®
`
`The
`-
`nco ogrst
`
`Breast Cancer
`
`
`
`
`
`Fulvestrant (Faslodex®)—How to Make a Good Drug Better
`
`JOHN F. R. ROBERTSON
`
`Professorial Unit of Surgery, Nottingham City Hospital, Nottingham, United Kingdom
`
`Key Words. Breast cancer 0 Dose—response relationship 0 Drug ° Estrogen receptor 0 Fulvestrant ° Pharmacokinetics
`
`
`ABSTRACT
`
`Fulvestrant (Faslodex®; AstraZeneca Pharmaceuticals,
`Wilmington, DE) is an estrogen receptor (ER) antago-
`nist with a novel mode of action; it binds, blocks, and
`increases degradation of ER. Fulvestrant (at the ap-
`proved dose [250 mg/month]) is at least as effective as
`anastrozole (1 mg/day) in the treatment of postmeno-
`pausal women with hormone receptor—positive ad-
`vanced breast cancer (HR+ ABC) progressing or
`recurring on antiestrogen therapy, and is also an active
`first-line treatment. Although fulvestrant (250 mg/
`month) is clearly effective, it takes 3—6 months to
`achieve steady-state plasma levels. Steady-state concen-
`trations are approximately twofold higher than those
`achieved with a single dose; reaching this earlier, for ex-
`ample, via a loading-dose (LD) regimen (250 mg/month
`plus 500 mg on day 0 and 250 mg on day 14 of month 1),
`may allow responses to be achieved more quickly and
`limit the possibility of early relapse.
`
`Fulvestrant high-dose (HD) regimens (500 mg/month)
`offer the possibility of greater antitumor activity, be-
`cause (a) ER downregulation is a dose-dependent pro-
`cess (an approximately 70% reduction is observed with
`a single 250 mg dose of fulvestrant) and (b) evidence cor-
`relates greater ER downregulation with superior effi-
`cacy. A fulvestrant HD regimen offers the potential of
`achieving near 100% ER downregulation. There is also
`potential to increase fulvestrant—ER binding by reduc-
`ing plasma estrogen levels, for example, with concomi-
`tant aromatase inhibitor treatment.
`
`Several ongoing trials use LD, HD, and combination
`regimens; results from these studies are awaited with
`interest. Meanwhile, fulvestrant (250 mg/month) re-
`mains a valuable additional endocrine treatment for
`
`postmenopausal women with HR+ ABC recurring or
`progressing on antiestrogen therapy. The Oncologist
`2007;12:774—784
`
`Disclosure of potential conflicts of interest is found at the end of this article.
`
`
`INTRODUCTION
`
`Approximately 75% of breast tumors in postmenopausal
`
`women are estrogen receptor (ER)-positive and/or pro-
`gesterone receptor (PgR)-positive and these patients are
`therefore candidates for endocrine treatment [1]. Tamox-
`
`ifen was the mainstay of endocrine treatment for these
`
`juvant [4] settings because of their superior efficacy and
`tolerability profiles. Tamoxifen continues to be com-
`
`monly used, but many clinicians use it further down the
`treatment sequence. Despite these changes in clinical
`
`practice, most patients with advanced breast cancer ulti-
`mately experience a relapse or disease progression fol-
`
`patients for many years [2], but recently the third-gener-
`ation aromatase inhibitors (AIs) have started to be used
`ahead of tamoxifen in the first-line advanced [3] and ad-
`
`lowing endocrine treatment. As a result there is a need
`for new, non—cross-resistant, well-tolerated agents that
`
`can be integrated into the endocrine treatment sequence.
`
`Correspondence: John F. R. Robertson, M.D., Professorial Unit of Surgery, Nottingham City Hospital, Hucknall Road, Nottingham NG5
`lPB, United Kingdom. Telephone: 44—0115—8231876; Fax: 44—0115—8231877; e—mail: john.robertson@nottingham.ac.uk Received
`August 1, 2006', accepted for publication April 12, 2007. ©AlphaMed Press 1083—7159/2007/$30.00/0 doi: lO.l634/theoncologist.12—7—
`774
`
`The Oncologist 2007; 12:774—784 WWW.TheOncologist.com
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aq510'sseldpeuqum'1s130103u09qw:duqLuor}peptzommoq
`
`InnoPharma Exhibit 1090.0001
`
`

`

`Robertson
`
`775
`
`This may delay the need for the use of less well-tolerated
`cytotoxic drugs.
`Fulvestrant (Faslodex®; AstraZeneca Pharmaceuticals,
`
`Wilmington, DE) is a new ER antagonist with no estrogen
`agonist effects [5] and a novel mode of action; it binds,
`blocks, and increases degradation of ER protein, leading to
`an inhibition of estrogen signaling through the ER [6, 7].
`Because of its mode of action, there is potential for enhanc-
`ing the efficacy of this agent by using alternative dosing
`regimens. This and the potential of fulvestrant in combina-
`tion regimens are the focus of this review and discussion.
`
`ESTABLISHED CLINICAL EFFICACY AND
`TOLERABILITY 0F FULVESTRANT
`
`Tamoxifen-Resistant Advanced Breast Cancer
`
`Fulvestrant is the only endocrine therapy targeting the ER
`that has been shown to have efficacy in tamoxifen-resistant
`disease in phase III clinical trials [8, 9]. Trials 0020 and
`0021 compared the efficacy and tolerability of fulvestrant
`(250 mg/month, i.m. injection) with those of anastrozole (1
`mg/day, orally) in the treatment of postmenopausal women
`with advanced breast cancer whose disease had progressed
`or relapsed on prior antiestrogen therapy. A prospectively
`planned combined analysis of the data from these trials
`showed that fulvestrant was at least as effective as anastro-
`
`zole in terms of time to progression (TTP) (5.5 months ver-
`sus 4.1 months, respectively) [10]. Objective response
`(OR) (partial or complete response) and clinical benefit
`(CB) (OR or stable disease [SD] for 224 weeks) rates were
`
`also similar, as were the median durations of response. A
`retrospective analysis of the combined data from these trials
`showed that these drugs had similar efficacies in patients
`with and without visceral metastases [11]. In a subsequent
`combined analysis of survival data, the median overall sur-
`vival was not significantly different between treatments
`[12].
`
`Both drugs were well tolerated in these trials, with only
`approximately 1% of patients in each group withdrawing as
`a result of treatment-related adverse events (AEs). Irrespec-
`tive of causality, the most common AEs in both groups
`were hot flashes, nausea, asthenia, pain, and headache. The
`fulvestrant injection was well tolerated locally, with injec-
`tion-site reactions occurring in only about 1% of courses
`[10]. Of the seven AEs prospectively defined for statistical
`analysis (gastrointestinal disturbances, hot flashes, vagini-
`tis, weight gain, thromboembolic disease, urinary tract in-
`fection, and joint disorders), only joint disorders differed
`significantly between groups (5.4% versus 10.6% for ful-
`vestrant and anastrozole, respectively; p = .0036).
`Based on these trial results, fulvestrant received regula-
`
`www.TheOncologist.com
`
`tory approval in many countries as a second-line treatment
`for postmenopausal women with hormone-sensitive ad-
`vanced breast cancer after progression or relapse on anties-
`trogen therapy.
`
`First-Line Treatment of Advanced Breast Cancer
`
`A double-blind, randomized phase III trial (trial 0025) later
`compared fulvestrant (250 mg/month) with tamoxifen (20
`mg/day) in the first-line treatment of postmenopausal
`women with advanced breast cancer [13]. TTP was not sig-
`nificantly different in the fulvestrant and tamoxifen groups,
`but fulvestrant did not meet the criteria for noninferiority to
`tamoxifen in the intent-to-treat population. In these patients
`tamoxifen was associated with significant benefits in terms
`of the CB rate (54.3% versus 62.0%; p = .026), time to
`treatment failure (5.9 months versus 7.8 months; p = .026),
`and overall survival (36.9 months versus 38.7 months; p =
`.04). However, in a prospectively planned analysis of pa-
`tients with ER-positive and/or PgR-positive tumors (ap-
`proximately 80% of the population), that is, those most
`likely to respond to endocrine therapy, the median TTP was
`8.2 months for fulvestrant and 8.3 months for tamoxifen,
`while the CB and OR rates and overall survival were also
`
`similar between groups. The results of this trial were unex-
`pected given the fact that the third-generation AIs are supe-
`rior to tamoxifen in the first-line setting [14, 15] and that
`fulvestrant is at least as effective as anastrozole in the sec-
`
`ond-line setting [10].
`In trial 0025, fulvestrant was as well tolerated as tamox-
`ifen in terms of treatment-related AEs, and the most com-
`
`mon AEs (irrespective of causality) in both groups were
`nausea, asthenia, vasodilation, pain, and bone pain. Of the
`four prospectively defined AEs in this trial (gastrointestinal
`disturbances, hot flashes, thromboembolic disease, and
`
`vaginitis) only hot flashes differed between groups (17.7%
`versus 24.7% for fulvestrant and tamoxifen, respectively;
`p = .0501).
`
`OPPORTUNITIES FOR ENHANCING THE EFFICACY
`OF FULVESTRANT
`
`Historically, it has been common practice for clinical expe-
`rience to play a role in the evolution and optimization of the
`use of licensed anticancer treatments. For instance, various
`
`loading-dose (LD) and high-dose (HD) regimens of oral ta-
`moxifen have been evaluated in patients with advanced
`breast cancer [16—18]. For example, one such study in-
`cluded 37 patients and tested three different LD schedules
`of tamoxifen: 20 mg/m2 twice daily (BID), 40 mg/m2 BID,
`and 80 mg/m2 BID for 7 days, followed by 20 mg/m2 once
`daily thereafter, as well as two different 20 mg/m2 per day
`regimens [16]. At 20 mg/m2 BID, three of four patients
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aqfilo'sseldpetutaqdm'1s130103u09qw:duq11101}peptzommoq
`
`InnoPharma Exhibit 1090.0002
`
`

`

`776
`
`Fulvestrant—How to Make a Good Drug Better
`
`reached steady state within 1 week. All four patients receiv-
`ing the 40 mg/m2 BID dose were at steady state within 1
`week and all were within the minimum range known to be
`associated with response (70 —1 50 ng/ml) by 72 hours. In
`two patients receiving the 80 mg/m2 BID dose, levels
`known to be associated with a response were observed
`within 3 hours. In contrast, steady-state values were only
`obtained after 16 weeks’ chronic dosing in patients receiv-
`ing the standard schedule of 20 mg/m2 per day. Steady-state
`levels of tamoxifen increased with dose. Unfortunately, in
`this study, time to response was only analyzed for the over-
`all population (median, 6 weeks) and so the shorter time to
`
`steady state/higher steady-state levels cannot be correlated
`with any change in time to response. Interestingly, blood ta-
`moxifen levels known to be associated with response were
`
`still present 21 days after discontinuation, and tamoxifen
`was still detectable 6 weeks after treatment. Consequently,
`the authors suggested that it may be prudent to delay ER
`sampling of the tumor for 4 weeks after treatment discon-
`tinuation to reduce the risk for obtaining false-negative re-
`sults
`[16]. The different
`treatment schedules were
`
`reasonably well tolerated, although one patient receiving
`the highest LD experienced paroxysmal atrial tachycardia
`
`and two patients experienced flare reactions (receiving
`20 mg/m2 BID and 20 mg/m2 per day, respectively).
`Other side effects included headache, hot flashes, and
`nausea.
`
`A second study, including 70 patients, showed that an
`LD regimen of 160 mg on day 1 followed by 20 mg/day
`thereafter was well tolerated [17]. The authors noted that, in
`
`patients receiving the standard dose (20 mg/day), the min-
`imum time to response was 6—8 weeks, whereas in those
`receiving the LD regimen, one third of patients responded
`within 4 weeks. An LD regimen of 160 mg on days 1 and 2
`
`followed by 30 mg/day thereafter was later evaluated in a
`pharmacokinetic study in 14 patients. This dose schedule
`allowed achievement of steady-state tamoxifen levels
`within 1—2 weeks (steady-state metabolite levels were at-
`
`tained after 24 weeks of dosing) [18].
`Whilst 250 mg/month of fulvestrant is a clinically effec-
`tive dose, experience suggests that there may be opportuni-
`ties for further enhancing its efficacy with the use of
`
`alternative dosing regimens. Its novel mode of action also
`makes it an attractive agent for use in combination with
`other agents such as AIs or trastuzumab. Because the 250
`mg dose of fulvestrant is well tolerated, there is an oppor-
`
`tunity to use LD (500 mg day 0, 250 mg days 14 and 28 of
`month 1, and 250 mg every 28 days thereafter) or HD (500
`mg on days 0, 14, and 28, and 500 mg every 28 days there-
`after) regimens (Fig. 1).
`
`Fulvestrant LD Regimens—Potential for Shorter
`Time to Steady State and Lower Risk for Early
`Progression?
`As endocrine agents suppress the growth of hormone-re-
`sponsive cancer cells as opposed to having a direct cyto-
`toxic effect, it may take more time to see a treatment
`response with endocrine therapy than with chemotherapy
`[19]. Indeed, it has been noted that some patients may show
`signs of progression early on in endocrine treatment (that is,
`during the first 2 months), but if maintained on treatment
`they then go on to achieve ORs when the drug reaches ther-
`apeutic levels. During the early weeks of endocrine therapy,
`therefore, the clinician may be faced with the dilemma of
`whether or not to continue therapy or change to another
`treatment (for example, chemotherapy). In patients with
`hormone receptor—positive tumors, OR rates may be lower
`with endocrine treatment than with chemotherapy, but
`overall CB rates are similar. This is of importance, because
`SD on an endocrine therapy gives similar survival benefit to
`an OR [20—22]. Furthermore, ORs and SD on endocrine
`
`therapy are, on average, more durable than those achieved
`with chemotherapy [23].
`Pharmacokinetic and clinical data from phase III trials
`of fulvestrant have led to speculation that there may be
`scope to optimize its activity via the use of an LD regimen.
`In trials 0020 and 0021 it was determined that steady-state
`plasma concentrations of fulvestrant are approximately
`twofold higher with repeated administration than those
`achieved following a single dose, and that it can take 3—6
`months for fulvestrant to reach steady-state levels at the 250
`mg/month dose [24]. Encouragingly, the pharmacokinetic
`behavior of fulvestrant observed in these trials closely re-
`sembled the behavior predicted in pharmacokinetic models
`(Fig. 2) [24]. As a result of this, models have since been de-
`veloped to estimate the pharmacokinetic behavior of ful-
`vestrant LD and HD regimens (Fig. 3). Both models predict
`that these regimens may help fulvestrant reach steady-state
`levels more rapidly. Furthermore, a preliminary phannaco-
`kinetic study of the LD regimen has shown that steady-state
`fulvestrant levels were achieved within 1 month of treat-
`
`ment (AstraZeneca, data on file). Although the exact ther-
`apeutic threshold for fulvestrant has not been determined,
`attainment of steady state earlier on in treatment may have
`the potential of reducing the time taken to achieve therapeu-
`tic levels. Ongoing clinical trials will determine whether the
`use of an LD regimen also reduces the time taken to achieve
`a response. However, it is important to note that despite the
`time taken to achieve steady state, in trials 0020 and 0021
`the 250 mg/month dosage of fulvestrant was associated
`with a median time to response and TTP similar to those of
`anastrozole [10, 25]—a drug that takes only approximately
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aq510'sseldpetueqdpz'13130103u09qw:duq11101}peptzommoq
`
`Oiiecologist‘
`
`InnoPharma Exhibit 1090.0003
`
`

`

`Robertson
`
`777
`
`A Loading—dose regimen
`EFECT, SOFEA and FACT trials:
`500 mg
`250 mg
`250 mg
`250 mg
`250 mg
`Fulvestrant
`l
`l
`l
`
`until disease
`'
`|
`'
`|
`|
`|
`I
`l
`I
`|
`| .........................................,.' 250 "lg/month
`l
`a
`23
`55
`34
`Days
`progression or relapse
`
`Fulvestrant
`
`B High-dose regimen
`CONFIRM trial:
`
`500 mg
`500 mg
`500 mg
`500 mg
`500 mg
`l
`l
`l
`
`l
`|
`|
`'
`l
`l
`l
`I
`|
`I
`0
`28
`56
`
`Fulvestrant
`until disease
`|
`|.............................................u} 500 "lg/month
`34
`Days
`progression or relapse
`
`Fulvestrant
`
`Figure 1. Treatment schedules in loading—dose (A) and high—dose (B) fulvestrant regimens and examples of trials using such
`regimens.
`Abbreviations: CONFIRM, Comparison of Faslodex in Recurrent Metastatic Breast Cancer; EFECT, Evaluation of Faslodex
`and Exemestane Clinical Trial; FACT, Fulvestrant and Anastrozole Clinical Trial; SOFEA, Study of Faslodex With or Without
`Concomitant Arimidex Versus Exemestane Following Progression on Aromatase Inhibitors.
`
`A Loading close
`
`250 mg monthly plus 500 mg on day 0
`and 250 mg on day 14 of month 1
`- - - 250 mg monthly
`
`30
`
`25
`
`20
`
`(ng/ml) a
`
`<3
`
`O I
`O
`
`I
`28
`
`I
`56
`
`I
`84
`
`I
`112
`
`I
`140
`
`I
`168
`
`I
`I
`I
`I
`196 224 252 280
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aq510'sseJdpeuqurtz'1st30103uoeq1//:duqLuci}pepeorumoq
`
`
`
`
`
`Predictedplasmaconcentration
`
`100
`
`Cm“: approximately 8 ng/ml
`
`Mean plasma concentration:
`
`approximately 5 ng/ml
`
`
`Predicted 250 mg
`
`— Predicted 125 mg
`Predicted 50 mg
`o Observed 250 mg
`A Observed 125 mg
`- Observed 50 mg
`
`
`
`
`0.1I
`I
`I
`I
`|
`I
`I
`I
`|
`I
`I
`|
`I
`I
`l
`O 714212835424956637077849198
`
`
`
`Concentration(ng/ml)
`
`Days
`
`Figure 2. Fulvestrant single—dose pharmacokinetics: compar—
`ison between modeled and observed behavior. From Robert—
`
`son JF, Odling—Smee W, Holcombe C et al. Pharmacokinetics
`of a single dose of fulvestrant prolonged—release intramuscular
`injection in postmenopausal women awaiting surgery for pri—
`mary breast cancer. Clin Ther 2003;25:1440—1452, with per—
`mission from Excerpta Medica, Inc.
`
`7 days to reach steady-state levels and leads to maximal es-
`trogen suppression within 2—4 days [26]. It is notable that
`some patients receiving fulvestrant respond very quickly to
`treatment, suggesting there may be some level of interpa-
`tient variability in sensitivity to fulvestrant [25].
`Early attainment of therapeutic levels through the use of
`an LD regimen may be of particular value for those patients
`at risk for progressing early on during endocrine treatment.
`It is important to note, however, that no direct relationship
`among plasma level, ER downregulation, and clinical effi-
`cacy has been defined as yet. Nonetheless, the higher rate of
`early progression/relapse noted in the fulvestrant group in
`trial 0025 may theoretically be related to the time taken for
`this drug to reach steady-state plasma concentrations and a
`subsequent potential delay in maximal ER downregulation
`[24]. However, the dose and schedule were the same as used
`
`in trial 0020, in which fulvestrant was clearly as effective as
`anastrozole. A possible explanation for this difference in
`
`www.TheOncologist.com
`
`Time (days)
`
`B Higher dose
`— 500 mg monthly plus 500 mg on day 0 and 14 of month 1
`- - - 250 mg monthly
`---- -- 125 mg monthly
`
` Predicted
`
`plasmaconcentration
`
`O
`
`28
`
`56
`
`84
`
`112
`
`140
`
`168
`
`196 224 252 280
`
`Time (days)
`
`Figure 3. Pharmacokinetic models for loading—dose (A) and
`high—dose (B) fulvestrant regimens.
`
`progression rate between studies is that a small number of
`patients get a withdrawal response when discontinuing ta-
`moxifen [27]. Therefore, in trials 0020 and 0021, in which
`
`patients had previously discontinued tamoxifen because of
`acquired resistance, it is possible that this tamoxifen-with-
`drawal response compensated for any delay in achieving a
`
`InnoPharma Exhibit 1090.0004
`
`

`

`778
`
`Fulvestrant—How to Make a Good Drug Better
`
`therapeutic dose of fulvestrant. In contrast, in trial 0025, pa-
`tients were receiving fulvestrant as first-line endocrine ther-
`apy and so no carryover effect from previous treatment
`would have occurred. Thus, especially in the first-line set-
`ting, the use of an LD regimen may, in theory, help prevent
`patients from relapsing early on in treatment. However, it
`must be noted that approximately 30%—40% of hormone
`receptor—positive tumors will show de novo resistance and
`that these patients will still relapse early on in treatment
`even if steady-state plasma levels have already been
`achieved, as was noted in the anastrozole group in trials
`0020 and 0021.
`
`Ongoing Trials Including Fulvestrant LD
`Regimens
`The International, phase III Evaluation of Faslodex and Ex-
`emestane Clinical Trial (EFECT) is comparing the LD ful-
`vestrant
`regimen (plus exemestane placebo) with
`exemestane (25 mg/day, orally, plus fulvestrant placebo) in
`postmenopausal women whose disease has recurred or pro-
`gressed after prior nonsteroidal AI therapy. First results
`from this trial have recently been reported; the median TTP
`was 3.7 months for both treatments [28]. OR (7.4% versus
`6.7%) and CB (32.2% versus 31.5%) rates were also similar
`
`for LD fulvestrant and exemestane, respectively. Fulves-
`trant plasma level data confirmed that steady state was
`achieved within 1 month with this treatment regimen. In ad-
`dition, the phase III Study Of Faslodex with or without con-
`comitant
`arimidex
`versus Exemestane
`following
`progression on Aromatase inhibitors (SOFEA) is compar-
`ing the efficacy of fulvestrant alone with that of fulvestrant
`plus anastrozole, with a comparison with exemestane being
`a secondary aim. An LD regimen of fulvestrant is being
`used in both the monotherapy and combination therapy
`arms of this trial. However, none of the above trials actually
`compare the LD regimen with the approved dosing sched-
`ule—such comparisons are included in the Comparison of
`Faslodex in Recurrent Metastatic Breast Cancer (CON-
`
`FIRM) and Faslodex INvestigation of Dose evaluation in
`Estrogen Receptor-positive advanced breast cancer
`(FINDER) 1 and 2 studies. Further information on these
`
`studies is provided below.
`
`Fulvestrant HD Regimens—Potential for Greater
`ER Downregulation and Greater Efficacy?
`
`Correlation of ER Downregulation with Fulvestrant
`Dose
`
`Unlike the AIs, which reach a peak of pharmacological ac-
`tivity at established clinical doses (that is, >90% suppres-
`sion of estradiol) [26], there may be potential for greater
`
`biological activity with the use of higher doses of fulves-
`trant. Dose-dependent effects of fulvestrant on ER down-
`regulation have been demonstrated in two previous studies.
`In study 0018, the effects of a single i.m. dose of long-
`acting fulvestrant (50 mg, 125 mg, or 250 mg), continuous
`daily tamoxifen, or placebo for 14—21 days prior to surgery
`were compared in patients with primary breast tumors. The
`effects of these treatments on ER and PgR protein expres-
`sion were assessed by immunohistochemistry and reported
`as ER and PgR indices. All fulvestrant doses produced sta-
`tistically significant reductions in ER expression compared
`with placebo (Fig. 4). At the 250 mg dose, the fulvestrant-
`induced reduction was significantly greater than that ob-
`served with tamoxifen [29]. Significant reductions in PgR
`expression were also observed with the 125 mg and 250 mg
`fulvestrant doses compared with placebo. In contrast, ta-
`moxifen resulted in a significant increase in PgR expres-
`sion, a finding attributed to its partial agonist effects and
`further emphasizing the differences in mode of action be-
`tween fulvestrant and tamoxifen [29]. However, the level of
`
`ER downregulation appeared incomplete (approximately
`70%) following a single 250 mg dose of fulvestrant com-
`pared with levels achieved in earlier studies. Furthermore,
`authors of a sequential biopsy study have recently reported
`that even after 6 months of fulvestrant treatment, ER is still
`
`present in the tumor (at approximately 50% of baseline lev-
`els) [30].
`
`Dose-dependent effects on ER levels were also seen in
`an earlier study (study 0002) of the effects of daily so in-
`jections of short-acting fulvestrant (either 6 mg or 18 mg)
`for 7 days prior to surgery for primary breast cancer in 56
`postmenopausal women [31]. In patients with ER-positive
`tumors (28/56), overall fulvestrant treatment caused a sig-
`nificant reduction in the median ER index (0.73 versus 0.02
`
`pre- and post-treatment, respectively; p < .001) and the me-
`dian PgR index was reduced from 0.50 to 0.01 post-treat-
`ment (1) < .05). Greater ER downregulation was observed
`with fulvestrant at the 18 mg/day dosage (0.73 versus 0.01
`pre- and post-treatment, respectively; p < .01) than with the
`6 mg/day dosage (0.6 versus 0.06 pre- and post-treatment,
`respectively; p < .05) [31].
`Because ER downregulation appears to be a dose-de-
`pendent process, it may be possible to enhance ER down-
`regulation by further increasing fulvestrant steady-state
`plasma concentrations. Single doses of fulvestrant 50 mg,
`125 mg, and 250 mg resulted in mean plasma concentra-
`tions of 1 ng/ml, 2.5 ng/ml, and 5.0 ng/ml, respectively [32],
`whereas, pharmacokinetic data from trials 0020 and 0021
`demonstrated that multiple dosing of fulvestrant at 250 mg
`resulted in steady-state (trough) plasma levels in the range
`of 6—9 ng/ml [24]. In line with this, 18 mg/day of the ful-
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aq510'sseldpeuqupz13601031109111”duqLuci}pemeumoq
`
`Oiiecologist‘
`
`InnoPharma Exhibit 1090.0005
`
`

`

`Robertson
`
`>
`
`8O
`60
`
`40
`
`20
`0
`
`
`
`-
`
`,
`I
`
`
`
`--
`
`I
`.,
`
`
`
`h ll '8S
`p : .0006
`l——l
`l—I
`120
`H
`p: 026
`
`E A ~ [+E 2 100 NS
`
`
`8 LU
`l—I
`
`
`a) (I)
`p = .024
`i? H
`__
`
`O(1
`.03 9
`
`
`v 8
`
`8 -‘-
`0 ES
`C
`9
`g m
`D:LIJ
`a;
`GE)
`
`
`
`_-
`
`I
`
`
`
`_
`
`
`Placebo FulvestrantFulvestrant Fulvestrant Tamoxifen
`(n = 29)
`50 mg
`125 mg
`250 mg
`(n = 25)
`07:31)
`(n=32)
`(n=32)
`
`Overall treatment efiectp = .0003
`
`B
`
`100
`
`E $
`
`.9 ::
`
`4O
`
`as
`L
`CL C
`
`5 g
`‘5
`l
`
`20
`0
`
`H
`g
`l—I
`n5 LLl
`p = .0002
`g g 80
`p : .003
`9 (n
`Z +’ I?
`.—.
`g e
`60
`--
`Q o
`
`
`
`
`p = .0001
`l—l
`p : .000‘
`p = .0001
`
`—'__
`
`
`
`
`
`..
`
`
`
`.—
`k
`
`I
`
`a
`
`I
`
`Placebo FulvestrantFulvestrant Fulvestrant Tamoxifen
`(n = 28)
`50 mg
`125 mg
`250 mg
`(n = 21)
`07:29)
`(n:29)
`(n: 29)
`
`Overall treatment effectp = .0001
`
`Figure 4. Effects on cellular ER (A) and PgR (B) levels with
`fulvestrant (single 250 mg injection) and tamoxifen (20 mg/
`day for 14—21 days) treatment. From Robertson JF, Nicholson
`RI, Bundred N] et al. Comparison of the short—term biological
`effects of 7alpha—[9—(4,4,5,5,5— pentafluoropentylsulfinyl)—
`nonyl]estra—1,3,5, [10]—triene—3,17beta—diol (Faslodex) versus
`tamoxifen in postmenopausal women with primary breast can—
`cer. Cancer Res 2001;61:6739—6746, with permission of the
`American Association for Cancer Research.
`
`Abbreviations: ER, estrogen receptor; NS, not significant;
`PgR, progesterone receptor; SEM, standard error of the mean.
`
`vestrant short-acting formulation results in a mean plasma
`fulvestrant concentration of approximately 23 ng/ml,
`whereas 6 mg/day of this formulation results in a mean
`plasma fulvestrant concentration of approximately 7 ng/ml.
`Indirect comparison across these two studies suggests that
`higher mean fulvestrant plasma concentrations may lead to
`greater ER downregulation (Fig. 5), thereby leading to an
`expected increase in the downregulation of ER signaling.
`The pharmacokinetic model of the HD regimen compared
`with the fulvestrant regimens of 125 mg/month or 250 mg/
`month also suggests that higher mean plasma fulvestrant
`
`www.1heOncologist.com
`
`120
`
`.2
`5 A
`g E 100
`g m
`4? H
`80
`g g
`% 60
`gfi
`40
`.9 I
`OJ
`*9 g
`g E
`20
`O
`Lu
`
`779
`
`
`
`I 2—week data
`
`
`1-week data
`
`1 ng/ml
`/
`
`2.5 ng/ml
`/
`
`5 ng/ml
`/
`
`‘~
`‘
`
`
`
`23 ng/ml
`V
`T’V//~
`
`
`,fi /
`7 ng/ml _.
`250 mg 6 mg 18 mg
`(77:32) (n:6)(n:12)
`l
`l
`l
`SA 50.
`
`Placebo
`(0:29)
`
`50 mg
`(n:31)
`
`l
`
`125 mg
`(n:32)
`LA i.m.
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aq510'sseldpetueqdm'1s180100u09qw:duqLuci}pepBOIUAAOG
`
`Figure 5. ER downregulation following single doses of ful—
`vestrant long—acting (LA) and short—acting (SA) formulations.
`Data shown are 2 weeks and 1 week postdose, respectively; the
`mean plasma drug concentrations are indicated for the same
`time points. The shaded area represents the likely ER expres—
`sion predicted for a single 500 mg dose of fulvestrant, which
`pharmacokinetic modeling suggests will achieve a mean
`plasma level of approximately 14 ng/ml [29, 31].
`Abbreviations: ER, estrogen receptor; SEM, standard error
`of the mean.
`
`levels will be achieved (approximately 20 ng/ml) and
`steady state will be reached more quickly with the high ful-
`vestrant dose (Fig. 3).
`Thus, there would appear to be an opportunity to im-
`prove the activity of fulvestrant either through attaining a
`therapeutic dose earlier or through delivering a higher dose
`that would result in a higher concentration of fulvestrant,
`which in turn would increase downregulation of ER.
`
`Correlation of ER Downregulation with Clinical
`Efficacy
`Although the exact relationship between the level of ER
`downregulation and clinical efficacy is yet to be deter-
`mined, there is some evidence to suggest that greater ER
`downregulation may be associated with better treatment re-
`sponse. For example, a greater reduction in ER level after 6
`weeks of tamoxifen treatment was associated with a signif-
`icantly better quality of response (OR versus SD/disease
`progression) in 51 patients receiving treatment for primary
`breast cancer [33]. Gamma linolenic acid (GLA), an agent
`known to modulate the structure and function of steroid
`
`hormone receptors, has been shown to have selective anti-
`tumor activity. In a study comparing the activity of tamox-
`ifen alone with tamoxifen in combination with GLA,
`
`patients receiving the combination had significantly greater
`reductions in tumor ER levels at 6 weeks (1) = .026) and 6
`months (p = .019) and significantly faster clinical re-
`sponses (p = .010) than those receiving tamoxifen alone
`[34]. Similarly, in ER-positive human breast cancer xeno-
`grafts, mice receiving GLA in combination with tamoxifen
`
`InnoPharma Exhibit 1090.0006
`
`

`

`780
`
`Fulvestrant—How to Make a Good Drug Better
`
`had significantly greater ER reductions than mice receiving
`tamoxifen alone [35]. These data suggest that GLA may en-
`hance tamoxifen-induced ER downregulation, with a re-
`sultant effect on time to response. Furthermore, results of a
`study examining the relationship between ER downregula-
`tion and response to fulvestrant treatment were recently
`presented at the San Antonio Breast Cancer Symposium.
`Significant ER downregulation was seen at 4—6 weeks in
`patients experiencing CB (n = 25) with fulvestrant, but not
`in those progressing de novo (n = 5) [30, 36]. However,
`there appeared to be no obvious relationship between the
`level of ER downregulation at 4—6 weeks and the median
`TTP.
`
`Correlation of Efficacy with Fulvestrant Dose
`Both trials 0020 and 0021 originally included a 125 mg/
`month fulvestrant treatment arm. However, at a preliminary
`analysis (performed by an independent data monitoring
`committee), after patients had received 3 months of fulves-
`trant treatment at the 125 mg dose, no ORs had occurred
`and so this arm was dropped. Subsequent analysis showed
`that patients receiving the 125 mg dose of fulvestrant pro-
`gressed more quickly than those receiving the 250 mg dose
`(Fig. 6). Furthermore, results from a previous study assess-
`ing the pharmacokinetic behavior of different single doses
`of fulvestrant demonstrate that plasma concentrations are
`lower following a single 125 mg dose of fulvestrant (mean
`plasma fulvestrant concentration of approximately 2.5 ng/
`ml) than with the 250 mg dose (mean plasma fulvestrant
`concentration of approximately 5 ng/ml) [32]. Therefore, it
`is expected that steady-state plasma levels in patients re-
`ceiving the 125 mg/month dosage of fulvestrant would also
`be lower than those observed in patients receiving the 250
`mg/month dosage of fulvestrant. Because patients receiv-
`ing the 125 mg dose of fulvestrant showed a lower response
`rate and shorter TTP than those receiving the 250 mg dose,
`it seems possible that efficacy may be improved further
`with dosages above 250 mg/month [8, 9].
`A further strand of support for this hypothesis can be
`drawn from presurgical studies of fulvestrant in premeno-
`pausal women. One such study, in which premenopausal
`women received a single dose of fulvestrant of 250 mg
`while awaiting surgery for primary breast cancer, reported
`no effect on ER, PgR, or Ki67 levels with fulvestrant com-
`pared with placebo [37]. This is in contrast to results from a
`similar study in postmenopausal women, in which signifi-
`cant effects on these markers were observed with the same
`
`fulvestrant dose [29]. Fulvestrant is known to compete for
`the ER on virtually a one-to-one basis with estradiol, and
`premenopausal women have almost logarithmically higher
`systemic estradiol levels than postmenopausal women. For
`
`100
`0.9
`0.8
`
`‘
`
`Fulvestrant 125 mg
`— Fulvestrant 250 mg
`— Anastrozole1 mg
`
`
`
`Proportionnotprogressed
`
`
`
`
`
`“oz‘01Amnutzfuo1sen8Aqfilo'sseldpetunqdpz'13130103u09qw:duq11101}peptzommoq
`
`0
`
`100 200 300 400 500 600 700 800 900 1,000
`
`Statistical comparisons
`
`Time to progression (days)
`
`Anastrozole 1 mg VS. fulvestrant 125 mg: HR: 0.63; 95.14% Cl: 0.47, 0.84; p = 0.0018
`Fulvestrant 250 mg vs. anastrozole 1 mg: HR: 0.95; 95.14% 01:081. 1.10; p = 0.4596
`Fulvestrant 250 mg vs. fulvestrant 125 mg: HR: 0.59; 95.14% Cl: 0.44, 0.80; p = 00005
`
`Figure 6. Combined analysis of time to progression data from
`trials 0020 and 0021. From Robertson JF, Osborne CK, Howell
`A et al. Fulvestrant versus anastrozole for the treatment