VOLUME 27 ~
`
`NUMBER 27 ~ SEPTEMBER 20 2009
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`NAL REPORT
`
`0 R I G I
`
`From the Division of Breast Surgery,
`University of Nottingham, Notting—
`ham, Department of Oncology,
`Ninevi/ells Hospital and Medical
`School, Dundee, AstraZeneca Pharma—
`ceuticals, Alderley Park, United King—
`dom, Hospital Arnau de Vilanova,
`Lerida, Spain, Centrum Onkologii,
`lnstytut im M Sklodovl/skiei—Curie,
`Krakow, Poland, Fackultni Nemocnice
`Ostrava, Radioterapeuticka klinika,
`Ostrava—Poruba, Czech Republic,
`Washington University School of
`Medicine, St Louis, MO
`Submitted November 25, 2008,
`accepted April 16, 2009, published
`online ahead of print at WWW ico org on
`August 24, 2009
`Authors’ disclosures of potential con—
`flicts of interest and author contribu—
`tions are found at the end of this
`article
`
`Clinical Trials repository link available on
`JCO org
`Corresponding author John F R
`Robertson, MD, Division of Breast
`Surgery, University of Nottingham,
`Nottingham City Hospital, Hucknall Rd,
`Nottingham, NG5 1PB, United King—
`dom, e—mai| John robertson@
`nottingham ac uk
`The Acknowledgment and Appendix
`are included in the fu||—te><t version
`of this article, they are available
`online at WWW ico org They are
`not included in the PDF version
`(via Adobe® Reader®)
`
`© 2009 by American Society of Clinical
`Oncology
`0732—183X/09/27274530/$20 00
`DOI 101200/JCO 2008 21 1136
`
`Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As
`First—Line Treatment for Advanced Breast Cancer: Results
`
`From the FIRST Study
`John F.R. Robertson, Antonio Llomhart—Cussac, Janasz Rolski, David Feltl, John Dewar, Eaan Macpherson,
`Justin Lindemann, and Matthew J. Ellis
`
`ABSTRACT
`
`Purpose
`To compare the clinical activity of the pure antiestrogen fulvestrant at 500 mg/mo (double the
`approved dose) with the aromatase inhibitor anastrozole as first—line endocrine therapy for
`advanced hormone receptor—positive breast cancer in postmenopausal women.
`Patients and Methods
`FIRST (Fulvestrant First—Line Study Comparing Endocrine Treatments) is a phase II, randomized,
`open—label, multicenter study of a fulvestrant high—dose (HD) regimen (500 mg/mo plus 500 mg on
`day 14 of month 1) versus anastrozole (1 mg/d). The primary efficacy end point was clinical benefit
`rate (CBR), defined as the proportion of patients experiencing an objective response (OR) or stable
`disease for 2 24 weeks. The primary analysis was performed 6 months after the last patient
`was randomly assigned.
`Results
`CBR was similar for fulvestrant HD (n = 102) and anastrozole (n = 103, 72.5% v 67.0%,
`respectively (odds ratio, 1.30; 95% Cl, 0.72 to 2.38; P = .386). Objective response rate (ORR) was
`also similar between treatments: fulvestrant HD, 36.0%; anastrozole, 35.5%. "ime to progression
`(TIP) was significantly longer for fulvestrant versus anastrozole (median T"P not reached for
`fulvestrant HD v12.5 months for anastrozole; hazard ratio, 0.63; 95% Cl, 0.39 o 1.00; P = .0496).
`Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well
`tolerated, with no significant diff
`r nc s in th
`incid nc
`of pr sp cifi
`ol adv rs
`v nts.
`Conclusion
`First—line fulvestrant HD was at least as effective as anastrozole for CBR and ORR and was
`
`associated with significantly longer TTP. Fulvestrant HD was generally well tolerated, with a safety
`profile similar to that of anastrozole.
`
`J Clin Oncol 27.'4530—4535. © 2009 by American Society of Clinical Oncology
`
`
`
`Fulvestrant (Faslodex, AstraZeneca, Macclesfield,
`United Kingdom) is an estrogen receptor (ER) an-
`tagonist with no known agonist effects1 and a mode
`of action distinct from other endocrine agents.2 The
`clinical effectiveness offulvestrant as a treatment for
`
`advanced breast cancer has previously been demon-
`strated at the approved dose (AD; 250 mg/mo) in
`several phase III clinical
`trials.“ A fulvestrant
`loading—dose regimen has also been shown to be
`effective following nonsteroidal aromatase inhibitor
`(AI) therapy.5 However, there is evidence to suggest
`that doses of fulvestrant higher than 250 mg may
`have greater pharmacodynamic activity against the
`ER pathway.6 It has been observed that ER, proges-
`terone receptor (PgR), and Ki67 are downregulated
`
`by fulvestrant in a dose—dependent manner and that
`the maximum effect on these markers is not reached
`
`with the 250—mg dose.7 In addition, dose—dependent
`clinical activity has been observed for fulvestrant: for
`example, in the initial clinical studies, patients receiving
`fulvestrant at 125 mg/mo showed a lower response rate
`and shorter time to progression (TTP) than those re-
`ceiving fulvestrant at the approved dose.3’6
`The activity of a fulvestrant high—dose (HD;
`500 mg/mo) regimen has been investigated in two
`recent studies. A small, pilot study in Japanese
`women (n = 20) showed fulvestrant HD to have
`clinical activity in the treatment of advanced or re-
`current breast cancer, to be well tolerated, and to
`result in plasma levels approximately double those
`seen with fulvestrant AD.8 Subsequently, a neoadju—
`vant study comparing fulvestrant AD and HD
`
`4530
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`© 2009 by American Society of Clinical Oncology
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`Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Ex. 2055 p. 1
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`

`
`Fulvestrant 500 mg for Advanced Breast Cancer: Results From FIRST
`
`(n = 211) reported that significantly greater Ki67 and ER downregu—
`lation was achieved with the HD compared with the AD regimen and
`that both doses were well tolerated.9
`
`Third—generation AIs, such as anastrozole and letrozole, have
`shown superior efficacy and tolerability compared with tamoxifen and
`are currently considered standard first—line treatment for advanced
`breast cancer in postmenopausal women with hormone receptor-
`positive (HR+) disease.1O’11 Previous phase III trials have demon-
`strated that fulvestrant AD is at least as effective as anastrozole as a
`
`second—lir1e treatment for advanced breast cancer following antiestro—
`gen therapy.3 The current study (FIRST; Fulvestrant First—Line Study
`Comparing Endocrine Treatments) examines the efficacy of fulves—
`trant HD versus anastrozole in the first—lir1e setting. Here, we present
`the data from the primary analysis of this trial.
`
`
`
`Study Design and Treatments
`This was a phase II, open—label, randomized, multicenter, parallel—group
`trial offulvestrant HD versus anastrozole as first—line treatment for postmeno-
`pausal women with advanced breast cancer (http://clinicaltrials.gov/ct2/show/
`NCT00274469). After enrollment, patients were randomly assigned to receive
`either fulvestrant HD (500 mg; ie, two 250 mg intramuscular injections on
`days 0, 14 : 3, 28 : 3, and every28 : 3 days thereafter) oranastrozole (1 mg/d
`orally). Anastrozole was dispensed once every 28 : 7 days; that is, the visit
`schedule and assessment frequency were symmetric across the study arms.
`Patients received treatment until they experienced disease progression or an-
`other event requiring discontinuation.
`The study was performed in accordance with the Declaration ofHelsinki
`and was consistent with International Conference on Harmonisation ofTech-
`nical Requirements for Registration ofPharmaceuticals for Human Use (ICH)
`Good Clinical Practice. The study protocol, patient consent forms, and infor-
`mation sheets were approved by the relevant independent ethics committees
`and institutional review boards. In North America, the study was conducted
`under a Food and Drug Administration investigational new drug application.
`
`Patients
`
`Eligible patients were postmenopausal women with ER+ and/or PgR+
`locally advanced or metastatic breast cancer who were not amenable to therapy
`of curative intent. Prior endocrine therapy for advanced disease was not
`permitted, but patients could have received adjuvant endocrine therapy for
`early disease, provided it was completed more than 12 months before random
`assignment. In addition, patients had to have a WHO performance status of
`zero to 2 and measurable disease per modified RECIST (Response Evaluation
`Criteria in Solid Tumors) criteria, or at least one bone lesion with a lytic
`component (as defined in the protocol).
`Exclusion criteria were the presence of life—threatening metastases; cur-
`rent or prior malignancy (except breast cancer or adequately treated skin
`cancer or in situ carcinoma of the cervix); treatment with a nonapproved or
`experimental drug in the 4 weeks before being randomly assigned; abnormal
`laboratory test values; history of bleeding diatheses; long—term anticoagulant
`therapy, hypersensitivity to excipients of fulvestrant, AIs, or castor oil; or any
`severe concomitant conditions. All recruited patients provided written in-
`formed consent before entering the study.
`
`Efficacy
`The primary end point was clinical benefit rate (CBR) , which was defined
`as the proportion of all randomly assigned patients who had a best overall
`response ofa complete response, apartial response, or stable disease (SD) for at
`least 24 weeks (SD 2 24 weeks). Secondary end points were objective response
`rate (ORR; the proportion of patients with a best overall response of either a
`complete response or a partial response), TTP, duration of clinical benefit
`(DOCB) and duration of response (DOR). TTP was assessed in all randomly
`
`assigned patients. DOCB was assessed only for patients who experienced clin-
`ical benefit. ORR and DoR were assessed only in evaluable patients; ie, those
`with measurable disease at baseline for OR and those with measurable disease
`
`who achieved a response for DOR.
`Tumor dimensions were assessed by site investigators, and response to
`treatment was determined according to a modified RECIST scheme, where
`progression of lytic bone lesions was regarded as a RECIST progression event.
`Tumor assessment (clinical and radiologic) occurred at the screening visit and
`then every 12 : 2 weeks following random assignment until progression.
`Copies ofscans for all patients were collated and reviewed in a blinded manner
`by an independent radiologist working for a contract services organization
`(Biolmaging Technologies, Leiden, the Netherlands).
`
`Safety and Tolerability
`Assessment ofthe safety and tolerability of fulvestrant HD and anastro-
`zole was a secondary study endpoint. Laboratorytests and incidence ofadverse
`events (AEs) were recorded throughout the study. The frequency of 10 pre-
`specified AEs was also evaluated in each treatment group.
`
`Table 1. Baseline Patient and Disease Characteristics
`
`Characteristic
`
`Age, years
`Median
`Range
`ER and PgR status
`HR——
`ER——, PgR+
`ER——, PgR—
`ER——, PgR unknown
`ER—, PgR+
`ER unknown, PgR+
`HER2 status
`2+/3+
`Negative
`Unknown
`Disease stage
`Locally advanced only
`Metastatic
`Measurable disease
`Metastatic sites
`Bone only
`Soft tissue only
`Any visceral disease
`Any liver metastases
`Any lung metastases
`Prior endocrine treatment*
`No prior endocrine treatment
`Completed adjuvant endocrine treatment
`for early disease > 12 months prior to
`random assignment
`Prior chemotherapy
`Chemotherapy for advanced breast
`cancer
`Adjuvant chemotherapy received for
`early breast cancer
`
`Fulvestrant
`HD
`(n : 102)
`No.
`%
`
`Anastrozole
`1 mg
`(n : 103)
`No.
`%
`
`66
`40-89
`
`68
`48-87
`
`102
`78
`19
`1
`3
`1
`
`100.0
`76.5
`18.6
`1.0
`2.9
`1.0
`
`103
`78
`19
`3
`3
`0
`
`100.0
`75.7
`18.4
`2.9
`2.9
`
`19
`48
`35
`
`19
`83
`89
`
`10
`2
`48
`15
`30
`
`73
`
`28
`
`0
`
`29
`
`18.6
`47.1
`34.3
`
`18.6
`81.4
`87.3
`
`9.8
`2.0
`47.1
`14.7
`29.4
`
`71.6
`
`27.5
`
`0.0
`
`28.4
`
`19
`49
`35
`
`18
`85
`93
`
`8
`0
`58
`14
`42
`
`80
`
`23
`
`0
`
`25
`
`18.4
`47.6
`34.0
`
`17.5
`82.5
`90.3
`
`7.8
`
`56.3
`13.6
`40.8
`
`77.7
`
`22.3
`
`0.0
`
`24.3
`
`Abbreviations: HD, high dose; ER, estrogen receptor; PgR, progesterone
`receptor; HR, hormone receptor.
`*One patient in the fulvestrant HD group received prior adjuvant endocrine
`treatment within 12 months of being randomly assigned.
`
`www.jc0.0rg
`
`© 2009 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 5, 2014. For personal use only. No other uses without permission.
`Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
`
`4531
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`

`
`Robertson et al
`
`Table 2. Response to Treatment
`
`All Randomly
`Assigned Patients
`CB
`
`No CB
`
`Abbreviation: CB, clinical benefit.
`
`Best Overall Response
`Complete response
`Partial response
`Stable disease 2 24 weeks
`Total with CB
`Stable disease < 24 weeks
`Progression
`Not evaluable
`Total with no CB
`
`Anastrozole 1 mg
`Fulvestrant HD
`(n : 103)
`(n : 102)
`A A
`No.
`%
`No.
`%
`0
`1
`1.0
`32
`32
`31.1
`42
`36
`35.0
`74
`69
`67.0
`15
`12
`11.7
`10
`20
`19.4
`3
`2
`1.9
`28
`34
`33.0
`
`31.4
`41.2
`72.5
`14.7
`9.8
`2.9
`27.5
`
`Fulvestrant HD was also as effective as anastrozole in terms of
`
`OR in evaluable patients (n = 89 for fulvestrant HD and n = 93 for
`anastrozole), which was virtually identical in the two groups (fulves-
`trant HD, 36.0%; anastrozole, 35.5%; odds ratio, 1.02; 95% CI, 0.56 to
`1.87; P = .947). In the overall population, more patients in the fulves-
`trant HD group (41.2%) achieved a best overall response of SD 2 24
`weeks compared with patients in the anastrozole group (35.0%), and
`fewer fulvestrant HD—treated patients showed a best overall response
`of progressive disease (9.8% v 19.4% in the anastrozole group; Table
`2). The average time between RECIST assessments was 78 days in the
`fulvestrant HD group and 74 days in the anastrozole group.
`At data cutoff, 29.4% of fulvestrant HD—treated patients had
`progressed compared with 41.7% of those in the anastrozole group.
`TTP was significantly longer for fulvestrant HD (hazard ratio, 0.63;
`95% CI, 0.39 to 1.00; P = .0496; Fig 1). The median TTP for anastro-
`zole was 12.5 months; the median TTP for fulvestrant HD had not
`
`been reached at the time of the analysis.
`Reflecting the TTP advantage, there were also differences in the
`DoR and DoCB curves favoring fulvestrant HD (Figs 2A and 2B). The
`median DoR for anastrozole was 14.2 months. The median DoR for
`fulvestrant and the median DoCB for both treatments had not been
`
`reached at the time of the analysis.
`
`Statistical Analysis
`Statistical analyses were performed using SAS software version 8.2 (SAS
`Institute, Cary, NC). Sample size calculations for this noninferiority trial
`estimated that 100 randomly assigned patients per treatment group would be
`required to give 80% power to rule out an absolute deficiency of 20% in CBR
`for fulvestrant HD with a two—sided 95% CI. The primary analysis was stipu-
`lated in the protocol to occur 6 months after the last patient had been ran-
`domly assigned.
`The primary end point (CBR) was compared in the two groups using a
`logistic regression model where the absolute differences, odds ratios, and
`associated 95% CIs and P values were reported. The same methods were used
`for the secondary end point of ORR. Kaplan—Meier plots were produced for
`TTP, DoR, and DOCB, and a log—rank test was used to generate the hazard
`ratios, 95% CIs, and P values for TTP. Treatment differences in the incidence
`of prespecified AEs were evaluated using a two—sided Fisher’s exact test.
`
`RES.U.LTS-I
`
`Patients
`
`In total, 205 patients were randomly assigned: 102 to fulvestrant
`HD and 103 to anastrozole (Appendix Fig A1, online only). Patients
`were recruited from 62 centers in nine countries (Brazil, Bulgaria,
`Czech Republic, France, Italy, Poland, Spain, United Kingdom, and
`the United States). All randomly assigned patients were included in
`the primary analysis, although one fulvestrant patient who received no
`randomly assigned treatment was excluded from the safety popula-
`tion. Overall, 182 patients were assessable for objective response.
`Baseline characteristics, including treatment history, were well
`balanced across the treatment groups (Table 1). Median age was 67
`years, the majority ofpatients (76.1%) were ER+ and PgR+, and 82%
`had metastatic disease. In total, 153 (74.6%) patients were completely
`endocrine—therapy naive, whereas 25.4% of patients had previously
`completed adjuvant endocrine treatment for early disease.
`
`Efficacy
`Analysis of the primary end point demonstrated that fulvestrant
`HD was at least as effective as anastrozole, with CBRs of 72.5% and
`67.0%, respectively (odds ratio, 1.30; 95% CI, 0.72 to 2.38; P = .386;
`Table 2). The absolute treatment difference was 5.6% (95% CI, — 7.8%
`to 15.8%). The blinded, independent review of the RECIST data used
`to determine CBR data resulted in concordance rates of 88.4% for
`fulvestrant HD and 86.3% for anastrozole.
`
`13
`
`Fulvestrant HD
`----- Anastrozole 1 mg
`
`15
`
`Time to Progression (months)
`
`96
`90
`
`76
`68
`
`46
`38
`
`31
`23
`
`17
`
`"C
`CD
`CC/J
`es
`‘CEOoQ_L
`3%0.0Z
`
`No. of patients at risk:
`Fulvestra nt HD
`102
`103
`Anastrozo|e1 mg
`
`1. Kaplan—Meier plot
`Fig
`hazard ratio.
`
`for
`
`time to progression. HD, high dose; HR,
`
`4532
`
`© 2009 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 5, 2014. For personal use only. No other uses without permission.
`Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL or CLINICAL ONCOLOGY
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`
`

`
`Fulvestrant 500 mg for Advanced Breast Cancer: Results From FIRST
`
`site pain (1.3% of all administrations; an administration comprises
`two 250—mg intramuscular injections). The most common treatment-
`related AEs in the fulvestrant HD group were hot flashes (7.9%),
`injection—site pain (5.0%), and hyperhidrosis (4.0%); in the anastro-
`zole group, the most common treatment—related AEs were hot flashes
`(12.6%), arthralgia (5.8%), and headache (5.8%). There were no
`significant differences between treatments in the incidence of any of
`the 10 prespecified AEs (Table 3). There were no clinically important
`changes in hematologic or clinical chemistry parameters with ei-
`ther treatment.
`
`
`
`This was an open—label, first—line study of fulvestrant HD versus anas-
`trozole in predominantly endocrine treatment—naive patients with
`advanced breast cancer. The high CBRs for fulvestrant HD and anas-
`trozole of 72.5% and 67.0%, respectively, confirm the high clinical
`efficacy of both agents. Furthermore, results from the analysis of the
`primary end point (CBR) indicated that fulvestrant HD was at least as
`effective as anastrozole. The secondary end points further confirmed
`the activity of fulvestrant HD in this setting, most notably median
`TTP, which was estimated to be 60% longer in patients treated with
`fulvestrant HD compared with TTP for those treated with anastrozole,
`a statistically significant difference. DoR and DoCB data also favored
`fulvestrant HD.
`
`>
`
`ProportionofPatients
`
`
`
`RespondingtoTreatment
`
`: Fulvestrant HD
`-- --- Anastrozole 1 mg
`
`3
`
`6
`
`9
`
`12
`
`15
`
`No. of patients at risk:
`Fu|vestrantHD
`32
`Anastrozo|e1 mg
`33
`
`Duration of Response (months)
`
`32
`33
`
`17
`11
`
`10
`7
`
`:- Fulvestrant HD
`-- --- Anastrozole 1 mg
`
`3
`
`6
`
`9
`
`12
`
`15
`
`Duration of Clinical Benefit (months)
`
`..03ProportionofPatients
`
`
`
`RespondingtoTreatment
`
`No. of patients at risk:
`Fulvestra nt HD
`74
`Anastrozo|e1 mg
`69
`
`74
`69
`
`69
`63
`
`17
`13
`
`This is the first clinical trial to compare fulvestrant with anastro-
`zole in first—line advanced breast cancer and to show that another
`
`Fig 2. Kaplan—Meier plots for (A) duration of response and (B) duration of clinical
`benefit. HD, high dose.
`
`Tolerability
`Median follow—up was 8 months (242.5 days) and 5.9 months
`(179 days), with median drug exposures of 9.2 months (range, 1 to
`20.5 months) in the fulvestrant HD group and 6.1 months (range, 0 to
`19.8 months) in the anastrozole group. Follow—up was defined as the
`number of days between random assignment and either progression
`or time oflast RECIST assessment. The number of patients remaining
`on randomized treatment at the time of data cutoffwas 64 (62.7%) for
`fulvestrant HD and 53 (51.5%) for anastrozole.
`Both fulvestrant HD and anastrozole were well tolerated. A
`
`total of 143 (70.1%) patients experienced at least one AE; the
`incidence of serious AEs was 11.9% with fulvestrant HD and 9.7%
`
`with anastrozole. Only three patients in each group (fulvestrant, 3.0%;
`anastrozole, 2.9%) discontinued treatment because of an AE. Overall,
`11 patients (5.4%) died during the study; the predominant cause of
`death was disease progression. Only one patient (from the anastro-
`zole group) died because of an AE, which was not considered to
`be treatment—related.
`
`The most common AEs in the fulvestrant HD group were bone
`pain (13.9%),nausea (10.9%), arthralgia (9.9%), constipation (9.9%),
`vomiting (8.9%), and dyspnea (8.9%). In the anastrozole group, the
`most common AEs were hot flashes (13.6%), headache (12.6%), bone
`pain (9.7%), arthralgia (8.7%), and myalgia (8.7%). Six patients
`(5.9%) treated with fulvestrant HD reported 14 instances ofinjection-
`
`endocrine agent may be more effective than a third—generation AI in
`this setting. Although this was an open—label, phase II study, CBR and
`OR data for anastrozole (67.0% and 35.5%, respectively) were con-
`sistent with previously reported data for an AI in the first—line ad-
`vanced disease setting (CBRs of 49% to 59% and ORRs of 28% to
`41%).12’14 There was also a close correspondence between the CBR
`results derived from the centers and those from the independent
`review with no evidence of bias. TTP was a secondary end point, and
`independent review beyond the first 6 months was not scheduled. TTP
`was therefore based on an open—label assessment by the treating clini-
`cian. When a statistically significant increase in TTP was identified in
`
`Table 3. Incidence of Prespecified Adverse Events (Safety Population)
`Fulvestrant
`Anastrozole
`HD
`1 mg
`(n : 101)
`(n : 103)
`
`Prespecified Adverse Event
`Endometrial dysplasia
`GI disturbances
`Hot flashes
`lschemic cardiovascular disorders
`Joint disorders
`Osteoporosis
`Thromboembolic events
`Urinary tract infections
`Vaginitis
`Weight gain
`
`Abbreviation: HD, high dose.
`*Tvvo—sided Fisher's exact test.
`
`No.
`0
`28
`13
`0
`14
`0
`0
`4
`0
`1
`
`%
`
`27.7
`12.9
`
`13.9
`
`4.0
`
`1.0
`
`No.
`0
`23
`14
`1
`10
`0
`0
`1
`0
`0
`
`%
`
`22.3
`13.6
`1.0
`9.7
`
`1.0
`
`P*
`1.000
`.420
`1.000
`1.000
`.391
`1.000
`1.000
`.210
`1.000
`.495
`
`www.jco.org
`
`© 2009 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 5, 2014. For personal use only. No other uses without permission.
`Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
`
`4533
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`

`
`Robertson et al
`
`the primary analysis, a retrospective inspection of the number of
`progression events determined by central review was considered. This
`was possible only in a subset of patients; nonetheless, the treatment
`effect remained numerically in favor of fulvestrant in the subset of
`patients in whom central review of progression was determined.
`This study of fulvestrant HD was initiated because of previous
`clinical and biologic studies that suggested there was a dose response to
`fulvestrant and that 250 mg might not be the optimal dose. This
`observation was based on a presurgical study that showed a dose
`response for three doses of fulvestrant (50 mg, 125 mg, and 250 mg)
`without reaching a plateau on the biologic effect.7 Similarly, a phase III
`clinical study had shown that the hazard ratio for estimating the
`treatment effect of fulvestrant 125 mg on TTP was inferior to fulves-
`trant 250 mg. The median TTP for fulvestrant AD (250 mg) was
`numerically but not statistically greater than that for anastrozole 1
`mg.3 The current study adds to the available data on the dose response
`of fulvestrant, reporting that the TTP for fulvestrant HD (ie, 500 mg)
`is statistically longer than that for anastrozole 1 mg.
`Numeric benefits in terms of DoR and DoCB have also been
`
`observed in previous phase III trials of fulvestrant. In a second—line
`trial following progression or recurrence on tamoxifen, median DoR
`was 16.7 months for fulvestrant AD and 13.7 months for anastrozole.3
`
`Similarly, in a second—/third—line trial following progression or recur-
`rence on a nonsteroidal AI, median DoCB was 9.3 months for a
`
`fulvestrant loading—dose regimen versus 8.3 months for exemestane.5
`In a previous first—line trial of fulvestrant AD versus tamoxifen (Trial
`0025), fulvestrant did not meet the criteria for noninferiority.15 How-
`ever, a relatively large proportion of patients in Trial 0025 had an
`unknown HR status, and a preplanned subgroup analysis showed that
`in patients with confirmed HR+ disease, the activity offulvestrant was
`similar to that oftamoxifen. In line with this, the FIRST study reported
`here included only HR+ patients. Indirect cross—trial comparisons
`between Trial 002515 and FIRST suggest that fulvestrant HD may offer
`higher CBR (from 57.1% to 72.5%) and prolonged TTP (from 8.2
`months to approximately 20 months), compared with fulvestrant AD
`in the same setting, although this remains to be confirmed in direct
`comparative phase III trials.
`The early separation of the Kaplan—Meier curves for TTP suggest
`that fulvestrant HD may be ofbenefit for patients who progress early,
`while the longer DoR and DoCB indicate that patients’ responses are
`more durable during fulvestrant HD treatment. The DoR and DoCB
`data reported here are supportive of observations in previous fulves-
`trant studies suggesting that prolonged response may be a consistent
`benefit of fulvestrant treatment. These observations may be attribut-
`able to the distinct mode of action of fulvestrant with downregulation
`of the ER resulting in less de novo resistance and delayed acquired
`resistance during fulvestrant treatment. These data are promising and
`in line with the increased Ki67 and ER downregulation seen for ful-
`vestrant HD versus AD in the recent NEWEST (Neoadjuvant Endo-
`crine Therapy for Women with Estrogen—Sensitive Tumors) study.9
`Collectively, these data provide further support for the improved
`clinical activity of the fulvestrant HD regimen.
`In further agreement with previous studies,” the fulvestrant HD
`regimen appeared to be well tolerated, with an AE profile comparable
`to that of anastrozole and consistent with that previously reported for
`fulvestrant AD.3 There were no unexpected AEs and no new safety
`concerns, and the incidence of injection—site pain with fulvestrant HD
`(5.9%) was similar to that previously seen with fulvestrant AD (4.6%)
`
`despite there being twice as many injections per month with the HD
`regimen.3 The relatively high incidence of arthralgia (9.9%) and joint
`disorders (13.9%), compared with those in previous fulvestrant stud-
`ies (5% to 14% and 5% to 9%, respectively),3’5 was noteworthy, and
`data from the ongoing phase III CONFIRM (Comparison of Fulves—
`trant in Recurrent or Metastatic Breast Cancer) trial will more fully
`elucidate the tolerability and efficacy profile of fulvestrant HD versus
`AD. Nonetheless, the overall tolerability profile of fulvestrant HD
`reported here is reassuring, particularly in light of the approximately
`50% increased exposure in the fulvestrant HD versus anastrozole
`group because of the improvement in TTP.
`In summary, fulvestrant HD is at least as effective as anastrozole
`in terms of CBR and OR, is associated with significantly longer TTP,
`and therefore may offer longer—lasting disease control in the first—line
`advanced breast cancer setting. The results from FIRST are therefore
`encouraging. Nonetheless, these data should be interpreted in the
`context of the limited power provided by a phase II, open—label study.
`The ongoing CONFIRM trial will provide further clarification of the
`role of fulvestrant HD in the treatment of patients with advanced
`breast cancer.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL GDNFLIGTS
`
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest that is relevant to the suhject
`matter under consideration in this article. Certain relationships marked
`with a “U” are those for which no compensation was received; those
`relationships marked with a “C” were compensated. For a detailed
`description ofthe disclosure categories, orfor more information ahout
`ASCO’s conflict of interest policy, please refer to the Author Disclosure
`Declaration and the Disclosures ofPotential Conflicts ofInterest section in
`Information for Contributors.
`Employment or Leadership Position: Euan Macpherson, AstraZeneca
`(C); Iustin Lindemann, AstraZeneca (C) Consultant or Advisory Role:
`Antonio Llombart—Cussac, AstraZeneca (C); Matthew I. Ellis,
`AstraZeneca (C) Stock Ownership: Euan Macpherson, AstraZeneca;
`Iustin Lindemann, AstraZeneca Honoraria: Iohn F.R. Robertson,
`AstraZeneca; Matthew I. Ellis, AstraZeneca Research Funding: Iohn F.R.
`Robertson, AstraZeneca; Iohn Dewar, AstraZeneca; Matthew I. Ellis,
`AstraZeneca Expert Testimony: None Other Remuneration: Iohn F.R.
`Robertson, AstraZeneca
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Iohn F.R. Robertson, Euan Macpherson, Iustin
`Lindemann, Matthew I. Ellis
`Provision of study materials or patients: Iohn F.R. Robertson, Antonio
`Llombart—Cussac, Ianusz Rolski, David Feltl, Iohn Dewar, Euan
`Macpherson, Iustin Lindemann, Matthew I. Ellis
`Collection and assembly of data: Iohn F.R. Robertson, Antonio
`Llombart—Cussac, Ianusz Rolski, Euan Macpherson, Iustin Lindemann,
`Matthew I. Ellis
`Data analysis and interpretation: Iohn F.R. Robertson, Iohn Dewar,
`Euan Macpherson, Iustin Lindemann, Matthew I. Ellis
`Manuscript writing: Iohn F.R. Robertson, Iohn Dewar, Euan
`Macpherson, Iustin Lindemann, Matthew I. Ellis
`Final approval of manuscript: Iohn F.R. Robertson, Antonio
`Llombart—Cussac, Ianusz Rolski, David Feltl, Iohn Dewar, Euan
`Macpherson, Iustin Lindemann, Matthew I. Ellis
`
`4534
`
`© 2009 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on September 5, 2014. For personal use only. No other uses without permission.
`Copyright © 2009 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`AstraZeneca Ex. 2055 p. 5
`
`

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`Fulvestrant 500 mg for Advanced Breast Cancer: Results From FIRST
`
`
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