original article
`
`O’"”:3lf1%fil;§::i;iZf.Ztf,2l‘;
`Published online 21 May 2010
`
`Three dose regimens of fulvestrant in postmenopausal
`Japanese women with advanced breast cancer:
`
`results from a double-blind, phase II comparative
`study (FINDER1)
`
`S. Ohnol*, Y. Raig, H. lwata3, N. Yamamoto4, M. Yoshida5, H. lwasea, N. Masuda7,
`S. Nakamuraa, H. Taniguchig, S. Kamigakilo & S. Noguchi”
`1Division of Breast Oncology, National Kyushu Cancer Center, Fukuoka; 2Departrnent of Breast Surgery, Sagara Hospital, Kagoshima; 3Department of Breast Oncology,
`Aicni Cancer Center Hospital, Nagoya; "Department of Breast Surgery, Chiba Cancer Center, Chiba; 5Departrnent of Breast Surgery, Seirei Hamamatsu General
`Hospital, Shtuoka; 6Department of Breast and Endocrine Surgery, Kumamoto University Hospital, Kurnarnoto; 7Departrnent of Surgery, National Hospital Organization
`Osaka National Hospital, Osaka; 8Department of Breast Surgical Oncology, St Luke ‘s lnternational Hospital, Tokyo; 9Department of Surgery, The Japanese Red Cross
`Nagasaki/Atornic Bomb Hospital, Nagasaki; “Department of Surgery, Sakai Municipal Hospital, Osaka; ”Department of Oncology, Osaka University Graduate School
`of Medicine, Osaka, Japan
`
`Received 25 Ianuary 2010; revised 30 March 2010; accepted 30 March 2010
`
`Ea)
`E?)
`07':
`
`CE0
`
`Background: FINDER1 compared efficacy, tolerability and pharmacokinetics (PK) of three fulvestrant dose regimens
`in postmenopausal Japanese women with estrogen receptor (ER)—positive locally advanced/metastatic breast cancer
`recurring or progressing after prior endocrine therapy.
`Patients and methods: The primary end point of this randomised, multicentre, phase II study was objective
`response rate (ORR) and the secondary end points included time to progression (TlP), clinical benefit rate (GBR),
`PK profiles and tolerability. Postmenopausal women with ER—positive advanced breast cancer were randomised to 28-
`day cycles of fulvestrant approved dose (AD), loading dose (LD) or high dose (HD) until disease progression.
`Results: Hundred and forty—three patients (median age 61 years) received fulvestrant AD (n = 45), LD (n = 51) or HD
`(n = 47). ORR was similar across close regimens: 11.1%, 17.6% and 10.6% for AD, LD and -lD, respectively, with
`overlapping confidence intervals. ‘l'l'P and CBR were also similar between groups (median ‘l"P: 6.0, 7.5 and
`6.0 months, respectively; CBR: 42.2%, 54.9% and 46.8% for AD, LD and HD, respectively). Cmax and area under the
`plasma concentration—time curve were close proportional and PK steady state was reached earlier with LD and HD
`than with AD. All three doses were well tolerated, with a similar adverse—event profile and no emerging safety
`concerns.
`
`Conclusion: Fulvestrant AD, LD and HD had similar efficacy and tolerability profiles in postmenopausal Japanese
`women with ER—positive advanced breast cancer.
`Key words: advanced breast cancer, endocrine, Faslodex, fulvestrant, high close, loading dose
`
`introduction
`
`Fulvestram (Faslodexml is an estrogen receptor (ER)
`antagonist that is devoid of agonist activity [1]. The mechanism
`of action of fulvestrant differs from that of other endocrine
`
`therapies; on binding to the ER, fulvestrant induces a rapid
`degradation and loss of the ER and the progesterone receptor
`(PgR) [24]. Fulvestrant has demonstrated efficacy in several
`phase III clinical trials in postmenopausal women with
`advanced breast cancer [5—8]. Notably, the different
`mechanism of action of fulvestrant compared with other
`endocrine therapies affords a lack of cross—resistance with other
`
`*Ccrrespondence to: Dr S. Ohno, Department of Breast Surgery, National Kyushu
`Cancer Center, 3—1—1 Notame, Mlnaml—l<u, Fukuoka 811—1395, Japan.
`Tel. 81—90—551—4585, Fax. 81—90—541—3231, Email. s0hn0@nl<—cc.g0.lp
`
`endocrine therapies, and, consequently, fulvestrant has
`demonstrated efficacy in patients with recurrent disease
`following prior tamoxifen [6 8] and nonsteroidal aromatase
`inhibitor (AI) therapy [5]_
`y
`Fulvestrant is currently licensed in Europe and the United
`States for the treatment of postmenopausal women with
`advanced breast cancer who have progressed or recurred after
`previous endocrine (antiestrogen) treatment [9]. The efficacy of
`fulvestrant at the approved dose (AD, 250 mg/month) is well
`established [7, 8], but there is evidence to indicate that the
`efficacy of fulvestrant could be further improved by increasing
`the dose [3, 6, 10]. It has been hypothesised that greater efficacy
`b
`h’
`b
`'
`1
`'
`LD t
`h’
`t
`may 8 ac levéd Y uslng a .Oad1ng.d0Se (
`) 0 ac lave S eady
`Stat? more ql-ncpkly Or‘ by us]-ng a h1gh'dOSe (HD) fulvestrant
`regimen to achieve higher mean plasma fulvestrant levels,
`
`© The Author 2010. Published by Oxtord University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oxtordlournalsorg
`
`
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`ztzIIO1S91'1g/g.vI()'S1'BIII110_l"p.I0!,]fXO'3Il'0IIlIE’.//IduqIIIDJJPQPEOIHMOG
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`Astrazeneca Ex. 2006 p. 1
`Mylan Pharins. Inc. v. Astrazeneca AB IPR2016-01324
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`

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`Annals of Oncology
`
`without affecting tolerability [11]. Two recent studies have
`confirmed the feasibility of this approach. A small, pilot study
`in Japanese women (n = 20) showed fulvestrant HD to have
`good clinical activity and a favourable tolerability profile in the
`treatment of advanced or recurrent breast cancer [12].
`Furthermore, pharmacokinetic (PK) analysis demonstrated that
`fulvestrant HD achieved plasma levels approximately double
`those seen with fulvestrant AD. Pharmacodynamic evaluation
`in a neoadjuvant study comparing fulvestrant AD and HD
`regimens (n = 211) reported significantly greater Ki67 and ER
`down—regulation with fulvestrant HD than AD and that both
`doses were similarly well tolerated [13].
`The FINDER1 (Faslodex INvestigation of Dose evaluation in
`Estrogen Receptor—positive advanced breast cancer) study
`evaluates the efficacy, tolerability and PK profile ofthree different
`fulvestrant dose regimens (AD, LD and HD) in postmenopausal
`Iapanese women with ER—positive advanced breast cancer
`recurring or progressing after previous endocrine therapy.
`
`patients and methods
`FINDER1 (923811./0066; NCT00305448) is a randomised, double—blind,
`parallel—group, multicentre, phase II study conducted in japan. The primary
`objective of the study was to evaluate the objective response rate (ORR) of
`patients treated with fulvestrant AD, LD or HD, and secondary end points
`included determination of time to progression (TTP), clinical benefit rate
`(CBR), PK profiles and tolerability.
`
`patients
`Eligible patients were postmenopausal women with locally advanced/
`metastatic breast cancer who had demonstrated a positive ER status of
`primary or metastatic tumour tissue (210% positive staining by
`immunohistochemistry by local laboratory testing). Patients were required
`to have relapsed during, or $12 months after completion of, adjuvant
`endocrine therapy; be progressing on an endocrine therapy which was
`started 212 months after prior adjuvant endocrine therapy or be
`progressing on an endocrine therapy administered for de novo advanced
`disease. In addition, patients had to have measurable disease as per
`modified RECIST.
`
`All patients provided written informed consent and the study was carried
`out in accordance with the Helsinki Declaration and was consistent with
`International Conference on Harmonisation Good Clinical Practice. The
`
`study protocol was approved by the review boards of participating
`institutions.
`
`study treatment
`Patients were randomised 1 : 1 : 1 to fulvestrant AD (250 mg fulvestrant
`on days 0 and 28 and every 28 days thereafter, with two placebo injections
`given on day 14), fulvestrant LD (after an initial dose of 500 mg at day
`0 and 250 mg fulvestrant on day 14 and 28 and every 28 days thereafter)
`or fulvestrant HD (500 mg fulvestrant on days 0, 14 and 28 and every 28
`days thereafter) (Figure 1). Treatment with fulvestrant was continued
`until disease progression or until any other discontinuation criterion was
`met.
`
`143 postmenopausal women with ER-positive advanced breast
`cancer, progressing or relapsing after prior endocrine therapy
`
`Randomisation 1:1 :1
`
`Fulvestrant AD‘
`(n=45)
`
`Fulvestrant LD"
`(n=51)
`
`Fulvestrant HD‘
`(n=47)
`
`Fo|low—up visits
`(study treament)
`
`Disease progression
`
`‘AD (approved dose) =250 mg (1 fulvestrant injection and 1 placebo injection) on Days 0, 28 (13) and
`every 26 (13) days thereafter, and 2 additional placebo injections on Day 14- (13).
`'LD (loading dose) = after an initial dose of500 mg at Day 0 (2 fulvestrant injections), 250 mg fulvestrant
`(1 fulvestrant injection and 1 placebo injection) on Days 14 (13). 25 (13) and every 28 (:1-3} days thereafter.
`‘HD (high dose) = 500 mg fulvestrant (2 fulvestrant Injections) on Days 0, 14 (13), 28 (13) and every
`28 (13) days thereafter.
`ER, oestrogen receptor.
`
`Figure 1. FINDER1 study design.
`
`84. Two additional PK samples were collected between days 5 and 10 and
`between days 33 and 38.
`Tolerability was evaluated by assessment of adverse events (AEs)
`classified according to the National Cancer Institute—Common Toxicity
`Criteria for AEs (version 3.0) at baseline and at 4—weekly intervals
`thereafter. The primary analysis was carried out when all ongoing patients
`had been followed up for at least 24 weeks.
`
`statistical analysis
`As the aim of the study was selection of a dose regimen, sample size was
`calculated based on selection formulation [14], instead of hypothesis testing
`formulation. Overall, 43 patients per group were required for 90% probability
`that the best dose regimen by response rate be correctly selected [assuming
`that the smallest response rate was 19.2% (based on the result ofAD in previous
`studies) and the difference in response rate between the best and next best dose
`regimen was 15%]. To allow for dropout, a total of 135 patients were to be
`recruited to this study (45 patients per group). The point estimate and the
`corresponding two—sided 95% confidence interval (CI) were calculated for
`ORR and CBR for each treatment group. Kaplan—Meier plots were produced
`for TTP for each treatinent group and subgroup. Drug concentration—time
`data were analysed with NONMEM V5.0 using a nonlinear mixed—effects model
`approach, and the PK parameters [clearance (CL/F) and volume ofdistribution
`at steady state (Vdss/F), Cm”, Tm”, Cmin, area under the plasma
`concentration—time curve from time 0 to the last measurable concentration
`(AUC0_,) and tlg] were determined.
`
`results
`
`study assessments
`Efficacy was assessed by ORR, TTP and CBR (complete response, partial
`response or stable disease lasting 224 weeks, according to RECIST). All
`patients were followed up every 12 weeks for progression.
`PK samples were collected from a cohort of 70 patients in total, with
`sample collection at baseline and just before injection on days 14, 28, 56 and
`
`In total, 143 patients were recruited from 40 centres in Japan
`and randomised to receive fulvestrant AD (11 = 45), fulvestrant
`LD (n = 51) or fulvestrant HD (11 : 47). All randomised patients
`were included in the main analysis (full analysis set population),
`but one patient received no randomised treatment and was
`excluded from the safety population. Overall, 70 patients were
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`included in the PK analysis set (25, 21 and 24 patients in the
`AD, LD and HD treatment arms, respectively).
`Baseline characteristics were generally well balanced across
`the treatment groups (Table 1). Median age was 61 years. All
`patients were ER positive and approximately two—thirds of
`patients (68.5%) were PgR positive as well as ER positive. The
`majority of patients (97.9%) had metastatic disease and more
`than half (56.6%) had visceral involvement. In total, 33.6% and
`66.4% of patients had received prior radiotherapy and/ or
`chemotherapy, respectively, as well as prior endocrine therapy.
`The majority of patients (72.8%) had progressed during
`adjuvant endocrine therapy (44.1%) or endocrine therapy for
`de 1101/0 metastatic disease (28.7%). Patients received fulvestrant
`therapy for a median of 197, 225 and 213 days in the AD, LD
`and HD groups, respectively.
`
`primary end point
`
`The ORRs with the different fulvestrant dose regimens were
`similar: 11.1% (95% C1 3.7—24.1), 17.6% (95% C1 8.4—30.9)
`and 10.6% (95% Cl 3.5—23.1) for fulvestrant AD, LD and HD,
`respectively (Table 2). The ORR was numerically higher in the
`fulvestrant LD regirnen, but the Cls of all three treatment arms
`overlapped. The limited numbers of responders in each of the
`predefined subgroups meant that further subgroup analyses for
`efficacy parameters were not useful.
`
`secondary end points
`
`Median TTP was similar across the dose regimens: 6.0, 7.5 and
`6.0 months for fulvestrant AD, LD and HD, respectively, with
`a similar number of events observed between groups:
`30, 31 and 31 events, respectively (Figure 2). CBRs were similar
`across the dose regimens: 42.2% (95% CI 27.7—57.8), 54.9%
`(95% CI 40.3-68.9) and 46.8% (95% CI 32.1-61.9) for
`fulvestrant AD, LD and HD, respectively (Table 2).
`
`PK parameters
`A two—compartment model, with first—order absorption and
`first—order elimination, was fitted to the fulvestrant
`concentration—time data. CL/F was estimated at a mean of
`
`35.4 l/h and varied between individuals by ~31%, and the
`mean estimate of Vdss/F (=Vd1/F + Vd2/F) was 35300 l, with
`variation of Vdl/F among individuals by ~42%. Residual
`variability was proportional in nature [coefficient of variation
`(CV): 25%] and parameters were generally well estimated. The
`secondary parameters derived from the model are shown in
`Table 3. In the fulvestrant AD regimen, Cmin, CW, and AUC0_T
`values were higher in month 3 compared with month 1, but the
`values for fulvestrant LD and HD were similar or decreased in
`
`month 3 compared with month 1. These data indicate that
`steady—state exposures were reached in the first month of
`dosing with the LD and HD regimens and this was the result of
`an additional dose of fulvestrant given around day 14. Mean
`ti/2 was similar among the treatment regimens at ~29 days,
`indicating that 90% of steady—state exposure should be achieved
`in ~3 months with the AD regimen. The estimates of exposure
`at month 3 with the AD regimen were similar to that with
`the LD regimen and were close to half of that with HD,
`indicating linear PK. The secondary PK parameters obtained in
`this study were similar to those previously reported [15—17].
`
`Annals of Oncology
`
`Table 1. Patient baseline demographics and disease characteristics
`
`Fnlvestrant reginreri
`AD
`LD
`(n = 45)
`(:1 = '51)
`61 (5(L77)
`62 (43—86)
`Median age, years (range)
`WHO performance status, 11 (0/3)
`0
`39 (86.7)
`1
`6 (13.3)
`2
`0
`HR status
`
`44 (86.3)
`6 (11.8)
`1 (2.0)
`
`HD
`(n = 47)
`61 (45—83)
`
`40 (85.1)
`7 (14.9)
`0
`
`ER positive, PgR
`positive, 11 (0/0)
`ER positive, PgR
`negative, 11 (%)
`HER2 status, n (9%))
`Positive
`Negative
`Unknown
`Disease stage, n (%)
`Locally advanced only
`Metastatic
`Visceral involvement, 11 (%)
`Tumour histology, n (%)
`Infiltrating ductal
`carcinoma
`
`Infiltrating lobular
`carcinoma
`
`Other
`Tumour grade, 11 (%)
`1
`2
`3
`Unevaluable/
`unknown
`
`32 (71.7)
`
`36 (70.6)
`
`30 (63.8)
`
`13 (28.9)
`
`15 (29.4)
`
`17 (36.2)
`
`6 (13.3)
`36 (80.0)
`3 (6.7)
`
`1 (2.2)
`44 (97.8)
`26 (57.8)
`
`1 (2.0)
`50 (90.8)
`0
`
`2 (3.9)
`49 (96.1)
`28 (54.9)
`
`7 (149)
`40 (851)
`0
`
`0
`47 (100.0)
`27 (57.4)
`
`41 (91.1)
`
`50 (98.0)
`
`44 (93.6)
`
`1 (2.2)
`
`3 (6.7)
`
`6 (13.3
`20 (44.4
`7 (15.6
`12 (26.7
`
`1 (2.0)
`
`0
`
`5 (9.8)
`19 (37.3
`12 (23.5
`15 (29.4
`
`2 (4.3)
`
`1 (2.1)
`
`3 (6.4)
`18 (38.3
`13 (27.7
`13 (27.7
`
`21 (44.7
`33 (70.2
`47 (100)
`27 (57.4
`23 (48.9
`8 (17.0
`
`28 (59.6
`0
`
`6 (12.8)
`
`12 (25.5)
`
`1 (2.1)
`
`Prior therapy, n (92))
`12 (23.5
`15 (33.3
`Radiotherapy
`37 (72.5
`25 (55.6
`Chemotherapy
`51 (100)
`45 (100)
`Endocrine therapya
`28 (54.9)
`26 (57.8)
`Anastrozole
`19 (37.3
`19 (42.2
`Tamoxifen
`10 (19.6
`9 (20.0
`Exemestane
`Time of relapse in relation to endocrine therapy
`During adjuvant therapy
`18 (40.0
`17 (33.3
`0—12 months after
`5 (11.1
`2 (3.9)
`completion of adjuvant
`therapy
`>12 months after
`completion of
`adjuvant therapy
`During therapy
`for de 1101/0
`advanced disease
`Other
`
`10 (22.2
`
`15 (29.4)
`
`12 (26.7)
`
`17 (33.3)
`
`0
`
`0
`
`aUse ofmore than one endocrine agent in the adjuvant setting was acceptable.
`Endocrine therapies with 210% incidence in total are given in the table.
`AD, approved dose; ER, estrogen receptor; HD, high dose; HER2, human
`epidermal growth factor receptor 2; HR, hormone receptor; LD, loading
`dose; PgR, progesterone receptor; WHO, World Health Organization.
`
`
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`g[0z‘vz/Qremqa:1uo1san%’/(q/3.10'S[2LIJfl0l‘p.I0‘]LXO'OIIOULl‘B/,/Id11L[moi}p9p'eo[uAAo(1
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`Annals of Oncology
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`Table 2. Summary of best objective response
`
`Complete response, 11 (%)
`Partial response, 11 (0/0)
`Stable disease 224 weeks, 11 (%)
`Stable disease <24 weeks
`Progression, n (%)
`Not assessable, n (%)
`Objective response rate, 11 (%) [95% CI]
`Clinical benefit rate, 11
`(W0) [95% Cl]
`
`Fulvestrant regimen
`AD (11 = 45)
`2 (4.4)
`3 (6.7)
`14 (31.1)
`9 (20.0)
`17 (37.8)
`0
`5 (11.1) [3.7—24.1]
`19 (42.2) [27.7—57.8]
`
`LT) (n = 51)
`0
`
`9 (17.6)
`19 (37.3)
`5 (9.8)
`17 (33.3)
`1 (2.0)
`9 (17.6) [84309]
`28 (54.9) [40.3—68.9]
`
`HD (:14 = 47)
`0
`
`5 (10.6)
`17 (36.2)
`10 (21.3)
`14 (29.8)
`1 (2.1)
`5 (10.6) [3.5—23.1]
`22 (46.8) [321419]
`
`AD, approved dose; CI, confidence interval; HD, high dose; LD, loading dose.
`
`Fulvestrant regimen
`— AD
`LD
`HD
`
`
`
`
`
` Proportionnotprogressed
`
`11me (months)
`
`No. of patients at risk
`Fulvestrant AD
`45
`Fulvestrant LD
`51
`Fulvestrant HD
`47
`
`36
`42
`36
`
`22
`29
`24
`
`13
`16
`15
`
`6
`7
`8
`
`2
`3
`5
`
`AD, approved dose; HD, high dose; LD, loading dose.
`1’1ck marks indicate censored observations.
`
`Figure 2. Kaplan—Meier plot of time to progression.
`
`21
`
`24
`
`NON
`
`—oo
`
`ooo
`
`tolerability
`
`A total of 765 AEs were reported by 137 (96.5%) of the 142
`patients, including 8 patients (5.6%) who experienced a serious
`adverse event (SAE). The incidence of AEs was similar among
`the three treatment arms. There were few SAEs and no clinically
`important differences in SAE profiles among the three
`treatment arms. The majority of AEs were of mild or moderate
`intensity, with only 16.2% of patients experiencing
`AEs Zgrade 3. AEs required treatment discontinuation in three
`patients overall (2.1%); one patient discontinued from each
`treatment group. There were no deaths attributable to AEs.
`AEs observed in 210% of patients were nasopharyngitis
`(33.8%), injection—site pain (27.5%), hot flushes (18.3%),
`nausea (18.3%), injection—site induration (17.6%), fatigue
`(14.8%), constipation (11.3%) and headache (10.6%) (Table 4).
`Notably, all injection—site AEs were Sgrade 2 intensity, with the
`majority grade 1, and there were no dose—dependent differences
`in frequency or intensity between the treatment arms. There
`were notable changes in neither haematology and clinical
`chemistry nor vital signs and electrocardiogram.
`
`discussion
`
`The phase II FINDER1 study evaluated the relative efficacy and
`tolerability of three different fulvestrant dose regimens in
`
`Table 3. Secondary pharmacokinetic parameters for months 1 and 3
`
`Fulvestrant regitrnen
`AD
`LD
`
`25
`30.5 (3.4)
`Month 1 (visit 4)
`25
`11.1 (35.9)
`
`21
`28.4 (2.1)
`
`20
`17.0 (29.6)
`
`HD
`
`24
`29.2 (2.3)
`
`24
`28.7 (27.0)
`
`4.5 (3.8—5.2)
`
`3.5 (3.2—3.8)
`
`3.9 (364.4)
`
`3.02 (16.4)
`
`10.7 (22.2)
`
`17.8 (19.2)
`
`4370 (27.7)
`
`9260 (29.4)
`
`13000 (25.9)
`
`Month 3 (visit 7)
`20
`15.5 (30.3)
`
`20
`14.1 (30.0)
`
`20
`29.4 (23.8)
`
`4.2 (3.7—4.6)
`
`4.2 (3.944)
`
`4.2 (3.9—4.5)
`
`5.39 (20.1)
`
`5.87 (23.9)
`
`11.4 (18.2)
`
`6630 (24.7)
`
`6600 (26.6)
`
`13300 (20.6)
`
`Number of patients
`Mean t./2, days (SD)
`
`Number of patients
`Mean Cm,
`ng/ml (CV)
`Median Tm, days
`(minimum—
`maximum)
`Mean Cm,
`ng/ml (CV)
`Mean AUC0_T,
`ng h/ml (CV)
`
`Number of patients
`Mean Cm,
`ng/ml (CV)
`Median Tm, days
`(minimum—
`maximum)
`Mean Cm,
`ng/ml (CV)
`Mean AUCM,
`ng h/ml (CV)
`
`AD, approved dose; CV, coefficient of variation; HD, high dose; LD,
`loading dose, SD, standard deviation.
`
`postmenopausal Japanese women with ER—positive advanced
`breast cancer. The study was initiated because previous clinical
`and biological studies had indicated that there was a dose-
`response to fulvestrant and that the efficacy of 250 mg might be
`improved by increasing the dose [3, 6, 10]. In a presurgical trial
`in which postmenopausal women received a single injection of
`fulvestrant, dose—dependent reductions in K167, ER and PgR
`were observed, with no evidence of a plateau effect up to the
`maximum dose tested (250 mg/month) [3]. Clinical evidence
`supporting further dose increases emerged from a combined
`interim analysis of two phase III studies (trials 0020 and 0021)
`comparing two doses of fulvestrant (125 and 250 mg/month)
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`Volume 21 |No. 12 | December 2010
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`

`
`Table 4. Most commonly reported adverse events (25% in total)
`
`Adverse event,
`14 £%)
`
`Nasopharyngitis
`Injection—site pain
`Nausea
`Hot flush
`Injection—site induration
`Fatigue
`Constipation
`Headache
`Back pain
`Arthralgia
`Pyrexia
`Injection—site pruritis
`Stomatitis
`Anorexia
`Prurilis
`Insomnia
`
`Fulvestrant regimen
`AD
`LD
`(21 = 45)
`(n = 51)
`17 (37.8)
`15 (29.4)
`14 (31.1)
`11 (21.6)
`11 (24.4)
`9 (17.6)
`8 (17.8)
`11 (21.6)
`9 (20.0)
`6 (11.8)
`7 (15.6)
`7 (13.7)
`4 (8.9)
`7 (13.7)
`3 (6.7)
`8 (15.7)
`3 (6.7)
`6 (11.8)
`2 (4.4)
`7 (13.7)
`2 (4.4)
`4 (7.8)
`4 (8.9)
`2 (3.9)
`2 (4.4)
`3 (5.9)
`2 (4.4)
`4 (7.8)
`2 (4.4)
`3 (5.9)
`4 (8.9)
`3 (5.9)
`
`AD, approved close; HD, high dose; LD, loading dose.
`
`HD
`({n = 46)
`16 (34.8)
`14 (30.4)
`6 (13.0)
`7 (15.2)
`10 (21.7)
`7 (15.2)
`5 (10.9)
`4 (8.7)
`3 (6.5)
`2 (4.3)
`5 (10.9)
`4 (8.7)
`5 (10.9)
`3 (6.5)
`4 (8.7)
`1 (2.2)
`
`with anastrozole (1 mg/ day) in postmenopausal women with
`advanced breast cancer [6, 10]. This analysis demonstrated
`insufficient clinical activity with fulvestrant 125 mg/month
`compared with the 250 mg/month arm or the comparator,
`anastrozole, which prompted closure of this treatment arm.
`In the current study, two fulvestrant dose regimen
`modifications were employed that differed from the approved
`fulvestrant regimen. The total doses administered in the first
`month were 500, 1000 and 1500 mg for AD, LD and HD,
`respectively.
`Although the ORR and CBR were numerically higher for
`the fulvestrant LD compared with AD and HD regimen, the
`95% CIs overlapped substantially among all three
`treatment regimens. Furthermore, the Kaplan—Meier plots
`were similar between the three treatment regimens, although
`the median TTP was numerically higher for the fulvestrant
`LD compared with AD and HD regimens. Some potential
`difference in efficacy may have been missed due to the
`relatively small size of the present dose selection phase II
`study and thus any definitive conclusions could not be drawn
`regarding the recommended fulvestrant dose regimen in this
`population. A far greater sample size would be required to
`achieve statistical significance for each of the study end
`points.
`Phase III data were recently reported for fiilvestrant LD in
`postmenopausal women with ER—positive advanced breast
`cancer progressing or recurring after nonsteroidal AI therapy
`[5]. In this setting, fialvestrant LD and exemestane were equally
`efficacious and well tolerated.
`
`The phase II NEWEST (Neoadjuvant Endocrine Therapy for
`Women with Estrogen—Sensitive Tumors) study was the first
`study designed to evaluate fiilvestrant HD and fulvestrant AD
`as neoadjuvant endocrine therapy in postmenopausal women
`with locally advanced breast cancer [13]. In NEWEST,
`fulvestrant HD reduced the mean Ki67 labelling index to
`
`Annals of Oncology
`
`a significantly greater extent than AD at week 4, and this
`corresponded to a significantly greater reduction in ER
`expression at week 4 for HD versus AD. Furthermore, recent
`findings from the phase II FIRST (Fulvestrant fIRst—line Study
`comparing endocrine Treatments) study demonstrated that
`fulvestrant HD was at least as effective as anastrozole in terms
`
`of CBR and ORR and was associated with significantly longer
`TTP in the first—line advanced breast cancer setting [18].
`Fulvestrant HD has also been further investigated in the
`advanced disease setting. The CONFIRM (COmparisoN of
`Fulvestrant In Recurrent or Metastatic breast cancer) study was
`a large, randomised, double—blind phase III study designed to
`elucidate fully any benefit of fulvestrant HD versus AD in
`postmenopausal women with metastatic disease. The primary
`study end point of TTP was significantly longer for fi1lvestrant
`HD compared with fulvestrant AD (6.5 versus 5.5 months;
`hazard ratio 0.80; 95% CI 0.68-0.94; P = 0.006), a difference
`that corresponds to a 20% reduction in the risk of progression.
`Numerical advantages were also observed in CBR (45.6% versus
`39.6%), duration of clinical benefit (16.6 versus 13.9 months)
`and overall survival (25.1 versus 22.8 months) for patients
`treated with HD versus AD. Together with a favourable
`tolerability profile and no evidence of dose—related AEs, this
`equated to an improved benefit—risk profile for HD compared
`with AD [19].
`The mean population clearance seen in this study (35.4 : 4.9
`1/h, CV 31%) was similar to that determined for Japanese
`patients in a phase I study (28.4 : 5.4 1/h) [12] and for western
`patients in phase III studies (33.2 : 1.1 l/h) [17], and the phase
`II NEWEST study (34.5 l/h, CV 30%) [15]. The estimate of
`Vdss/F (35300 1, CV 42% for Vd1/F) was also similar between
`this study and the phase II NEWEST study (34400 1, CV up to
`72%). As expected, PK steady state was achieved earlier with
`fulvestrant HD and LD than with fulvestrant AD. Furthermore,
`the steady—state levels achieved were higher with fulvestrant HD
`than with fulvestrant AD and LD. The current results for
`
`fulvestrant LD are also consistent with the recently reported
`Evaluation of Faslodex versus Exemestane Clinical Trial
`(EFECT) PK data [16].
`In line with the findings of other fi1lvestrant studies in the
`advanced and early breast cancer settings [5, 13, 18], all three
`fulvestrant dose regimens (AD, LD and HD) were well
`tolerated, with no emerging safety concerns, and no differences
`were observed between the regimens. As expected, the most
`frequently reported treatment—related AEs were injection—site
`reactions, but all injection—site AEs were of Sgrade 2 intensity,
`with the majority being grade 1. None of the AEs at the
`injection site led to discontinuation of study treatment.
`A parallel study is being undertaken in Caucasian patients
`(FINDER2) and it is anticipated that evaluation of data from
`both these studies will help to determine any ethnic differences
`in the efficacy, tolerability and PK profiles of fulvestrant in ER-
`positive postmenopausal women with advanced breast cancer.
`
`conclusion
`
`While the current data alone do not allow determination of the
`
`optimum fi1lvestrant dose regimen, they confirm the clinical
`feasibility of the fulvestrant HD and LD regimens and add to
`
`2346 | Ohno et al.
`
`Volume 21 |No. 12 | December 2010
`
`
`
`g[0z‘vz/Qtemqa:1uo1s9n%’/(q)3Jo's1'euIt1o_l‘p.Iop:o'ou0uu12/,/:duqmoi}p9p'e0[uAA0(1
`
`
`
`
`
`Astrazeneca Ex. 2006 p. 5
`
`

`
`Annals of Oncology
`
`the data supporting the clinical efficacy and favourable
`tolerability of fulvestrant and its potential to overcome tumour
`resistance to previous endocrine agents, including Als, in
`patients with advanced breast cancer. However, together with
`the findings of the phase III CONFIRM study, which has since
`definitively clarified the tolerability and efficacy profiles of
`fulvestrant HD and AD, these data indicate that fiilvestrant HD
`may replace AD for treatment of postmenopausal women
`with ER—positive advanced breast cancer.
`
`funding
`
`AstraZeneca (for the conduct of the study, data collection and
`project management).
`
`acknowledgements
`
`We thank all the patients and investigators who participated in
`the FINDER1 study. We also thank Katrina de Saram, PhD,
`from Complete Medical Communications, who provided
`medical writing support funded by AstraZeneca.
`
`disclosures
`
`Hiroji lwata has received honoraria form AstraZeneca.
`Masayuki Yoshidahas received honoraria from Astrazeneca,
`Nippon Kayaku, Novartis. Hirotaka lwase has received
`honoraria from AstraZeneca and research funding from
`AstraZeneca, Chugai—Roche. Seigo Nakamura has received
`honoraria from AstraZeneca, Novartis, Pfizer, Ihonson &
`Ihonson. Shinzaburo Noguchi has received honoraria from
`AstraZeneca, Taiho, Chugai, Novartis, Pfizer, Takeda, Bristol-
`Myers Squibb.
`
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