AI treat-
`ment. Data from this trial will help to address this part
`of the algorithm,
`If a patient has a disease-free interval >12 monthsfol-
`lowing adjuvant or first-line tamoxifen,
`the choice of
`subsequent treatmentis slightly different, With no evi-
`dence indicating superiority of fulvestrant over tamoxi-
`fen in the first-line
`setting,
`a more appropriate
`treatment choice may be a non-steroidal AI [4~7]. A sec-
`ond possibility, after a disease-free interval of >12
`months would be to rechallenge with tamoxifen and fol-
`low a similar schedule to that shown previously. How-
`ever, a patient may be uncomfortable receiving the
`same treatment and may want to receive a new agent,
`in which case an AI would be recommended,
`
`6.2. Treatment options following adjuvant anastrozole
`
`Anastrozole is the only non-steroidal AI to have pro-
`ven efficacy for adjuvant
`treatment and provides an
`alternative to tamoxifen in this setting. Treatment op-
`tions following the use of adjuvant anastrozole are pre-
`sented in Fig. 4(b). There is a lack of randomised
`controlled trial data to support an optimal sequence fol-
`lowing either failure on adjuvant anastrozole or a dis-
`ease-free interval of >12 months. However,
`it would
`seem sensible in both situations to try an agent with a
`different mechanism of action such as an anti-oestrogen,
`although following a disease-free interval of >12
`months, rechallenge with anastrozole may also be a pos-
`sibility. However, these authors suggest that fulvestrant
`or tamoxifen would both be the valid choicesin this set-
`ting, but because of the wealth of clinical experience
`with tamoxifen over the last 25 years, they would rec-
`ommend tamoxifen after adjuvant anastrozole treat-
`ment. A further
`reason for
`the use of tamoxifen
`followed by fulvestrant rather than the reverse sequence
`is that data from the two large Phase III fulvestrant ver-
`sus anastrozole trials show that this particular sequence
`works well [38,39]. While the reverse sequence has also
`been shown to be effective the volume of data is less
`extensive.
`The sequence of treatment choices following fulves-
`trant are similar to those presented earlier; the only dif-
`ference is that following disease recurrence on adjuvant
`anastrozole, there is a rationale for the use of meges-
`trol acetate ahead of exemestane, due to its different
`mechanism of action, Another possibility is the use of
`high-dose oestrogens [27]. Overall however, there is a
`lack of randomised trial data to clearly define an opti-
`mum sequence of endocrine therapies and until this be-
`comes available, clinical experience should shape future
`use.
`
`AstraZeneca Exhibit 2073 p. 7
`
`
`
`J.F.R. Robertson et al. | European Journal of Cancer 41 (2005) 346-356
`
`te
`
`aa
`
`loading-dose regimen may allow steady-state levels of
`fulvestrant to be achieved more rapidly. Such an ap-
`proach may not impact on the long-term efficacy of
`the drug, but may allow early responses to be identified.
`It is possible to model the effects of the addition of a
`loading regimen on the attainment of steady-state ful-
`vestrant levels (Fig. 5). Here, an initial dose of 500 mg
`fulvestrant is given on day 0, followed by 250 mg fulves-
`trant on day 14. This is followed 14 days later by the
`standard fulvestrant 250 mg monthly dose. The model
`demonstrates that steady-state is achieved betw