VOLUME 27 -
`
`NUMBER 27 - SEPTEMBER 20 2009
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`NAL REPORT
`
`From the Division of Breast Surgery,
`University of Nottingham, Notting-
`ham; Department of Oncology,
`Ninewells Hospital and Medical
`School, Dundee; AstraZeneca Pharma-
`ceuticals, Alderley Park, United King-
`dom, Hospital Arnau de Vilanova,
`Lérida, Spain, Centrum Onkologti,
`Instytut im M. Sktodowskiej-Cune,
`Krakow, Poland; Fackultni Nemocnice
`Ostrava, Radioterapeuticka klinika,
`OstravaPoruba, 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.jco_org on
`August 24, 2009
`Authors’ disclosures of poteritial cori-
`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 FR
`Robertson, MD, Division of Breast
`Surgery, University of Nottingham,
`Nottingham City Hospital, Hucknall Rd,
`Nottingham, NGS 1PB, United King-
`dom; email john.robertson@
`nottingham.ac.uk
`The Acknowledgment and Appendix
`are included in the full-text version
`of this article; they are available
`online at wwwjco.org. They are
`not meluded inthe PDF version
`(via Adobe® Reader®)
`
`© 2009 by American Society of Clinical
`Oncology
`0782-183X/09/2727-4530/$20.00
`DOL 10.1200/JCO.2008.21.1136
`
`Activity of Fulvestrant 500 mg Versus Anastrozole 1 mg As
`First-Line Treatment for Advanced Breast Cancer: Results
`From the FIRST Study
`John F.R. Robertson, Antonio Llombart-Cussac, Janusz Rolski, David Feltl, John Dewar, Euan Macpherson,
`Justin Lindemann, and Matthew J. Ellis
`
`A
`
`B
`
`§$
`
`T
`
`R
`
`A
`
`¢
`
`T
`
`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 ||, 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 = 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 (mn = 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%. Time to progression
`(TTP) was significantly longer for fulvestrant versus anastrozole (median TTP not reached for
`fulvestrant HD v12.5 months for anastrozole; hazard ratio, 0.63; 95% Cl, 0.39 to 1.00; P= .0496).
`
`Duration of OR and CB also numerically favored fulvestrant HD. Both treatments were well
`tolerated, with no significant differences in th
`incidence
`of prespecified adverse events.
`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
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`Fulvestrant (Faslodex, AstraZeneca, Macclesfield,
`United Kingdom) is an estrogen receptor (ER) an-
`tagonist with no known agonisteffects’ and a mode
`of action distinct from other endocrine agents.” The
`clinical effectiveness of fulvestrant 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
`(Al) therapy.” However,there is evidence to suggest
`that doses of fulvestrant higher than 250 mg may
`have greater pharmacodynamicactivity against the
`ER pathway.” It has been observedthat ER, proges-
`terone receptor (PgR), and Ki67 are downregulated
`
`by fulvestrant in a dose-dependent manner and that
`the maximumeffect on these markers is not reached
`with the 250-mg dose.’ In addition, dose-dependent
`clinical activity has been observedfor 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) thanthose re-
`ceiving fulvestrantat the approved dose.*®
`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 orre-
`current breast cancer, to be well tolerated, and to
`result in plasma levels approximately double those
`seen with fulvestrant AD.* Subsequently, a neoadju-
`vant study comparing fulvestrant AD and HD
`
`4530
`
`© 2009 by American Society ofClinical Oncology
`Downloadedfrom 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.
`
`AstraZeneca Exhibit 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.”
`Third-generation Als, such as anastrozole and letrozole, have
`shown superiorefficacy andtolerability compared with tamoxifen and
`are currently considered standard first-line treatment for advanced
`breast cancer in postmenopausal women with hormone receptor—
`positive (HR+) disease.’°"' Previous phase III trials have demon-
`strated that fulvestrant AD is at least as effective as anastrozole as a
`second-line treatmentfor advanced breast cancerfollowingantiestro-
`gen therapy.The current study (FIRST; Fulvestrant First-Line Study
`Comparing Endocrine Treatments) examines the efficacy of fulves-
`Safety and Tolerability
`trant HD versus anastrozole in thefirst-line setting. Here, we present
`Assessment ofthe safety andtolerability offulvestrant HD and anastro-
`the data from the primary analysis ofthis trial.
`zole was.asecondary study endpoint. Laboratorytests and incidence ofadverse
`events (AEs) were recorded throughout the study. The frequency of 10 pre-
`specified AEs wasalso evaluated in each treatment group.
`
`assigned patients. DoCB wasassessed 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 ORR and those with measurabledisease
`whoachieved a response for DoR.
`Tumordimensions were assessed by site investigators, and response to
`treatment was determined according to a modified RECIST scheme, where
`progression oflytic bonelesions was regarded asa RECIST progression event.
`Tumorassessment(clinical and radiologic) occurredat the screening visit and
`then every 12 + 2 weeks following random assignment until progression.
`Copies ofscansforall patients were collated and reviewed ina blinded manner
`by an independentradiologist working for a contract services organization
`(Biolmaging Technologies, Leiden, the Netherlands).
`
`
`
`
`Characteristic
`No.
`%
`No.
`%
`
`(n = 102)
`
`66
`40-89
`
`68
`48-87
`
`
`Study Design and Treatments
`This wasaphase II, open-label, randomized, multicenter, parallel-group
`Table 1. Baseline Patient and Disease Characteristics
`trial offulvestrant HD versus anastrozoleas first-line treatmentfor postmeno-
`pausal women with advanced breast cancer(http://clinicaltrials.gov/ct2/show/
`Fulvestrant
`Anastrozole
`NCT00274469). After enrollment, patients were randomly assigned to receive
`1 mg
`(n = 103)
`either fulvestrant HD (500 mg; ie, two 250 mg intramuscular injections on
`days 0, 14 + 3,28 + 3,and every 28 + 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-
`otherevent requiring discontinuation.
`The study was performedin accordance with the Declaration ofHelsinki
`and was consistent with International Conference on Harmonisation ofTech-
`nical Requirements for Registration ofPharmaceuticals for Human Use (ICH)
`GoodClinical Practice. The study protocol, patient consent forms, and infor-
`mation sheets were approved by the relevant independent ethics committees
`andinstitutional review boards. In North America, the study was conducted
`under a Food and Drug Administration investigational new drug application.
`
`Age, years
`Median
`Range
`ER and PgR status
`HR+
`ER+, PgR+
`ER+, PgR-
`ER+, PgR unknown
`ER-, PgR+
`ER unknown, PgR+
`HER2 status
`2a
`Negative
`Unknown
`Disease stage
`Locally advanced only
`Metastatic
`Measurable disease
`Metastatic sites
`Bone only
`Soft tissue only
`Any visceral disease
`Anyliver 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 24.3 29 28.4 25
`
`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.
`
`
`
`102
`78
`19
`1
`3
`1
`
`100.0
`76.5
`18.6
`1.0
`2.9
`16
`
`103
`78
`19
`3
`3
`0
`
`100.0
`7Bz
`18.4
`2.9
`29
`
`Patients
`
`Eligible patients were postmenopausal women with ER+ and/or PgR+
`locallyadvanced 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 performancestatus 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 oflife-threatening metastases; cur-
`rent or prior malignancy (except breast cancer or adequately treated skin
`cancer or in situ carcinomaof 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, Als, or castor oil; or any
`severe concomitant conditions. All recruited patients provided written in-
`formed consentbefore entering the study.
`
`Efficacy
`The primary end pointwasclinical benefit rate (CBR), which was defined.
`as the proportion of all randomly assigned patients who had a best overall
`response ofa complete response,a partial response, or stable disease (SD) forat
`least 24 weeks (SD = 24 weeks). Secondary end points were objective response
`rate (ORR;the proportion ofpatients with a best overall response of either a
`complete response or a partial response), TTP, duration ofclinical benefit
`(DoCB)and duration of response (DoR). TTP wasassessed in all randomly
`
`19
`48
`39
`
`tT)
`83
`89
`
`10
`2
`48
`15
`30
`
`a3
`
`28
`
`Q
`
`
`
`18.6
`47.1
`64.3
`
`18.6
`81.4
`87.3
`
`2.8
`20
`a7.
`14.7
`29.4
`
`71.6
`
`27.5
`
`0.0
`
`
`
`19
`49
`35
`
`18
`85
`93
`
`8
`0
`58
`14
`42
`
`80
`
`@2
`
`0
`
`
`
`18.4
`47.6
`34.0
`
`17.5
`e258
`80.3
`
`78
`
`56.3
`13.6
`40.3
`
`777
`
`22.3
`
`0.0
`
`www.jco.org
`
`© 2009 by American Society of Clinical Oncology
`Downloadedfrom 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.
`
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`Robertson et al
`
`
`
`Table 2. Response to Treatment
`Fulvestrant HD
`Anastrozole 1 mg
`(n = 102)
`(n = 103)
`All Randomly
`7 SS
`
`Assigned Patients
`Best Overall Response
`No.
`%
`No.
`%
`
`CB
`
`1.0
`i
`0
`Complete response
`81.1
`32
`31.4
`32
`Partial response
`35.0
`36
`a2
`42
`Stable diseasé = 24 weeks
`67.0
`69
`#25
`74
`Total with CB
`UL
`i
`14.7
`15
`Stable disease < 24 weeks
`19.4
`20
`5.8
`10
`Progression
`16
`2
`28
`3
`Not evaluable
`
`
`
`
`28 27.5 34Total with no CB 33.0
`
`No CB
`
`Abbreviation: CB, clinical benefit.
`
`
`Fulvestrant HD wasalsoas effective as anastrozole in terms of
`ORR in evaluable patients (n = 89 for fulvestrant HD and n = 93 for
`anastrozole), which wasvirtually 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%) achieveda best overall response of SD = 24
`weeks compared with patients in the anastrozole group (35.0%), and
`fewerfulvestrant 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 TTPfor anastro-
`zole was 12.5 months; the median TTP for fulvestrant HD had not
`been reachedat the time ofthe analysis.
`Reflecting the TTP advantage, there werealso differences in the
`DoR and DoCBcurves favoring fulvestrant HD (Figs 2A and 2B). The
`median DoR for anastrozole was 14.2 months. The median DoR for
`fulvestrant and the median DoCBfor both treatments had not been
`reachedat the timeof the analysis.
`
`a3
`
`®n
`
`Soa
`ee
`oDSoeS
`ftas=
`
`No, of patients at risk:
`Fulvestrant HD
`102
`103
`Anastrozole 1 mg
`
`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 randomlyassigned patients per treatment group would be
`required to give 80%powerto rule out an absolute deficiency of 20% in CBR
`for fulvestrant HD with a two-sided 95% CI. The primary analysis wasstipu-
`lated in the protocol to occur 6 monthsafter 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. Treatmentdifferences in the incidence
`ofprespecified AEs were evaluated using a two-sided Fisher's exact test.
`
`
`
`Patients
`In total, 205 patients were randomly assigned: 102 to fulvestrant
`HD and 103 to anastrozole (Appendix Fig Al, 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 treatmentforearly disease.
`
`Efficacy
`Analysis of the primary end point demonstratedthat fulvestrant
`HDwasatleast as effective as anastrozole, with CBRs of 72.5% and
`67.0%, respectively (oddsratio, 1.30; 95%CI, 0.72 to 2.38; P = .386;
`Table 2). The absolute treatmentdifference 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.
`
`
`
`Fulvestrant HD
`‘oo. Anastrozole 1 mg
`
`Time to Progression (months)
`
`96
`90
`
`16
`68
`
`46
`38
`
`31
`23
`
`W
`13
`
`1. Kaplan-Meier plot
`Fig
`hazard ratio,
`
`for
`
`time to progression. HD, high dose; HR,
`
`4532,
`
`© 2009 by American Society of Clinical Oncology
`Downloadedfrom 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
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`

`Fulvestrant 500 mg for Advanced Breast Cancer: Results From FIRST
`
`ProportionofPatients
`
`
`
`RespondingtoTreatment
`
`=== Fulvestrant HD
`taos8 Anastrozole 1 mg
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`No. of patients at risk:
`FulvestrantHD
`32
`Anastrozoleimg
`33
`
`Duration of Response (months)
`
`32
`33
`
`32
`29
`
`28
`18
`
`WT
`WI
`
`10
`#
`
`5
`4
`
`13
`
`site pain (1.3% of all administrations; an administration comprises
`two 250-mg intramuscular injections). The most commontreatment-
`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 hotflashes
`(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 e1-
`ther treatment.
`
`
`
`This was an open-label,first-line study offulvestrant HD versus anas-
`trozole in predominantly endocrine treatment—naive patients with
`advanced breast cancer. The high CBRsfor 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 wasatleast as
`effective as anastrozole. The secondary end points further confirmed
`the activity of fulvestrant HD in this setting, most notably median
`TTP, which wasestimated to be 60% longer in patients treated with
`fulvestrant HD compared with TTP for those treated with anastrozole,
`a statistically significant difference. DoR and DoCBdata also favored
`fulvestrant HD.
`Thisis thefirst clinical trial to compare fulvestrant with anastro-
`zole in first-line advanced breast cancer and to show that another
`endocrine agent may be moreeffective than a third-generation AI in
`this setting. Althoughthis was an open-label, phase II study, CBR and
`ORR data for anastrozole (67.0% and 35.5%,respectively) were con-
`sistent with previously reported data for an AI in thefirst-line ad-
`vanced disease setting (CBRs of 49% to 59% and ORRsof 28% to
`41%).!°* 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 beyondthefirst 6 months was not scheduled. TTP
`wastherefore based on an open-label assessmentbythetreating clini-
`cian. Whena statistically significant increase in TTP was identified in
`
`
`
`
`Table 3. Incidence of Prespecitied Adverse Events (Safety Population)
`Fulvestrant
`Anastrozole
`HD
`1 mg
`(n = 101)
`(n = 103)
`
`Prespecified Adverse Event
`No.
`%
`No.
`%
`Pe
`Endometrial dysplasia
`0
`0
`1.000
`Gl disturbances
`28
`23
`420
`Hot flashes
`13
`14
`1.000
`Ischemic cardiovascular disorders
`0
`1
`1.000
`Joint disorders
`14
`10
`321
`Osteoporosis
`0
`0.
`1.000
`Thromboembolic events
`0
`0
`1,000
`Urinary tract infections
`4
`1
`210
`Vaginitis
`0
`0
`1,000
`
`Weight gain A95 1 1.0 0
`
`
`Abbreviation: HD, high dose.
`*Two-sided Fisher's exact test.
`
`
`Qh
`128
`
`12.8
`
`4.0
`
`
`
`223
`13.6
`1.0
`oF
`
`1.0
`
`B
`
`ProportionofPatients
`
`
`
`RespondingtoTreatment
`
`Fulvestrant HD
`‘- Anastrozole 1 mg
`
`3
`
`6
`
`9
`
`12
`
`15
`
`18
`
`21
`
`No. of patients at risk:
`FulvestrantHD
`74
`Anastrozolelmg
`69
`
`Duration of Clinical Benefit (months)
`
`74
`69
`
`69
`63
`
`46
`38
`
`7
`
`Fig 2. Kaplan-Meier plots for (A) duration of response and (B) duration ofclinical
`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 asthe
`numberof days between random assignment and either progression
`or time oflast RECIST assessment. The numberof patients remaining
`on randomized treatmentat 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 wasdisease progression. Only onepatient (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 (9.99%), constipation (9.9%),
`vomiting (8.9%), and dyspnea (8.9%). In the anastrozole group, the
`most common AEs werehotflashes (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 instancesofinjection-
`
`www.jco.org
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`© 2009 by American Society of Clinical Oncology
`Downloadedfrom 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.
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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 centralreview of progression was determined.
`This study of fulvestrant HD wasinitiated because of previous
`clinicaland biologic studies that suggested there was a dose responseto
`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 biologiceffect.” Similarly, a phaseIII
`clinical study had. shown that the hazard ratio for estimating the
`treatment effect of fulvestrant 125 mg on TTP wasinferior to fulves-
`trant 250 mg. The median TTP for fulvestrant AD (250 mg) was
`numerically but notstatistically greater than that for anastrozole 1
`mg.° The current study addsto 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 havealso 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 monthsfor fulvestrant AD and 13.7 monthsfor anastrozole.”
`Similarly, ina 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 monthsfor exemestane.”
`In a previousfirst-linetrial of fulvestrant AD versus tamoxifen (Trial
`0025), fulvestrant did not meet thecriteria for noninferiority.'* How-
`ever, a relatively large proportion of patients in Trial 0025 had an
`unknown HRstatus, and a preplanned subgroup analysis showed that
`in patients with confirmed HR-+disease, the activity offulvestrant was
`similar to that oftamoxifen.In line withthis, the FIRST study reported
`here included only HR+ patients. Indirect cross-trial comparisons
`between Trial 0025'° and FIRSTsuggest that fulvestrant HD mayoffer
`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 samesetting, although this remains to be confirmed in direct
`comparative phaseIIItrials.
`The early separation of the Kaplan-Meier curves for TTP suggest
`that fulvestrant HD maybe ofbenefit for patients who progressearly,
`while the longer DoR and DoCBindicate 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 maybe a consistent
`benefit of fulvestrant treatment. These observations may beattribut-
`able to the distinct modeof 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.”
`Collectively, these data provide further support for the improved
`clinical activity of the fulvestrant HD regimen.
`In further agreement with previousstudies,®” 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.* There were no unexpected AEs and no new safety
`concerns, and the incidence of injection-site pain with fulvestrant HD
`(5.9%) wassimilar to that previously seen with fulvestrant AD (4.6%)
`
`despite there being twice as many injections per month with the HD
`regimen.’ Therelatively high incidenceofarthralgia (9.9%) and joint
`disorders (13.9%), compared with those in previous fulvestrant stud-
`ies (5% to 14% and 5% to 9%, respectively),*° was noteworthy, and
`data from the ongoing phase III CONFIRM(Comparisonof 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 isatleast as effective as anastrozole
`in terms of CBR and ORR,is associated with significantly longer TTP,
`and therefore may offer longer-lasting disease controlin thefirst-line
`advanced breast cancersetting. The results from FIRST are therefore
`encouraging. Nonetheless, these data should be interpreted in the
`context of the limited power provided bya phase II, open-labelstudy.
`The ongoing CONFIRM trial will provide furtherclarification of the
`role of fulvestrant HD in the treatment of patients with advanced
`breast cancer.
`
`EUSeBle POTENTIAL CONFLICTS
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest that is relevantto the subject
`matter under consideration in this article. Certain relationships marked
`with a “U”ave 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 about
`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); Justin Lindemann, AstraZeneca (C) Consultant or Advisory Role:
`Antonio Llombart-Cussac, AstraZeneca (C); Matthew J. Ellis,
`AstraZeneca (C) Stock Ownership: Euan Macpherson, AstraZeneca;
`Justin Lindemann, AstraZeneca Honoraria: John F.R. Robertson,
`AstraZeneca; MatthewJ. Ellis, AstraZeneca Research Funding: John F.R.
`Robertson, AstraZeneca; John Dewar, AstraZeneca; MatthewJ. Ellis,
`AstraZeneca Expert Testimony: None Other Remuneration: John E.R.
`Robertson, AstraZeneca
`
`LeeEte
`
`Conception and design: John F.R. Robertson, Euan Macpherson,Justin
`Lindemann, MatthewJ. Ellis
`Provision of study materials or patients: John F.R. Robertson, Antonio
`Llombart-Cussac, Janusz Rolski, David Feltl, John Dewar, Euan
`Macpherson,Justin Lindemann, Matthew J. Ellis
`Collection and assembly of data; John F.R. Robertson, Antonio
`Llombart-Cussac, Janusz Rolski, Euan Macpherson, Justin Lindemann,
`Matthew J. Ellis
`Data analysis and interpretation: John F.R. Robertson, John Dewar,
`Euan Macpherson, Justin Lindemann, MatthewJ.Ellis
`Manuscript writing: John F.R. Robertson, John Dewar, Euan
`Macpherson,Justin Lindemann, MatthewJ.Ellis
`Final approval of manuscript: John F.R. Robertson, Antonio
`Llombart-Cussac, Janusz Rolski, David Feltl, John Dewar, Euan
`Macpherson,Justin Lindemann, Matthew J. Ellis
`
`4534
`
`© 2009 by American Society of Clinical Oncology
`Downloadedfrom 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 Exhibit 2055 p. 5
`
`

`

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