I), S|57S| 8
`British journal of Cancer (2004) 90(Suppl
`Q
`© 2004 Cancer Research UK All rights reserved 000770920/04
`$25.00
`www.bjcancer.com
`
`Fulvestrant and the sequential endocrine cascade for advanced
`breast cancer
`
`
`
`S johnston*"
`lDepartment of Medicine (Breast Unit), The Royal Marsden Hospital NHS Trust & Institute of Cancer Research, Fulham Road, London SW3 61/, UK
`
`
`
`is common for patients to
`it
`Following relapse on endoc ine therapy for advanced, hormone receptor—positive breast cancer,
`experience responses to alte native endocrine agents. Fulvestrant (‘Faslodex’) is a new type of endocrine treatment 7 an oestrogen
`receptor (ER) antagonist with no agonist effects. Fulvestrant downregulates cellular levels ofthe ER resulting in decreased expression
`of the progesterone recepto . This unique mode of action means that it
`is important that fulvestrant is placed optimally within the
`sequence of endocrine therapies to ensure that patients gain maximum benefit. Fulvestrant has shown efficacy when used after
`progression on tamoxifen or anastrozole in postmenopausal women with advanced breast cancer. After progression on fulvestrant,
`subsequent endocrine treatments can produce responses in many patients, demonstrating that fulvestrant does not
`lead to
`crossresistance with other endocrine therapies. Responses to fulvestrant have also been observed in patients heavily pretreated with
`prior endocrine therapy. Fulvestrant is a versatile endocrine agent that may be integrated into the therapeutic sequence prior to, or
`subsequent to, other hormonal therapies, and represents a valuable additional antioestrogen for the treatment of postmenopausal
`women with advanced breast cancer.
`
`British journal of Cancer (2004) 90(Suppl
`© 2004 Cancer Research U
`
`l), Sl578l8. doi: l0. l038/sj.bjc.660l632 www.bjcancer.com
`
`
`
`Keywords: breast cancer; endocrine therapy; sequencing; fulvestrant; 'Faslodex’
`
`The efficacy and tolerability advantages associated with the use of
`endocrine agents in the treatment of hormone receptor-positive
`advanced breast cancer have been clearly established in many
`clinical studies. However, despite an initial
`response, many
`patients will eventually experience disease progression and require
`further endocrine treatment options. In patients who respond to
`endocrine treatments, additional responses to further agents are
`common (Buzdar and Hortobagyi, 1998; Hortobagyi, 1998). This
`potential responsiveness to multiple endocrine therapies means
`that patients may continue to derive clinical benefit while avoiding
`the marked, and often distressing, adverse side effects associated
`with chemotherapy. This is a particularly important consideration
`in a predominantly elderly patient population who may be least
`able to tolerate severe adverse events. Disease control
`is also
`
`important in this patient group for whom an absolute cure may not
`be achievable, and instead, prevention of disease progression and
`the maintenance of quality of life may be more important.
`The activity of sequential endocrine therapies is dependent upon
`them possessing different mechanisms of action.
`In this way,
`crossresistance between sequential therapies may be avoided. It is
`therefore important that, as new endocrine therapies with different
`mechanisms of action become available,
`they are integrated
`effectively into the sequential hormonal regimens to allow patients
`to derive maximum benefit.
`
`FULVESTRANT AND THE ENDOCRINE SEQUENCE
`CASCADE
`
`Fulvestrant (‘Faslodex’) is a new type of endocrine treatment — an
`oestrogen receptor
`(ER) antagonist with no agonist effects
`(Wakeling et al, 1991; Robertson et al, 2001). Fulvestrant binds
`to the ER but, due to its steroidal structure and long side-chain,
`induces a different conformational shape with the receptor to that
`achieved by the nonsteroidal antioestrogen tamoxifen. As a result
`of this, fulvestrant prevents ER dimerisation and leads to the rapid
`degradation of the fulvestrant—ER complex, producing the loss of
`cellular ER (Borras et al, 1996). As a result, fulvestrant (unlike
`tamoxifen) inhibits ER—DNA binding and produces abrogation of
`oestrogen-sensitive gene transcription (Dauvois et al, 1993).
`The unique mode of action of fulvestrant presents a useful
`addition to the endocrine agents currently available for use in
`sequential therapeutic regimens. Fulvestrant has been approved in
`the United States and Brazil
`for
`the treatment of hormone
`
`in postmenopausal
`receptor-positive metastatic breast cancer
`women with disease progression following antioestrogen therapy.
`An increasing number of studies are demonstrating the versatility
`of fulvestrant for the treatment of advanced breast cancer (Howell
`et al, 2002; Osborne et al, 2002; Perey et al, 2002; Steger et al,
`2003a, b). An understanding and appreciation of these data will be
`important for determining the optimal placing of fulvestrant in the
`sequence cascade of hormonal therapy.
`
`
`
`Efficacy post-tamoxifen
`
`*Correspondence: Dr 5RD Johnston;
`E—mail: Stephenjohnston@rmh.nthames.nhs.ul<
`
`The efficacy of fulvestrant has been proven in two phase III trials
`conducted in postmenopausal patients with hormone-sensitive
`
`AstraZeneca Exhibit 2065 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`
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`

`Fulvestrant and the sequential endocrine cascade
`S Iohnston
`SI6
`
`advanced breast cancer progressing on prior tamoxifen. In both
`these trials, the efficacy of fulvestrant was comparable to the highly
`selective,
`third-generation aromatase inhibitor (AI) anastrozole
`(‘Arimidex’) (Howell et al, 2002; Osborne et al, 2002). Fulvestrant
`is
`the only antioestrogen acting directly on ER that has
`demonstrated efficacy post-tamoxifen,
`illustrating the lack of
`crossresistance between these two therapies. This is in contrast to
`the selective oestrogen receptor modulators (SERMs) such as
`droloxifene,
`idoxifene,
`toremifene, and benzothiophene arzoxi-
`fene, all of which have shown minimal activity in tamoxifen-
`resistant disease (Johnston, 2001).
`
`Efficacy post-AI
`
`improved efficacy and tolerability, AIs are
`Owing to their
`increasingly being used in the first-line treatment of breast cancer,
`in both early and advanced disease (Nabholtz et al, 2000; ATAC
`Trialists’ Group, 2002; Mouridsen et al, 2003). Preclinical data
`indicate that exposure to long-term oestrogen deprivation (similar
`to that caused by AIs) and subsequent development of acquired
`resistance may be accompanied by adaptive increases in ER gene
`expression and intercellular signalling, resulting in hypersensitiv-
`ity to low oestradiol levels (Ieng et al, 1998; Shim et al, 2000; Chan
`et al, 2002; Martin et al, 2003). In this situation, tamoxifen may be
`perceived as an agonist. As a result, it is important to establish the
`efficacy of fulvestrant after progression on AIs. In vitro, fulvestrant
`significantly inhibited the expression of genes such as c-myb and
`c-myc in cells resistant to long-term oestrogen deprivation (Ieng
`et al, 1998) and may therefore be an appropriate therapeutic
`option after progression on AIs.
`Clinical data so far are limited, but preliminary results from an
`ongoing phase II study have shown that fulvestrant produced
`clinical benefit
`(CB, complete response (CR)+partial response
`(PR) +stable disease (SD) >24 weeks) in seven out of 17 (41%)
`patients who had received, and had progressed on, prior treatment
`with tamoxifen and an AI (Perey et al, 2002). These results suggest
`that in addition to producing responses after prior tamoxifen,
`disease progression after anastrozole may not preclude subsequent
`treatment with fulvestrant. Further trials in this setting are now in
`progress and are discussed later in this paper.
`
`Efficacy in heavily pretreated patients
`
`Many patients may receive a number of different endocrine
`therapies as well as chemotherapies during the course of their
`disease. Preliminary data are becoming available from centres
`using fulvestrant
`in Named Patient Programmes
`involving
`patients heavily pretreated with endocrine therapies including
`tamoxifen, anastrozole,
`letrozole,
`exemestane, and goserelin.
`In 67 postmenopausal women with metastatic breast cancer, 64
`of whom (96%) had progressed on one,
`two or three prior
`endocrine agents for advanced disease, fulvestrant produced CB in
`40 patients (60%) overall. A total of six patients (9%) derived a PR.
`Of these, one had received fulvestrant as first-line therapy for
`advanced disease,
`two had received fulvestrant as second-line
`therapy, and three had received it as third-line therapy. No
`objective responses were seen in patients receiving fourth-line
`fulvestrant therapy. This might suggest that fulvestrant produces
`better responses when given earlier in the treatment sequence
`(Steger et al, 2003a).
`Similar results have been obtained in a separate single-centre
`study. Postmenopausal women with metastatic breast cancer who
`had been heavily pretreated with prior hormonal
`therapy
`(including tamoxifen, AIs, androgens, and high-dose oestrogens)
`and chemotherapy (including taxanes, capecitabine, doxorubicin,
`and cisplatin) were treated with fulvestrant; SD >24 weeks was
`achieved in eight out of 42 (19%) patients (Franco et al, 2003).
`
`Endocrine therapy after progression on fulvestrant
`
`Two studies have provided evidence that the marked reduction in
`ER expression produced by fulvestrant
`is not associated with
`crossresistance to subsequent endocrine therapies (Howell, 2002;
`Vergote et al, 2003). These studies used the retrospective analysis
`of data derived from questionnaires sent to clinicians who were
`involved in trials of fulvestrant as first- or second-line therapy
`(Osborne et al, 2002; Robertson et al, 2002). This methodology
`imposes
`certain limitations on the analyses. However,
`the
`information obtained from these studies does provide further
`evidence with regard to establishing sequencing regimens.
`Responses to subsequent endocrine therapy in patients who
`progressed on fulvestrant or tamoxifen as first-line therapy for
`advanced disease have been examined in a retrospective analysis
`(Howell, 2002). The limitations of this analysis are illustrated by
`the fact that while 170 patients derived CB on fulvestrant, follow-
`up data on patients who received subsequent endocrine therapy
`were available for only 35 of these. In these patients, subsequent
`endocrine therapy produced CB in 20 out of 35 (57%) patients,
`with AI-based therapy producing CB in 11 out of 22 (50%) patients
`(Table 1). It is interesting to note that in those patients who failed
`to derive CB from fulvestrant, subsequent endocrine therapy
`produced a similar number of responses to those seen in patients
`who did derive CB from fulvestrant (15 out of 35 (43%) and 20 out
`of 35 (57%), respectively; Table 2). While the selection of patients
`and patient numbers included in this analysis are limited by the
`nature of the data collection, they do indicate that responses may
`be obtained with AIs and other endocrine therapies
`after
`progression on fulvestrant.
`In another retrospective analysis, 186 patients in total derived
`CB on second-line fulvestrant, although questionnaire-based
`follow-up data were available for only 54 of these patients (Vergote
`et al, 2003). The results showed that treatment with endocrine
`therapy (predominantly AIs) after second-line fulvestrant pro-
`duced CB in 25 out of 54 (46%) patients and objective response
`(OR, CR+PR) in four out of 54 (7%) patients who obtained CB
`with second-line fulvestrant (Table 1). In patients who failed to
`derive CB from second-line fulvestrant, further endocrine therapy
`produced CB in 18 out of 51 (35%) patients and OR in one out of
`51 (2%) patients (Table 2). Preliminary analyses demonstrated a
`median duration of response to subsequent therapy of 383 and 318
`days, for patients who did and who did not derive CB from second-
`line fulvestrant,
`respectively. Further endocrine therapy after
`progression on fulvestrant
`is therefore a viable and effective
`therapeutic option, with responses seen in patients treated with
`
`Response to subsequent therapy in patients who derived clinical
`Table l
`benefit (CB) from fulvestrant
`
`Number of patients
`
` CR PR SD 224 weeks PD Total
`
`Patients who derived CB from first-line fulvestrant
`Endocrine therapy tota/
`|
`2
`I7
`Aromatase inhibitors
`|
`|
`9
`Tamoxifen
`O
`|
`7
`Megestrol acetate
`0
`O
`|
`Medroxyprogesterone acetate
`0
`O
`O
`
`Patients who derived CB from second-line fulvestrant
`Endocrine therapy tota/
`O
`4
`2|
`Aromatase inhibitors
`0
`3
`I6
`Megestrol acetate
`0
`|
`5
`
`I5
`|
`|
`2
`O
`2
`
`29
`27
`2
`
`35
`22
`IO
`|
`2
`
`54
`46
`8
`
`(2002) with permission of Breast Cancer Research and
`Adapted from Howell
`Treatment (Vergote et a/, 2003). CR:compIete response; PR:partiaI response;
`SD : stable disease; PD : progressive disease.
`
`British Journal of Cancer (2004) 90(Suppl
`
`I), S I 575 I 8
`
`© 2004 Cancer Research UK
`
`AstraZeneca Exhibit 2065 p. 2
`
`

`

`tamoxifen and megestrol acetate as well as AIs such as anastrozole
`and letrozole.
`
`fulvestrant has
`and postanastrozole setting. More specifically,
`been shown to be at least as effective as anastrozole in women
`
`Fulvestrant and the sequential endocrine cascade
`S Iohnston
`SI7
`
`DISCUSSION
`
`It is important to be aware of the sequence versatility of fulvestrant
`so that it may be effectively and appropriately incorporated into
`the endocrine sequence cascade. Fulvestrant has demonstrated
`efficacy in the
`treatment of postmenopausal women with
`advanced, hormone-sensitive breast cancer, with data indicating
`that fulvestrant exhibits this activity in both the post-tamoxifen
`
`Table 2 Response to subsequent therapy in patients who did not derive
`clinical benefit (CB) from fulvestrant
`
`Number of patients
`
`CR PR SD 224 weeks PD Total
`
`Patients who did not derive CB from first-line fulvestrant
`Endocrine therapy tota/
`O
`3
`I2
`Aromatase inhibitors
`0
`O
`8
`Tamoxifen
`O
`3
`2
`Megestrol acetate
`0
`O
`I
`Medroxyprogesterone acetate
`0
`O
`I
`
`20
`I
`I
`7
`O
`2
`
`Patients who did not derive CB from second-line fulvestrant
`Endocrine therapy tota/
`O
`I
`I7
`33
`Aromatase inhibitors
`0
`I
`I5
`26
`Megestrol acetate
`0
`O
`I
`5
`Medroxyprogesterone acetate
`0
`O
`I
`2
`
`35
`I9
`I2
`I
`3
`
`5|
`42
`6
`3
`
`(2002) with permission of Breast Cancer Research and
`Adapted from Howell
`Treatment. (Vergote et ai, 2003). CR:compIete response; PR:partiaI response;
`SD : stable disease; PD : progressive disease.
`
`First-line
`
`Tamoxifen
`
`Second-line Fulvestrant AI
`
`AI
`Fulvestrant
`
`
`Tarn'oxifen Fulvestiant Tainoxifen
`
`Third-line
`
`AI Fulvestrant Tanioxifen AI
`
`Fulvestrant
`
`MA
`Fourth-line
`AI = aromatase inhibitor
`
`MA
`
`MA = megestrol acetate
`
`MA
`
`MA
`
`Tamoxifen
`
`MA
`
`fulvestrant within the available
`Proposed positions of
`I
`Figure
`endocrine therapies for the sequential
`treatment of postmenopausal
`women with hormone receptor—positive, advanced disease. Adapted from
`Carlson (2002) with permission of Breast Cancer Research and Treatment.
`
`on
`progressed
`have
`disease who
`hormone-sensitive
`with
`(Howell
`et
`al,
`2002;
`first-line
`therapy (mainly tamoxifen)
`Osborne et al, 2002; Robertson et al, 2003), with preliminary
`data
`showing promising results
`after progression on AIs
`(Perey et al, 2002). Fulvestrant has also been used in patients
`pretreated with several endocrine agents
`as well as chemo-
`therapy. In one report, an overall CB rate of 60% was obtained,
`although patients who were treated with fulvestrant earlier
`in the sequence appeared to obtain better
`responses
`than
`those who received it after progression on three endocrine agents
`(Steger et al, 2003a).
`In patients who undergo disease progression on fulvestrant, the
`novel mode of action of this new endocrine therapy ensures a lack
`of crossresistance to other current endocrine agents (Howell, 2002;
`Vergote et al, 2003). Thus,
`the early use of fulvestrant
`in the
`sequence of endocrine therapies may not limit later choices of
`endocrine therapy. Fulvestrant can,
`therefore, potentially be
`integrated into sequential endocrine regimens at a number of
`positions, including the second-line setting after tamoxifen, or,
`potentially, after AIs
`(Figure 1). Endocrine therapies such as
`megestrol acetate or the steroidal AI exemestane may then be
`employed as necessary after progression on fulvestrant. In this
`way, the potentially most effective and well-tolerated agents are
`used earlier in the treatment sequence.
`To optimise the positioning of fulvestrant in the sequence of
`endocrine therapies, additional
`studies will be required to
`elaborate upon the data so far accrued. New phase II and III
`clinical trials of fulvestrant in over 3000 patients are either planned
`or currently in progress (Table 3). These will investigate additional
`roles for fulvestrant in breast cancer therapy, either following prior
`nonsteroidal AI treatment or in combination with AIs as first-line
`
`loading-dose fulvestrant regimens will be
`therapy. In addition,
`tested. Two randomised, controlled trials are comparing the
`efficacy and tolerability of fulvestrant vs exemestane in post-
`menopausal women progressing after long-term oestrogen depri-
`vation resulting from prior AI therapy. The primary aim of the
`Study Of Faslodex vs Exemestane with/without Arimidex (SOFEA)
`trial is to compare progression-free survival in patients who have
`progressed on a nonsteroidal AI, and who are subsequently treated
`with either
`fulvestrant plus continued anastrozole, or with
`fulvestrant alone. Secondary aims
`include a comparison of
`fulvestrant vs exemestane and an examination of biological
`markers of response. A further trial, the Evaluation of Faslodex
`vs Exemestane Clinical Trial
`(EFECT)
`is currently recruiting
`patients to assess the efficacy of fulvestrant vs exemestane in
`patients who have progressed on treatment with nonsteroidal AIs.
`In addition, two trials (FACT and SWOG 226) will compare the
`efficacy of a combination of fulvestrant plus anastrozole with
`anastrozole alone in the first-line setting (Table 3). The results of
`
`Table 3 New phase II/II clinical trials of fulvestrant in over 3000 breast cancer patients
`
`Phase
`
`Population
`
`Treatments
`
`Patients (n)
`
`
`
`Trial
`
`
`
`NCCTG
`SAKK
`EFECT
`SOFEA
`FACT
`SWOG 226
`0057
`FAST
`
`I
`I
`
`I
`I
`
`I
`I
`I
`I
`
`
`
`Pos—tamoxifen or pos—AIs
`Pos—tamoxifen or pos—AIs
`Pos—nonsteroidal AI
`Pos—nonsteroidal AI
`Firs—line
`Firs—line
`Neoadjuvant
`Neoadjuvant
`
`
`
`Fulves'rant 250 mg
`Fulves'rant 250 mg
`Fulves'rant LD 250 mg vs exemestane
`Fulves'rant LD 250 mgianastrozole vs exemestane
`Fulves'rant LD 250 mg+anastrozo|e vs anastrozole
`Fulves'rant 25O mgfianastrozole vs anastrozole
`Fulves'rant 25O mgfianastrozole vs anastrozole
`Fulves'rant HD vs tamoxifen
`
`
`
`
`
`89
`93
`660
`75O
`558
`690
`|2O
`60
`
`NCCTG : North Central Cancer Treatment Group; SAKK: Swiss Group tor Clinical Cancer Research; EZECT: Evaluation of Faslodex vs Exemestane Clinical Trial;
`SOFEA: Study Of Faslodex vs Exemestane with/without Arimidex; SWOG : Southwest Oncology Group; LD 250 mg : loading—dose schedule of fulvestrant: 500 mg day 0,
`250 mg days I4 and 28, tulves rant 250 mg per monthly thereafter; HD : high—dose schedule of uIvestrant 750 mg 273 weeI<s presurgery.
`
`© 2004 Cancer Research CK
`
`British Journal of Cancer (2004) 90(Suppl
`
`I), SI57SI8
`
`AstraZeneca Exhibit 2065 p. 3
`
`

`

`Fulvestrant and the sequential endocrine cascade
`S Iohnston
`818
`
`these will further define endocrine-sequencing
`trials such as
`strategies, particularly as AIs move forward into the first-line or
`adjuvant settings.
`Currently available data therefore indicate that fulvestrant will
`be a useful therapeutic option that may extend the opportunity for
`
`using endocrine therapies before reliance upon cytotoxic che-
`motherapy is necessary. Fulvestrant is also a versatile endocrine
`therapy that may be used at a variety of positions in the sequential
`use of endocrine therapy for postmenopausal women with
`advanced, hormone-sensitive breast cancer.
`
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`British Journal of Cancer (2004) 90(Suppl 1), 5157518
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`© 2004 Cancer Research UK
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`AstraZeneca Exhibit 2065 p. 4
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`