Review
`
`Fulvestrant Revisited: Efficacy and Safety of the
`SOD—mg Dose
`
`Anthony Howell,1 Francisco Sapunar2
`
`Abstract
`
`Postmenopausal women with hormone receptor-positive advanced breast cancer are candidates for endocrine
`therapy. As the disease will eventually progress in most patients,
`it is important to investigate agents with novel
`modes of action to reduce the likelihood of treatment cross-resistance. Fulvestrant is an estrogen receptor antagonist
`with no known agonist effects that has been shown to be as effective as anastrozole following failure on tamoxifen,
`at the approved dose of 250 mg/mo. However, pharmacokinetic modeling and evidence of clinical efficacy in early
`trials, together with the favorable tolerability profile of fulvestrant 250 mg,
`led to suggestions that increasing the
`fulvestrant dose would lead to an improved benefit-risk profile. This review describes the rationale behind the
`development of a 500 mg/mo higher dose of fulvestrant and details relevant clinical trials,
`including the pivotal
`phase III COmparisoN of Faslodex In Recurrent or Metastatic breast cancer (CONFIRM) study. CONFIRM demon-
`strated a significant improvement in progression-free survival for fulvestrant 500 mg versus 250 mg in postmeno-
`pausal patients who had progressed on previous endocrine therapy. Here, we present and discuss a pooled safety
`analysis of CONFIRM and three further clinical studies demonstrating fulvestrant 500 mg to be well-tolerated with no
`evidence of dose-related adverse events. Overall, these data indicate an improved benefit-risk profile for fulvestrant
`500 mg versus 250 mg following failure on prior endocrine therapy, and suggest that fulvestrant 500 mg may be
`considered in future as initial endocrine treatment for advanced breast cancer.
`
`
`Clinical Breast Cancer, Vol. 11, No. 4, 204—10 © 2011 Published by Elsevier Inc.
`Keywords: Advanc d br ast canc r, Faslod x, Fulv strant, Hormone receptor, Postmenopausal
`
`Introduction.
`.
`.
`Breast cancer is the most common cancer in women in Europe and
`the United States and, because of a high prevalence of metastatic
`disease, is the most common cause of cancer deathl’2 Current treat—
`
`ment options for patients who have breast cancer depend on the
`extent of the disease, hormone receptor status, and the patient situ—
`ation in relation to menopause. For postmenopausal women with
`hormone receptor—positive early breast cancer, the recommended
`treatment is surgery, with or without radiotherapy, followed by en—
`docrine therapy.3 Patients with advanced disease are usually treated
`with a series of hormone therapies that follow one another after
`progression until the disease is considered endocrine non—responsive.
`
`
`
`1CRUK Department of Medical Oncology, University of Manchester, Christie
`Hospital NHS Trust, Manchester, UK
`2Formerly AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, UK
`Submitted: Oct 25, 2010; Revised: Jan 20, 2011; Accepted: Feb 16, 2011
`
`Address for correspondence: Anthony Howell, MD, CRUK Department ofMedical
`Oncology, University of Manchester, Christie Hospital NHS Trust, Wilmslow Road,
`Manchester, M20 4BX UK
`E-mail contact: anthony.howell@christie.nhs.uk
`
`At that point patients become candidates to receive less—tolerable
`-
`4,5
`CYtOtOXlC chemotherapy.
`Steroidal aromatase inhibitors (A1s; exemestane) and non—steroi—
`
`dal A1s (anastrozole and letrozole) have been established as the pre—
`ferred agents for the treatment of advanced breast cancer due to
`demonstrated increased eH‘icacy over tamoxifen, and are now used as
`
`first—line therapy for advanced disease.69 Despite these improve—
`ments, the disease will eventually progress in most patients, leaving a
`requirement for additional, non— cross—resistant treatment options to
`provide optimal disease control.10
`Fulvestrant is a selective estrogen receptor (ER) antagonist that,
`unlike tamoxifen, which exhibits partial agonist properties (associ—
`ated with increased risk of endometrial cancer, thromboembolic
`
`events, and tumor flare), has no known agonist effects. It has a novel
`mode of action, binding to the ER causing downregulation and deg—
`radation1 1; and tumors resistant to prior endocrine treatment such as
`tamoxifen and anastrozole remain responsive to treatment with ful—
`vestrant.12/15 Given as a 250 mg/ mo intramuscular injection, fulves—
`trant was approved for the treatment ofpostmenopausal women with
`advanced breast cancer who have progressed or recurred on prior
`anti—estrogen therapy following the results of registration Trials 0020
`
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`doi:
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`

`and 0021. Fulvestrant was well—tolerated and efficacious, demon—
`
`strating non—inferiority to anastrozole in this setting.16’18
`\Whereas fulvestrant 250 mg/mo was shown to be effective and
`potentially as good as any other hormone treatment in its licensed
`setting,
`its novel mode of action together with early clinical data
`suggested there may be an opportunity to further enhance eH‘icacy by
`investigating alternative dosing regimens. This review describes
`the rationale and subsequent clinical development of a higher
`500 mg/ mo dose of fulvestrant.
`
`Rationale for Using a Higher Dose
`of Fulvestrant
`
`The registration Trials 0020 and 0021 established the clinical
`efficacy and tolerability of fulvestrant 250 mg, but a third arm ini—
`tially investigating fulvestrant 125 mg was withdrawn from these
`studies due to lack of clinical benefit. Based on this observation, and
`
`with the favorable tolerability profile observed with fulvestrant
`250 mg in these trials, the possibility was raised that increasing the
`dose may improve the benefit—risk profile by further increasing ER
`downregulation and improving clinical efficacy.‘l6’18 In addition,
`Trial 0025 compared fulvestrant 250 mg/ mo with tamoxifen as a
`first—line treatment in postmenopausal women with advanced breast
`cancer. Although efficacy was similar between treatments, fulvestrant
`failed to meet the non—inferiority endpoint and patients seemed to
`progress quicker on fulvestrant than tamoxifen during the first 3
`months of therapy. Given that it takes 3 to 6 months for fulvestrant
`to achieve steady state, the authors hypothesized that the inclusion of
`a loading dose may also contribute to improve efficacy.19
`Evidence that increasing the dose of fulvestrant may improve
`efficacy was available from biological data in early clinical trials.
`Defriend et al20 first demonstrated a dose—dependent ER down—
`regulation after fulvestrant administration with a daily dose of
`either 6 mg or 18 mg fulvestrant (short—acting formulation) be—
`fore surgery. Study 0018 later demonstrated a dose—response ef—
`fect across the dose range for both ER and progesterone receptor
`expression and the Ki67 labeling index, following administration
`ofa single fulvestrant dose of50, 125, or 250 mg.19 ER reduction
`with fulvestrant 250 mg was greater than that achieved with ta—
`moxifen. However, ER expression was not completely suppressed
`(approximately 70% reduction from baseline) and it was sug—
`gested that further increasing the dose of fulvestrant could lead to
`even greater ER downregulation.
`Because of the importance of achieving therapeutic drug levels
`quickly, pharmacokinetic models were developed to evaluate the
`effect ofboth a loading dose component and a high dose (500 mg)
`of fulvestrant. Reassuringly,
`the predicted pharmacokinetic
`model data were shown to closely match the pharmacokinetic
`data from Trials 0020/0021 with plasma fulvestrant concentra—
`tions approximately two—fold higher following repeat administra—
`tions of fulvestrant 250 mg versus a single administration, and
`steady—state plasma concentrations reached at 3 to 6 months with
`the fulvestrant 250 mg/mo dosing regimen.21 Subsequently, the
`model predicted that a 500 mg/mo high—dose regimen could re—
`sult in higher fulvestrant plasma concentrations (approximately
`two—fold higher than with fulvestrant 250 mg) and enable steady—
`
`state levels to be achieved more quickly (within 1 month) com—
`pared with the approved 250—mg dose.22
`
`Clinical Evidence To Support a
`Higher Dose of Fulvestrant
`At the approved dose, fulvestrant
`is administered as a single
`250—mg intramuscular injection every 28 days. In the 250—mg load—
`ing—dose regimen, referred to here as fulvestrant 250 mg + LD, an
`initial dose of 500 mg (2 x 250 mg injections) is given on day 0,
`followed by 250 mg fulvestrant on day 14 and day 28, with the
`250—mg dose continuing monthly thereafter. In the high—dose regi—
`men, which also incorporates a loading dose, 500 mg fulvestrant is
`administered on days 0, 14, 28, and every 28 days thereafter. Several
`key clinical studies have been conducted to investigate the alternative
`dosing regimens of fulvestrant in postmenopausal women with ad—
`vanced breast cancer, and these are summarized in Table 1.12’23’28
`
`The phase 111 Evaluation of Fulvestrant versus Exemestane Clin—
`ical Trial (EFECT) was designed to compare the fulvestrant 250 mg
`+ LD regimen with exemestane in women with advanced breast
`cancer who had progressed on prior non—steroidal A1 treatment. The
`clinical efficacy of fulvestrant 250 mg + LD was confirmed, and
`median time—to—progression (TTP) was 3.7 months for both treat—
`ments [hazard ratio (HR) = 0.963; 95% confidence interval (CI)
`
`0.819, 1.133; P = .65]. This study provided the first clinical evi—
`dence that steady—state plasma levels were achieved more quickly
`with the addition of a loading dose and the pharmacokinetic data
`generated closely matched the previous pharmacokinetic modeling
`data.‘l2’29
`
`The first clinical study to use the fulvestrant high—dose was a phase
`I trial in Japan, in which 10 patients received the 500—mg dosing
`regimen.24 Steady—state fulvestrant plasma levels were shown to be
`approximately two—fold higher than those achieved with the 250 mg
`+ LD regimen. In addition, the 500—mg fulvestrant dose was shown
`to be well—tolerated.24 In a phase 11 study, Neoadjuvant Endocrine
`therapy for Women with Estrogen—Sensitive Tumours (NEWEST),
`the biological activity of fulvestrant 500 mg was compared with
`fulvestrant 250 mg in the neoadjuvant setting. A significantly greater
`reduction in Ki67 labeling index was observed at week 4
`for fulvestrant 500 mg compared with the 250—mg dose (—78.8%
`versus —47.3% for the fulvestrant 500—mg and 250—mg groups, re—
`spectively; P < .0001). ER expression also showed a significantly
`greater reduction at week 4 for the fulvestrant 500 mg dose compared
`with the 250—mg dose (—25.0% versus —13.5% for the 500 mg and
`250 mg groups, respectively; P = .0002).25 Again, the pharmacoki—
`netic data confirmed that steady—state conditions were reached
`within the first month of dosing with fulvestrant 500 mg (compared
`with 3 months for fulvestrant 250 mg) and that steady—state expo—
`sures were approximately double those seen with the 250—mg dose.30
`The phase 11 Fulvestrant flet—line Study comparing endocrine
`Treatments (FIRST) trial compared fulvestrant 500 mg with anas—
`trozole in the first—line setting. Fulvestrant 500 mg was at least as
`effective as anastrozole in terms of the primary endpoint with clinical
`benefit rates of 72.5% and 67.0%, respectively [odds ratio (OR),
`1.30; 95% CI, 0.72, 2.38; P = .386]. Encouragingly, at the time of
`the primary analysis, TTP had not been reached for fulvestrant
`500 mg compared with 12.5 months for anastrozole (HR, 0.63; 95%
`
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`
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`Fulvestrant SOD—mg Dose
`
`Table 1 Overview of Key Trials Investigating Dosing Regimens of Fulvestrant
`Study Design and
`Reference
`
`Indication
`
`Treatment Groups
`
`Study Name
`
`EFEGT (D6997COOO48)
`
`Phase III; rando ized; double-blind;
`double-dum y; multicenter12
`
`Postmenopausal women With ER+
`advanced BC progressing af er prior non-steroidal Al
`
`Fulvestrar 250 mg —— LD
`Exemesta e 25
`g
`
`Study 062 (Dfiggscooom)
`
`Phase I, Open abely multicenter24
`
`Postmenopausal women With ER+; advanced or
`recurrent breast cancer
`
`Fulv_estrar 260 mg —— LD
`-, ves a
`500
`g
`
`NEWEST (D6997coooo3)
`
`FIRST (Dsggscooom)
`
`Phase II; randomized; 'Opei laggel;
`parallel gro,p; multicen er
`
`Phase II; randomized; opei label;
`parallel gro,p; multicen er28
`
`Pos
`
`Pos
`
`enopausal women Witr newly diagnosed; EH,
`locally advaiced BC
`
`enopausal women Witr advanced BC — first-line
`reatment
`
`FINDEm (D699700004)
`
`Phase II; rando lzed; doub e-Ebéind;
`parallel gro,p; multicen er
`
`_
`Post enopausal women With :R—I—; locally advanced BC
`rec. ring or progressng afte pror endocrine therapy
`
`FINDERZ (D6997coooo3)
`
`Phase II; rando lzed; doub e-Elind;
`parallel gro,p; multicen er
`
`_
`Post enopausal women With :R—I—; locally advanced BC
`rec. ring or progressng afte pror endocrine therapy
`
`3 ves a: 250
`-, ves a
`500
`
`3, ves a” 500
`Aiast ozole 1 mg
`
`Eves a” 250
`Fleestran
`250
`g + L)
`Eves a” 500
`
`Eves a” 250
`Fleestran
`250
`g + L)
`Eves a” 500
`
`CONFIRM (D699700002)
`
`Phase III; rando ized; doub e-Ebalind;
`parallel gro,p; multicen er
`
`Post enopausal women With :R—I—; locally advanced BC
`rec. ring or progressng afte pror endocrine therapy
`
`3 ves a: 250
`-, ves a
`500
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`g
`g
`
`g
`
`g
`
`g
`
`g
`
`g
`
`g
`g
`
`,D : loading dose (500 m on day 0; 250 mg on day 14).
`Abbreviations: Al : aromatase inhibitor; BC : breast cancer; ER+ : estrogen receptoripositive;
`Fulvestrant 250 mg: 250 mg days 0 and 28; 250 mg/mothereafter; Fulves rant 250 mg + LD: 500 mg day 0; 250 in days 1[ and 28; 250 mg/mo thereafter; Fulvestran 500 m : 500 in days 0;
`14 and 28; 500 mg/mo thereafter.
`
`CI, 0.39, 1.00; P = .0496).28 In an updated analysis, performed
`when 79.5% of patients had discontinued study treatment, median
`TTP was 23.4 months for fulvestrant 500 mg compared with 13.1
`months for anastrozole (HR, 0.66; 95% CI, 0.47, 0.92; P = .01).31
`Duration of response and duration of clinical benefit were also nu—
`merically in favor of fulvestrant 500 mg compared with anastro—
`zole.28 With FIRST and NEWEST investigating biological and clin—
`ical activity for fulvestrant 500 mg in the neoadjuvant and first—line
`advanced disease settings, the Comparison of FaslodeX in Recurrent
`or Metastatic Breast Cancer (CONFIRM) study was designed to
`elucidate the clinical role of fulvestrant 500 mg in ER—positive
`(ER+) advanced breast cancer following failure on prior endocrine
`therapy.
`The pivotal phase III CONFIRM study is a randomized, double—
`blind, placebo—controlled trial that was designed to assess the efficacy
`and safety of fulvestrant 500 mg versus fulvestrant 250 mg in patients
`who have progressed following prior anti—estrogen or AI therapy.23
`In total, 736 patients treated at 128 centers in 17 countries were
`randomized to receive fulvestrant 500 mg (n=362) or 250 mg
`(n= 374). The majority of patients had relapsed or progressed during
`adjuvant endocrine therapy (48.3% versus 45.2% for the fulvestrant
`500—mg and 250—mg groups, respectively) or were progressing on
`first—line endocrine therapy having previously presented with
`de novo advanced disease (35.9% versus 33.4% for the fulvestrant
`
`500—mg and 250—mg groups, respectively). No important differences
`in baseline characteristics were recorded between the groups.
`Progression—free survival, which was the primary endpoint of the
`trial, was 6.5 months in the 500—mg group, compared with 5.5 months
`for the 250—mg group (HR, 0.80; 95% CI, 0.68, 0.94; P = .006),
`indicating a significant improvement for the higher dose (Fig 1). This is
`equivalent to a 20% reduction in the risk of progression, clinically
`meaningful in the proposed indication. There was also a numerical
`
`advantage in the secondary endpoints of clinical benefit rate (OR,
`1.28; 95% CI, 0.95, 1.71; P = .100), overall survival (25.1 versus
`
`22.8 months for the 500—mg and 250—mg treatment groups, respec—
`tively; HR, 0.84; 95% CI, 0.69, 1.03; P = .091) and duration of
`clinical benefit (16.6 versus 13.9 months for the 500—mg and 250—mg
`treatment groups, respectively) for patients receiving fulvestrant 500
`mg. The objective response rate in patients with measurable disease
`at baseline was 33/240 (13.8%) for fulvestrant 500 mg and 38/261
`(14.6%) for fulvestrant 250 mg. Duration of response was similar
`between the two treatment groups (19.4 versus 16.4 months for the
`500—mg and 250—mg groups, respectively, calculated from the date of
`randomization). The pre—planned subgroup analysis showed a con—
`sistent treatment effect favoring fulvestrant 500 mg over fulvestrant
`250 mg across all subgroups analyzed; the eH‘icacy results were found
`to be similar, irrespective of whether the patient had progressed on
`prior anti—estrogen or prior AI therapy (Fig 2).
`In addition to the CONFIRM study, the phase II FaslodeX Inves—
`tigatioN of Dose evaluation in Estrogen Receptor—positive advanced
`breast cancer (FINDER) 1 and 2 studies were conducted onJapanese
`and European populations,
`respectively. Although the relatively
`small sample sizes did not permit confirmation of improved efficacy
`for fulvestrant 500 mg in the individual studies, the data allowed
`concerns of any ethnic differences in the efficacy and tolerability
`profiles of fulvestrant to be dispelled.26’27 The efficacy results from
`all of the described trials, including the phase III CONFIRM trial,
`definitively demonstrate that fulvestrant 500 mg is associated with
`increased efl'icacy over and above the 250—mg dose.
`
`Safety Analysis of Fulvestrant
`500 mg
`The safety data analysis of fulvestrant 500 mg and 250 mg was
`conducted on pooled data from four studies — CONFIRM, NEWEST,
`
`206
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`Figure 1 Kaplan-Meier Estimates for Progression-Free Survival (CONFIRM Study). Reprinted with permission. ©2008 American Society of Clinical Oncology. All rights reserved
`
`Anthony Howell, Francisco Sapumzr
`
`1 .0
`
`0.9
`
`
`
`Fulvestrant500 mg
`----- Fulvestrant 250 mg
`
`0'8
`0.7
`0.6
`
`0.5
`
`0.4
`
`Hazard ratio (95% CI): 0.80 (0.68, 0.94)
`Pvalue: 0.006
`
`ProportionofPatientsProgression-free
`
`
`
`0.3
`
`0.2
`
`0.1
`
`0.0
`
`Number of patients at risk:
`Fulvestrant 500 mg at risk
`Fulvestrant 250 mg at risk
`
`362
`374
`
`216
`199
`
`163
`144
`
`113
`85
`
`90
`60
`
`)
`
`Time Mo
`(
`37
`25
`
`19
`12
`
`54
`35
`
`12
`4
`
`7
`3
`
`3
`1
`
`2
`1
`
`0
`
`0 A
`
`bbreviation: CI, confidence interval.
`Tick marks indicate censored observations.
`
`Figure 2 Forest Plot from CONFIRM Showing Consistent Benefits of Fulvestrant 500 mg Over 250 mg in All Pre-planned Subgroup
`
`Analyses. Reprinted with permission. ©2008 American Society of Clinical Oncology. All rights reserved
`
`Receptor status
`
`Visceral involvement
`
`Response to last endocrine
`therapy prior to fulvestrant
`
`Measurable disease
`
`Age
`
`Last endocrine therapy
`prior to fulvestrant
`
`All patients
`
`—§—I——
`ER+ and PgR+
`ER+ and PgR— —l—l—
`or unknown
`I
`
`No
`Yes
`
`—-—E—
`—:.—
`
`—E—.——
`Responsive
`Poorly responsive —l—}—
`or unknown
`;
`No
`—-—I—
`Yes
`—§—l~——
`
`<65 years
`265 years
`
`—IE—
`—§—l——
`
`Aromatase inhibitor
`Antiestrogen
`
`—3—l——
`—I—}—|
`
`
`
`I
`0.40
`
`I
`0.60
`
`—I—
`i
`0.80
`
`1.00
`
`I
`1.25
`
`I
`1.50
`
`I
`1.75
`
`Hazard ratio (fulvestrant 500 mg vs fulvestrant 250 mg) and 95% Cl
`4 ------- - -
`Favors fulvestrant 500 mg
`Favors fulvestrant 250 mg
`------- - - >
`
`
`
`Abbreviations: CI, confidence interval; ER+, estrogen receptoripositive; PgR+, progesterone receptoripositive; PgRi, progesterone receptorinegative.
`
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`

`Fulvestrant SOD—mg Dose
`
`Table 2 Summary of Safety Data from Pooled Analysis
`
`Category of AE
`
`Any AE
`
`Any AE with Outcome =
`Death
`
`Any SAEa
`
`Any SAE with Outcome Other
`than Deathb
`Any CTCAE Grade 3 or
`Higher
`Any AE Leading to
`Discontinuation of Treatment
`(DAE)
`
`Fulvestrant
`500 mg
`n=560 (%)
`
`Fulvestrant
`250 mg
`n=567 (%)
`
`393 (70.2)
`
`387 (68.3)
`
`6 (1.1)
`
`48 (8.6)
`
`44 (7'9)
`
`84 (15.0)
`
`11 (2.0)
`
`7 (1.2)
`
`43 (7.6)
`
`38 (6'7)
`
`83 (14.6)
`
`13 (2.3)
`
`
`
`Any OAE 0 0
`
`
`
`Patients with multiple events in the same category are counted only once in that category.
`Patients with events in more than one category are counted in each of those categories.
`Abbreviations: AE : adverse event; CTCAE : common terminology criteria for AEs; DAE : disconi
`tinuation due to an AE; OAE : other significant AE; SAE : serious adverse event
`3The “Any SAE” category was not summarized in the NEWEST study.
`bAll patients experiencing an SAE with nonifatal outcome (regardless if they later had a fatal
`SAE).
`
`FINDERl and FINDER2 — which included data from 560 patients
`treated with fulvestrant 500 mg and 567 patients treated with
`250 mg. In the CONFIRM and both FINDER studies, patients
`were postmenopausal women with ER+ advanced breast cancer
`whose disease had relapsed either while receiving, or within 1 year
`of receiving, adjuvant endocrine therapy, or who had progressed
`on first endocrine therapy for advanced disease. However, in the
`NEWEST study, patients were postmenopausal women with
`newly—diagnosed ER+ locally advanced breast cancer in the neo—
`adjuvant setting.
`In general, both treatments were well—tolerated across the pooled
`studies. At least one AE was reported in 70.2% of patients in the
`500—mg group and 68.3% of patients in the 250—mg group, respec—
`tively. Six patients in the fulvestrant 500—mg group (1.1%) and seven
`patients in the 250—mg group (1.2%) died due to an AE. Serious AEs
`were reported in 8.6% ofpatients in the 500—mg group and 7.6% of
`patients in the 250—mg group. The incidence of AEs that led to
`discontinuation of study treatment was low: 2.0% and 2.3% for the
`500—mg and 250—mg groups, respectively (Table 2).
`In the overall pooled safety data analysis, the most frequently re—
`ported AEs were injection—site pain, nausea, hot flush, and headache.
`There was a small but not significant difference in the occurrence of
`injection—site pain, which was slightly higher in the 500—mg group
`(13.9%) than the 250—mg group (10.2%). There was a small increase
`in patients experiencing anorexia in the 500—mg group (5.7% versus
`3.5% for the 500—mg and 250—mg groups, respectively), but this was
`not associated with any change in mean weight. Incidence of back
`pain was slightly lower in the 500—mg group (7.1%) than the 250—mg
`group (9.5%). The number of patients experiencing events classified
`as Common Toxicity Criteria (CTC) grade 3 or higher was similar
`between the two groups: 84 (15.0%) in the 500—mg group and 83
`(14.6%) in the 250—mg group.
`
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`
`Clinical Breast Cancer August 2011
`
`Based on the known safety profile of fulvestrant and the potential
`safety issues associated with endocrine treatments, pre—specified AE
`categories were determined. These were endometrial dysplasia; gas—
`trointestinal disturbances; hot flushes; injection—site reactions; isch—
`emic cardiovascular disorders; joint disorders; osteoporosis; throm—
`boembolic events; urinary tract infection; vaginitis; and weight gain.
`These categories were analyzed using the Mantel—Haenszel test to
`estimate the overall relative risk (Table 3). Although there were some
`small numerical differences between the two treatment groups, these
`were not significant. Additionally, because the higher dose is associ—
`ated with more injections, a grouped analysis of hypersensitivity re—
`actions was also included using the same analytical approach. Slightly
`more hypersensitivity reactions were reported in the 500—mg group
`(5.5% versus 2.8% for the 500—mg and 250—mg groups, respectively)
`with the risk ratio determined to be 1.66 (95% CI, 0.91, 3.04).
`
`However, most reactions were CTC grade 1, and pruritus was the
`most common pre—specified AE reported (4.1% versus 1.4% for the
`500—mg and 250—mg groups, respectively). The occurrence of hyper—
`sensitivity reactions is not unexpected with the formulation limita—
`tions of fulvestrant requiring two 250 mg 5 mL injections for the
`high—dose 500—mg regimen.
`This large database can therefore provide reassurance that the
`500—mg dose has been sufficiently characterized in terms of safety.
`Fulvestrant 500 mg was well—tolerated with no clinically important
`differences compared with the 250—mg dose.
`
`Clinical Implications
`Treatment with tamoxifen or an AI is associated with a clinically
`meaningful benefit and an improved tolerability profile over chemo—
`therapy in women with hormone receptor—positive advanced breast
`cancer. However, most patients with advanced disease will ultimately
`progress; therefore, there is still a need to improve and build on
`current therapies.32 With an increasing number ofwomen treated in
`the first—line with tamoxifen or an AI, there is a key requirement to
`develop agents with novel modes of action which improve progres—
`sion—free survival following failure on these endocrine therapies. Ful—
`vestrant is an ER antagonist with no known agonist effects which has
`demonstrated efficacy at the currently approved dose of 250 mg
`following failure on prior endocrine therapy.18 The findings pre—
`sented here show that increasing the dose of fulvestrant is associated
`with improved eH‘icacy, based on a clinically relevant improvement
`in progression—free survival (20% reduction in the risk ofprogression
`for fulvestrant 500 mg versus 250 mg). This appears to be irrespective
`of the initial type of endocrine treatment received.
`It is possible that the higher dose of fulvestrant (500 mg) may lead
`to a reduction in rate or time to emergence of endocrine resistance.
`Cross—talk between the ER and the growth factor signaling pathways,
`such as the epidermal growth factor receptor (EGFR)/human epider—
`mal growth factor receptor 2
`pathway, is thought to be a
`mechanism of resistance to endocrine therapy in breast cancer.33 The
`greater reduction in available ER seen with fulvestrant 500 mg may
`therefore reduce or prevent such cross—talk, compared with tumors
`treated with the fulvestrant 250—mg dose regimen.
`With the ultimate aim of endocrine therapy in patients with ad—
`vanced breast cancer being to prolong progression—free survival and
`maintain a good quality oflife, it is important that any new treatment
`
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`

`Table 3 Relative Risk for Pre-Specified Adverse Events — Pooled Data
`
`
`Fulvestrant 500 mg (n=560)
`Fulvestrant 250 mg (n=567)
`
`Anthony Howell, Francisco Sapunar
`
`Mantel-Haenszel
`Relative Risk
`Estimate and
`95% c|c
`
`—
`
`0.83 0.65; 1.07
`
`0.96 0.65; 1.40
`
`1.07 0.80; 1.43
`
`0.56 0.20; 1.58
`
`0.82 0.62; 1.09
`
`—
`
`0.48 0.16; 1.42
`
`1.13 0.47; 2.67
`
`2.47 (0.26; 23.74)
`
`
`
`
`
`Specified AEsa
`
`Exposure (Patient Years)
`
`Endomefrial Dysplasia
`
`GI Disturbances
`
`Hot Flushes
`
`Injection-Site Reactions
`
`Events
`
`0
`
`119 (21.3%)
`
`55 (9.8%)
`
`101 (18.0%)
`
`lschemic Cardiovascular Disorders
`
`6 1.1%)
`
`Joint Disorders
`
`Osteoporosis
`
`Thromboembolic Events
`
`Urinary Tract Infection
`
`Vaginitis
`
`96 17.1%)
`
`4 0.7%)
`
`5 0.9%)
`
`12 (2.1%)
`
`3 0.5%)
`
`Event Rate/1000
`Patients"
`
`
`
`401.8 years
`
`Events
`
`
`
`Event Rate/1000
`Patients"
`
`339.3 years
`
`0
`
`299.0
`
`139.0
`
`255.8
`
`14.9
`
`239.8
`
`10.3
`
`12.6
`
`30.1
`
`7.4
`
`0
`
`123 (21.7%)
`
`50 (8.8%)
`
`82 (14.5%)
`
`9 (1.6%)
`
`99 (17.5%)
`
`0
`
`9 (1.6%)
`
`9 (1.6%)
`
`1 (0.2%)
`
`0
`
`360.1
`
`145.2
`
`240.2
`
`26.6
`
`291.1
`
`0
`
`26.4
`
`26.7
`
`3.0
`
`
`
`Weight Gain
`3 0.5%)
`7.7
`4 (0.7%)
`11.5
`0.66 0.15; 2.97
`
`
`Abbreviations: AE : adverse event; Cl : confidence interval; GI : gastrointestinal.
`3The combined analysis used the ManteliHaenszel approach 0 estimate the overall relative risk and 95% Cl; stratified by study.
`bThe AE event rate was calculated as the total number of AEs per group relative to exposure; measured as the total number of patient years on treatment; with the resultant rate expressed per 1000
`CIIalI/IlzrrlittZI*Haenszel <1.0 indicates a lower event risk in the ulvestrant 500 mg group; relative risk >1 indicates a lower event risk in the fulvestrant 250 mg group.
`
`demonstrating superior efficacy also has a favorable tolerability pro—
`file. The lack of evidence for any relevant dose—related AEs when
`using fulvestrant 500 mg/mo (other than allergic and injection—site
`reactions, which are expected with the higher dose) therefore makes
`it an attractive treatment option. Extended tamoxifen use is associ—
`ated with an increase in endometrial cancer34 and thrombogenic
`disease,35 and the third—generation AIs are associated with increased
`fractures and joint disorders.36’37 In contrast, joint disorders do not
`seem to be associated with fulvestrant, which may be important in
`some patient populations. The long—term safety of fulvestrant
`500 mg, however, is yet to be reported.
`Although several hormone therapies are indicated following
`failure on prior endocrine therapy, there is no clear consensus on
`the best approach. Until recently, current options were limited to
`steroidal AIs or fulvestrant 250 mg/mo, both of which have
`shown similar efficacy.12 The data described here indicate that
`fulvestrant 500 mg is associated with an improved benefit—risk
`profile versus fulvestrant 250 mg, and as such, has recently re—
`ceived approval in Europe and the United States for the treatment
`of postmenopausal women with locally advanced or metastatic
`breast cancer failing on prior anti—estrogen therapy. Fulvestrant
`500 mg may become the preferred treatment option for patients
`failing their initial endocrine therapy for early or advanced breast
`cancer, although no studies comparing fulvestrant 500 mg with
`exemestane are currently in progress.
`in
`impact
`Fulvestrant 500 mg/mo may also have a potential
`women with advanced breast cancer who have not received prior
`endocrine therapy for advanced disease. Unlike Trial 0025 which
`failed to demonstrate non—inferiority of fulvestrant 250 mg versus
`tamoxifen (the standard first—line treatment option at that time),38
`findings from the FIRST study, with a significant improvement in
`
`TTP and a greater duration of clinical benefit, suggest that fulves—
`trant 500 mg is at least as effective as anastrozole, a preferred endo—
`crine therapy in this setting.28 Indirectly, this suggests an improve—
`ment in clinical benefit for fulvestrant 500 mg versus fulvestrant
`250 mg as first—line endocrine treatment for advanced breast cancer.
`Based on the findings from CONFIRM and data from FIRST, one
`might speculate that fulvestrant 500 mg may also have a role in future
`first—line treatment of hormone receptor—positive patients with ad—
`vanced breast cancer, but its role remains to be proven in clinical
`studies in this setting.
`
`Conclusions
`
`Although the efficacy of fulvestrant 250 mg is well—established,
`pharmacokinetic modeling and early clinical data suggested that a
`higher dose may confer additional benefits. This has led to further
`clinical evaluation of fulvestrant 500 mg in hormone receptor—posi—
`tive women with advanced breast cancer.
`
`Strong evidence is described here to show that fulvestrant 500 mg
`is associated with an improved benefit—risk profile and, as such,
`should replace 250 mg as the preferred dose for postmenopausal
`women with advanced breast cancer.
`
`Acknowledgment
`We thank Simon Vass, PhD, from Complete Medical Commu—
`nications, who provided medical writing support,
`funded by
`AstraZeneca.
`
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`
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`
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