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`original article
`
`Annals of Oncology 21: 2342—2347, 2010
`
`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. Ohno”, Y. Rai2, H. lwata3, N. Yamamoto“, M. Yoshida5, H. lwasee, N. Masuda7,
`S. NakamuraB, H. Taniguchig, S. Kamigaki1O & S. Noguchi11
`7Division of Breast Oncology, National Kyushu Cancer Center, Fukuoka; 2Department of Breast Surgery, Saga/a Hospital, Kagoshima; 3Department of Breast Oncology,
`Aichi Cancer Center Hospital Nagoya; 4Department of Breast Surgery, Chiba Cancer Center, Chiba; 5Department of Breast Surgery, Seirei Hamamatsu General
`Hospital, Shizuoka; 6Department of Breast and Endocrine Surgery, Kumamoto University Hospital, Kumamoto; 7Depan‘ment of Surgery, National Hospital Organization
`Osaka National Hospital, Osaka; BDepan‘ment of Breast Surgical Oncology, St Luke’s International Hospital, Tokyo; gDeparhnent of Surgery, The Japanese Red Cross
`Nagasaki Atomic Bomb Hospital, Nagasaki; 1(Department of Surgenl, Sakai Municipal Hospital, Osaka; 77Department of Oncology, Osaka University Graduate School
`of Medicine, Osaka, Japan
`
`Received 25 January 2010; revised 30 March 2010; accepted 30 March 2010
`
`
`Background: FINDER1 compared efficacy, tolerability and pharmacokinetics (PK) ofthree 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 (TfP), clinical benefit rate (CBR),
`
`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 dose regimens: 11.1%, 17.6% and 10.6% for AD, LD and -lD, respectively, with
`
`overlapping confidence intervals. ‘I'I'P and GER were also similar between groups (median T'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 dose 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 h postmenopausal Japanese
`
`women with ER—positive advanced breast cancer.
`Key words: advanced breast cancer, endocrine, Faslodex, fulvestrant, high dose, loading dose
`
`introduction
`
`Fulvestrant (FaslodeXT'V') 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) [2—4]. 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
`
`_
`*
`Correspondence to. Dr S. Ohno, Department of Breast Surgery, National Kyushu
`Cancer Center, 37171 Notame, Minamieku, Fukuoka 81171395, Japan.
`Tel: 81790755174585; Fax; 81790754173231; Eemail: sohno@nkecc.go.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].
`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
`may be achieved by using a loading dose (LD) to achieve steady
`,
`,
`,
`State 1’1’101‘9 qulckly 01‘ by usmg a high—dose (HD) fulvestrant
`regimen to achieve higher mean plasma fulvestrant levels,
`
`© The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
`All rights reserved. For permissions, please email: journals.permissions@oxtordjournalsorg
`
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`
`143 postmenopausal women with ER-positive advanced breast
`cancer, progressing or relapsing after prior endocrine therapy
`
`
`
`
`
`
`Randomisation 1 :1 :1
`
`
`
`
`
`Fulvestrant ADa
`
`(n=45)
`
`Fulvestrant LDb
`(n=51)
`
`Fulvestrant HDc
`(n=47)
`
`
`
`
`
`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 of three different
`fulvestrant dose regimens (AD, LD and HD) in postmenopausal
`Japanese women with ER—positive advanced breast cancer
`recurring or progressing after previous endocrine therapy.
`
`patients and methods
`
`FINDERI (9238IL/0066; NCT00305448) is a randomised, doubleeblind,
`parallele group, multicentre, phase H study conducted in Japan. The primary
`objective of the study was to evaluate the objective response rate (OR) 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 312 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 : I : 1 to fulvestrant AD (250 mg fulvestrant
`on days 0 and 28 and eveiy 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 eveiy 28 days thereafter)
`or fulvestrant HD (500 mg fulvestrant on days 0, l4 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.
`
`
`
`
`
`
`
`
`
`Follow-up visits
`(study treament)
`
`
`
`Disease progression
`'AD (approved dose) =250 mg (1 fulvestrant injection and 1 placebo injection) on Days 0,28 (t3) and
`every 28 (13) days thereafter; and 2 additional placebo injections on Day 14 (:3).
`hLD (loading dose) = after an initial dose of 500 mg at Day 0 (2 fulvestrant injections), 250 mg fulvestrant
`(1 fulvestrant injection and 1 placebo injection) on Days 14 (i3). 28 (i3) and every 28(t3) days thereafter.
`‘HD (high dose) = 500 mg fulvestrant (2 fulvestrant injections) on Days 0, 14 (:3), 28 (t3) and every
`28 (:3) days thereafter.
`ER, oestrogen receptor.
`
`Figure 1. FINDERI 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 InstituteiCommon Toxicity
`Criteria for AEs (version 3.0) at baseline and at 4eweekly 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 twoesided 95% confidence interval (CI) were calculated for
`OR and CBR for each treatment group. KaplaniMeier plots were produced
`for TTP for each treatment group and subgroup. Drug concentrafionitime
`data were analysed with NONMEM v5.0 using a nonlinear mixedreffects model
`approach, and the PK parameters [clearance ( CL/F) and volume ofdistribution
`at steady state (Vdss/F), Cmax, Tum, Cmin, area under the plasma
`concentrationrtime curve from time 0 to the last measurable concentration
`
`(AUC0_T) and tl/Z] were determined.
`
`results
`
`
`
`[oz[VZAmmqa:1Ho159mgAqfilo'sjiemnofpaogxo'ouot‘rue/fiduqmoi;pepBOIUMOG
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`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 (71 = 45), fulvestrant
`LD (11 = 51) or fulvestrant HD (71 = 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
`
`Volume 21 | No. 12 | December 2010
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`Annals of Oncology
`
`Table 1. Patient baseline demographics and disease characteristics
`
`
`1: feg‘ifiifll
`1321.)
`82512
`62 (43486)
`
`
`
`61 (SW77)
`Median age, years (range)
`WHO performance status, n (96)
`0
`39 (86.7)
`1
`6 (13.3)
`2
`0
`HR status
`
`HI}
`94:42)
`61 (45e83)
`
`44 (86.3)
`6 (11.8)
`1 (2.0)
`
`40 (85.1)
`7 (14.9)
`0
`
`ER positive, PgR
`positive, it (%)
`ER positive, PgR
`negative, 11 (0/0)
`HER2 status, 11 (0/0)
`Positive
`Negative
`Unknown
`Disease stage, n (%)
`Locally advanced only
`Metastatic
`Visceral involvement, n (0/6)
`Tumour histology, n (0/0)
`Infiltrating ductal
`carcinoma
`
`Infiltrating lobular
`Carcinoma
`
`Other
`Tumour grade, 11 (0/0)
`1
`2
`3
`Unevaluable/
`unknown
`
`1 (2.2)
`
`3 (6.7)
`
`6 (13.3
`20 (44.4
`7 (15.6
`12 (26.7
`
`10 (22.2
`
`
`
`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 (14.9)
`40 (85.1)
`0
`
`O
`47 (100.0)
`27 (57.4)
`
`41 (91.1)
`
`50 (98.0)
`
`44 (93.6)
`
`1 (2.0)
`
`2 (4.3)
`
`0
`
`5 (9.8)
`19 (37.3
`12 (23.5
`15 (29.4
`
`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
`
`Prior therapy, 11 (%)
`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 (2.0.0
`Exemestane
`Time of relapse in relation to endocrine therapy
`During adjuvant therapy
`18 (40.0
`17 (33.3
`0712 months after
`5 (11.1
`2 (3.9)
`completion of adjuvant
`therapy
`>12 months after
`completion of
`adjuvant therapy
`During therapy
`for dc: nova
`advanced disease
`Other 1 (2.1) 0 0
`
`15 (29.4)
`
`6 (12.8)
`
`12 (26.7
`
`17 (33.3)
`
`12 (25.5)
`
`
`
`
`
`
`
`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 novo 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% CI 37—241), 17.6% (95% CI 84—309)
`and 10.6% (95% CI 3.5—23.1) for fulvestrant AD, LD and HD,
`respectively (Table 2). The OR was numerically higher in the
`fulvestrant LD regimen, but the C15 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 1, with
`variation of Vd1/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, Cmax 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), was similar among the treatment regimens at ~29 days,
`indicating that 90% of steady—state exposure should be achieved
`in N3 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].
`
`aUse of more 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.
`
`2344 | Ohno et al.
`
`Volume 21 |No. 12 | December 2010
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`Annals of Oncology
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`Table 2. Summary of best objective response
`
`
`13141186512811; regime:
`ED ()4: 4?)
`ID CW=>SU
`AD (511 =’ 1:453
`0
`O
`24.(4)
`(51.06)
`9 (17.6)
`36(7)
`17 (362)
`19 (37.3)
`4(31. 1)
`0(21.3)
`5 (9.8)
`9 (20.0)
`429(8)
`7(33. 3)
`17 (37.8)
`Progression, 11 ~(%)
`Not assessable, n (%)
`1(21)
`1 (2.0)
`0
`51( 0.6) [3.523.1]
`9 (17.6) [8.A30.9]
`5 (11.1) [3.74241]
`Objective response rate, 11 (%) [95% CI]
`
`19 (42.2) [27.77578] 2(46.8) [32.14319] 28 (54.9) [40.3689]
`Clinical benefit rate, n (%) [95% CI]
`
`
`Complete response, 11 (%)
`Part1al response, 11 (%)
`Stable disease 224 weeks, n (%)
`Stable disease <24 weeks
`
`AD, approved dose; CI. confidence intewal; HD, high dose; LD, loading dose.
`
`
`
`Fulvestrant regimen
`— AD
`LD
`
`
`
`
`
`
`Proportionnotprogressed
`
`21
`
`24
`
`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
`
`Tlme (months)
`
`AD, approved dose; HD, high dose; LD, loading dose.
`Tickmarks indicate censored observations.
`
`Figure 2. KaplaniMeier plot of time to progression.
`
`NON
`
`Hoe
`
`000
`
`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 ABS 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
`
`
`Fulwsfimt regimen:
`AD
`ID
`
`'HD
`
`25
`30.5 (3.4)
`Month 1 (visit 4)
`25
`11.1 (35.9)
`
`21
`28.4 (2.1)
`
`24
`29.2 (2.3)
`
`20
`17.0 (29.6)
`
`24
`28.7 (27.0)
`
`4.5 (3.84.2)
`
`3.5 (3.24.3.8)
`
`3.9 (3.64.4)
`
`3.02 (16.4)
`
`10.7 (22.2)
`
`17.8 (19.2)
`
`4370 (27.7)
`
`9260 (29.4)
`
`13000 (25.9)
`
`Number of patients
`Mean am days (SD)
`
`Number of patients
`Mean Cmax,
`ng/ml (CV)
`Median Tnm, days
`(minimumi
`maximum)
`Mean Cm,
`ng/ml (CV)
`Mean AUC0_.E,
`ng h/ml (CV)
`
`Month 3 (visit 7)
`20
`15.5 (30.3)
`
`20
`14.1 (30.0)
`
`20
`29.4 (23.8)
`
`Number of patients
`Mean Cmax,
`ng/ml (CV)
`Median Tm“, days
`(minimumi
`maximum)
`Mean Cm,
`ng/ml (CV)
`13300 (20.6)
`6600 (26.6)
`6630 (24.7)
`Mean AUCM,
`ng h/ml (CV)
`
`4.2 (3.74.6)
`
`4.2 (3.94.4)
`
`4.2 (3.94.5)
`
`5.39 (20.1)
`
`5.87 (23.9)
`
`11.4 (18.2)
`
`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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`[oz:17Z£12qu:1Ho1san3Aqfilo'sfemnofplogxo'ouotme/fiduqmoi;papeoIU/yxoq
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`Volume 21 |No. 12 | December 2010
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`cloi:10.1093/annonC/mdq249 | 2345
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`If? (1%?)
`
`Table 4. Most commonly reported adverse events (25% in total)
`
`
`’Fulyemafitregimen
`HD
`224D:
`LD
`(“at 1:45)
`()fi;4:5)
`(m = 51;
`16 (34.8)
`17 (37.8)
`15 (29.4)
`Nasopharyngitis
`14 (30.4)
`14 (31.1)
`11 (21.6)
`Injectionesite pain
`6 (13.0)
`11 (24.4)
`9 (17.6)
`Nausea
`7 (15.2.)
`8 (17.8)
`11 (21.6)
`Hot flush
`10 (21.7)
`9 (20.0)
`6 (111.8)
`Injectionesite induration
`7 (15.2)
`7 (15.6)
`7 (13.7)
`Fatigue
`5 (10.9)
`4 (8.9)
`7 (13.7)
`Constipation
`4 (8.7)
`3 (6.7)
`8 (15.7)
`Headache
`3 (6.5)
`3 (6.7)
`6 (11.8)
`Back pain
`2 (4.3)
`2 (4.4)
`7 (13.7)
`Arthralgia
`5 (10.9)
`2 (4.4)
`4 (7.8)
`Pyrexia
`4 (8.7)
`4 (8.9)
`2 (3.9)
`Injectionesite pruritis
`5 (10.9)
`2 (4.4)
`3 (5.9)
`Stomatitis
`3 (6.5)
`2 (4.4)
`4 (7.8)
`Anorexia
`4 (8.7)
`2 (4.4)
`3 [15.9)
`Pruritis
`
`Insomnia 1 (2.2) 4 (8.9) 3 (5.9)
`
`
`
`AD, approved dose; HD, high dose; LD, loading dose.
`
`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 fulvestrant LD in
`postmenopausal women with ER—positive advanced breast
`cancer progressing or recurring after nonsteroidal AI therapy
`[5]. In this setting, fulvestrant 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 fulvestrant 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 OR 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 fulvestrant
`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 i 4.9
`l/h, CV 31%) was similar to that determined for Japanese
`patients in a phase I study (28.4 i 5.4 l/h) [12] and for western
`patients in phase III studies (33.2 i 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 VdI/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 fulvestrant 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 treatrnent—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 fulvestrant 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
`
`
`
`[oz[VZA‘mmqa:1Ho1sen3Aqfilo'sremnofpmgxo'ouotrtre/fiduqmoi;papeoIU/noq
`
`.C
`
`AstraZeneca Exhibit 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 A15, 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 fulvestrant 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 FINDERl 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 Iwase has received
`honoraria from AstraZeneca and research funding from
`AstraZeneca, Chugai—Roche. Seigo Nakamura has received
`honoraria from AstraZeneca, Novartis, Pfizer, Ihonson &
`Jhonson. Shinzaburo Noguchi has received honoraria from
`AstraZeneca, Taiho, Chugai, Novartis, Pfizer, Takeda, Bristol—
`Myers Squibb.
`
`references
`
`1. Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of the
`new oestrogen receptor antagonist fulvestrant on the endometrium in healthy
`postmenopausal volunteers. BrJ Cancer 2002; 87 135471359.
`2. DeFriend DJ, Howell A, Nicholson RI et al. Investigation of a new pure
`antiestrogen (ICI 182780) in women with primary breast cancer. Cancer Res
`1994; 54: 4084114.
`3. Robertson JF, Nicholson RI, Bundred NJ et al. Comparison of the shorteterm
`biological effects of 7alphae[97(4,4,5,5,57pentafluoropentylsulfinyl)
`nonyl]estrae1,3,5, (10)etrienee3,17betaediol (Faslodex) versus tamoxifen in
`postmenopausal women with primary breast cance'. Cancer Res 2001; 61:
`67396746.
`
`4. Wakeling AE. Similarities and distinctions in the mode of action of different
`classes of antioestrogens. Endocr Relat Cancer 2000; 7: 17728.
`
`10.
`
`11.
`
`12.
`
`13.
`
`
`
`Chia S, Gradishar W, Mauriac L et al. Doubleeblind, randomized placebo
`controlled trial of fulvestrant compared with exemestane after prior honsteroidal
`aromatase inhibitor therapy in postmenopausal women with hormone
`receptorepositive, advanced breast cancer: results from EFECT. J Clin Oncol
`2008; 26: 166471670.
`Howell A, Robertson JFR, Quaresma Albano J et al. Fulvestrant, formerly ICI
`182,780,
`is as effective as anastrozole in postmenopausal women with
`advanced breast cancer progressing after prior endocrine treatment. J Clin Oncol
`2002; 20: 339673403.
`Howell A, Pippen J, Elledge RM et al. F Ivestrant versus anastrozole for
`the treatment of advanced breast carcino na: a prospectively planned
`combined survival analysis of two multicenter trials. Cancer 2005; 104:
`2367239.
`Robertson JF, Osborne CK, Howell A et al. F Ivestrant versus anastrozole for the
`treatment of advanced breast carcinoma in 30stmenopausal women:
`a prospective combined analysis of two mul icenter trials. Cancer 2003; 98:
`2297238.
`
`
`
`Howell A. Fulvestrant (‘Faslodex’): current ard future role in breast cancer
`manage nent. Crit Rev Oncol Hematol 2006; 57: 2657273.
`Osborne CK, Pippen J, Jones SE et al. Doubleehlind, randomized trial
`comparhg the efficacy and tolerability of f Ivestrant versus a astrozole in
`postmenopaJsal women with advanced breast cancer progressing on prior
`endocrire therapy: results of a North Amer'can trial. J Clin 01ml 2002; 20:
`338673395
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Robertson JFR. Fu vestrant (Faslodex)ihow to make a good d ug better.
`Oncolog'st 2007; ‘2: 7747784.
`Fujiwara Y, Ohno S,
`lwata H et al. Tolerability of fulvestrant higfdose (HD) in
`postmeropaJsal Japanese women with hormone receptoreposi 've (HR+)
`advanced (ABC) or ecurrent breast cancer (RBC) 2007 Abstract aresented at the
`ASCO B east Cancer Symposium, San Francisco, CA, USA, September 778,
`(Abstr 192).
`irst results from
`K ter l, -legg R, Sirger CF et al. Fulvestrant 500 mg vs 250 mg:
`NEWES", a randomized, phase II neoadjuvant trial
`in post fenooausal women
`w'th locally advanced, estrogen receptorepositive breast cancer. Breast Cancer
`Res Treat 2007; 106: (Suppl 1): S7 (Abstr 23).
`S'mon R, thes RE, Ellenberg SS. Randomized phase II cinica trials. Cancer
`" eat Rep 1985; 69: 137571381.
`KJter l, Sapunar F, McCormack P. Pharmacokiretic profile of fulvestrant
`500 ng vs 250 rrg: results from the NEWEST study. J C in 0 col 2008; 26:
`Abst 579).
`cCormack P, Sapunar F. Pharmacokinetic profi e of the fu vestrant loading dose
`egirren in postmenopausal women with hormone receptorepos‘tive advanced
`3 east cancer. Clin Breast Cancer 2008; 8: 3477351.
`Robetson JF, Erikstein B, Osborne KC et al. Pfarmacokiretic profile of
`'r tramuscular fulvestrant in advanced breast cancer. Clin Dharrracokinet 2004;
`43: 5297538.
`Robe ‘tson JFR, Llombart A, Rolski J et al. Activ'ty of fulvestrant 500 mg versus
`aias rozolei mg as firsteline treatment for advanced breast cancer: results from
`re FIRST study. J Clin Oncol 2009; 27: 453074535.
`3' Leo A, Jerusalem G, Petruzelka L et al. CO FIRM: a phase III, randomized,
`Jaral elegroup trial comparing fulvestrant 250 mg vs fulvestrant 500mg in
`30stmenopaJsal women with estrogen receptorepositive adv