Published Ahead of Print on September 14, 2015 as 10.1200IJCO.2015.61.5831
`The latest version is at http:lljco.ascopubs.orgIcgiIdoiI10.1200IJCO.2015.61.5831
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`ORIGINAL REPORT
`
`Matthew J Ellis, Baylor College of
`Medicine, Houston, TX, Antonio
`L|ombart—Cussac, Hospital Arnau de
`Vilanova, Lérida, Spain; David Feltl,
`FNsP Ostrava, OstraVa—Poruba, Czech
`Republic, John A Dewar, Ninewells
`Hospital and Medical School, Dundee,
`Nicola Hewson and Yuri Rukazenkov,
`AstraZeneca Pharmaceuticals, Macc|es—
`field, John F R Robertson, University of
`Nottingham, Derby, United Kingdom.
`and Marek Jasiowka, Instytut im Marii
`SklodowskieiCurie, Krakow, Poland
`Published online ahead of print at
`www JCO org on September 14, 2015
`Supported by AstraZeneca
`Terms in blue are defined in the g|os—
`sary, found at the end of this article
`and online at www JCD org
`Presented at the 2014 San Antonio
`Breast Cancer Symposium, San Anto-
`nio, TX, December 913, 2014
`Authors‘ disclosures of potential
`conflicts of interest are found in the
`article online at www JCO org Author
`contributions are found at the end of
`this article
`Clinical trial information NCT00274469
`
`Corresponding author MatthewJ Ellis,
`MD, Lester and Sue Smith Breast
`Center, One Baylor Plaza, Baylor
`College of Medicine, Houston, TX
`77030, e—mail Matthew E||is@bcm edu
`© 2015 by American Society of Clinical
`Oncology Licensed under the Creative
`Commons Attribution 3 0 License
`
`exa-
`0732—183X/15/33994/$20 00
`DOI 101200/JCO 2015 61 5831
`
`Fulvestrant 500 mg Versus Anastrozole 1 mg for the
`First— Line Treatment of Advanced Breast Cancer: Overall
`
`Survival Analysis From the Phase II FIRST Study
`Matthew]. Ellis, Antonio Lloml7an‘— Cussac, David Feltl, Iolm A. Dewar, Marek Iasiéwka, Nicola Hewson,
`Yuri Rukazenkov, and Iolm F.R. Robertson
`
`ABSTRACT
`
`Purpose
`"0 compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first—line endocrine
`therapy for advanced breast cancer.
`
`Patients and Methods
`The Fulvestrant First—Line Study Comparing Endocrine Treatments (FIRST) was a phase II,
`randomized, open—IabeI, multicenter trial. Postmenopausal women with estrogen receptor-
`positive,
`locally advanced/metastatic breast cancer who had no previous therapy for advanced
`disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or
`anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a
`follow—up analysis (median time to progression [234 months and 13.1 months]) have been
`reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently,
`the
`protocol was amended to assess OS by unadjusted Iog—rank test after approximately 65% of
`patients had died. Treatment effect on OS across several subgroups was examined. Tolerability
`was evaluated by adverse event monitoring.
`
`Results
`In total, 205 patients were randomly assigned lfulvestrant 500 mg, n = 102; anastrozole, n = 103).
`At data cutoff, 61 8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The
`hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98;
`P = .04; median OS, 54.1 months i/48.4 months). Treatment effects seemed generally consistent
`across the subgroups analyzed. No new safety issues were observed.
`
`There are several limitations of this OS analysis, including that it was not planned in the original
`protocol but instead was added after time—to—progression results were analyzed, and that not
`all patients participated in additional OS foIIow—up. However, the present results suggest
`fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective
`confirmation in the larger phase III FALCON (FuIvestrant and Anastrozole Compared in
`Hormonal Therapy Naive Advanced Breast Cancer)
`trial
`(ClinicalTrials.gov Identifier:
`NCTO1602380).
`
`J Clin Oncol © 2015 by American Society of Clinical Oncology. Licensed under the Creative
`Commons Attribution 3.0 License.‘ http://creativecommons.org/licenses/by/3. 0/
`
`
`
`Tamoxifen and third—generation aromatase in hibi-
`tors (Als), such as anastrozole, exemestane, and
`letrozole are established first—line endocrine thera-
`
`pies for the treatment of postmenopausal women
`with estrogen receptor (ER) —positiVe, advanced
`breast cancer.” Given the high prevalence of resis-
`tance to AI therapy, multiple treatment options with
`distinct mechanisms of action are desirable.4
`
`Fulvestrant, a 17[3—estradiol analog, is a selec-
`tive ER antagonist that suppresses estrogen signaling
`by binding to ER and inducing a conformational
`change.” Dimerization is subsequently blocked,
`triggering accelerated degradation and downregula—
`tion of the ER protein? Fulvestrant exhibits lack of
`cross—reactiVity with tamoxifen. Consequently, pa-
`tients whose disease progresses on fulvestrant may
`retain sensitivity to treatment with further endo-
`crine therapies.7’8 The clinical efficacy of fulvestrant
`
`© 2015 by American Society of Clinical Oncology
`on September 14, 2015 from 212.209.42.182
`Information downloaded from jco.ascopubs.org and provided by at AZ Library
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`Copyright 2015 by American Society of Clinical Oncology
`
`l
`
`Astrazeneca Ex. 2058 p. 1
`Mylan Pharrns. Inc. V. AstraZeneca AB IPR2016-01324
`
`

`
`Ellis et al
`
`was initially demonstrated in two phase III trials that compared ful-
`vestrant 250 mg per month with anastrozole 1 mg daily as a second-
`line therapy for advanced breast cancer.9’1° A combined analysis of
`these trials demonstrated that time to progression (TTP) with fulves-
`trant 250 mg was noninferior to anastrozole.“
`Fulvestrant 250 mgwas not proven to be superior to tamoxifen in
`a double—blind, randomized trial.” This finding was unexpected given
`the superiority of anastrozole over tamoxifen” and the comparable
`efficacy of anastrozole and fulvestrant 250 mg as second—line ther-
`apy.u Pharmacokinetic modeling, as well as observations made dur-
`ing early clinical studies,11 suggested the efficacy of fulvestrant could
`be improved with use of a higher dose, which led to the development
`of a dosage regimen of fulvestrant 500 mg, including a loading dose
`component to reduce the time to reach steady—state plasma levels.
`Subsequently, the phase III Comparison of Faslodex in Recurrent
`or Metastatic Breast Cancer (CONFIRM) trial found that fulves-
`trant 500 mg was associated with improved progression—free sur-
`vival (PFS) and overall survival (OS) compared with the 250—mg
`dose in patients who experienced disease recurrence or progression
`after previous endocrine therapy.”’15
`The Fulvestrant First—Line Study Comparing Endocrine Treat-
`ments (FIRST) was a phase II, randomized, open—label, multicenter
`trial that also used the fulvestrant 500—mg dose regimen, comparing
`efficacy and safety with anasnrozole in the first—line setting. The pri-
`mary end point of clinical benefit rate was noninferior for fulvestrant
`500 mg compared with anastrozole,” with both treatments demon-
`strating similar, well—tolerated safety profiles. A follow—up analysis,
`performed because only 35.6% of patients experienced disease pro-
`gression at the time of the primary analysis, reported a hazard ratio
`(HR) of TTP for fulvestrant 500 mg versus anastrozole of 0.66 with a
`95% CI of 0.47 to 0.92 (P = .01; median TTP, 23.4 months 1/
`13.1 months). No additional safety issues were reported.” Given the
`improvement in TTP observed during fulvestrant 500 mg treatment
`comparedwith anastrozole in this phase II trial, a subsequent protocol
`amendment was made to address whether this apparent extension in
`disease control would translate into an improvement in OS.
`
`AND METl-l0,DS’
`
`Study Design and Participants
`FIRST was a phase II, randomized, open—label, multicenter, parallel-
`group trial comparing fiilvestrant 500 mg with anastrozole 1 mg. Postmeno—
`pausal women with ER—positive locally advanced or metastatic breast cancer
`who had not received any previous systemic therapy for locally advanced or
`metastatic disease were included. Patients were permitted to have received
`previous endocrine therapy for early disease, providing this had been com—
`pleted more than 12 months before random assignment. This trial was con-
`ducted in accordance with the Declaration ofHelsinki, was consistent with the
`International Conference on Harmonisationiiood Clinical Practice guide-
`lines, and is registered with Clinicaltrialsgov. All patients provided written,
`informed consent. Full details ofthis trial have been reported previously.15’17
`
`Random Assignment and Procedures
`Eligible patients were randomly assigned sequentially 1:1 to either fulves-
`trant 500 mg (administered intramuscularly on days 0, 14, 28, and every
`28 days thereafter) or anastrozole 1 mg (administered orallyonce per day). The
`data cutoff for the primary analysis was 6 months after the last patient was
`randomly assigned. On disease progression or after data cutofffor the primary
`analysis, all patients entered a follow—up phase after a protocol amendment for
`
`an analysis of TTP. The TTP follow—up required a questionnaire to be com-
`pleted for each patient 12 months after the patient entered the follow—up phase
`and every 12 months thereafter for patients continuing to receive randomized
`treatment After the TTP analysis was performed, a fiirther protocol amend-
`ment was developed to enter patients into an optional follow—up phase to
`establish OS. To ensure sufficient maturity, the OS analysis was planned for
`when approximately 65% of patients had died. Patients who did not c0ntrib—
`ute additional data to the follow—up extension were right—censored at the last
`known date theywere alive, and their data until this point were included in the
`analysis. Sites were invited to request written consent from patients for the
`collection ofadditional data Patients were contacted every 3 months until the
`first ofthe following events: death, patient withdrawal, data cutoffwas reached,
`or the patient was lost to follow—up. Patients with a last known survival status of
`alive were contacted within 2 weeks ofdata cutoffto ensure theywere still alive.
`
`Outcomes
`The primary study end point was clinical benefit rate; secondary end
`points included objective response rate, TTP, duration of clinical benefit, and
`duration of response. These primary and secondary end points have been
`reported previously. 16’17
`The follow—up analysis assessed OS, defined as the time from being
`randomly assigned to death from any cause. A log—ranktest (unadjusted model
`with treatment factoronly) was performed for the primary analysis ofOS. HRs
`with 95% CIs were used to compare fulvestrant 500 mg with anastrozole; no
`adjustments were made for multiplicity. A statistical significance level of .05
`was used to indicate a difference i_n OS between the treatrnent groups. For
`patients for whom follow—up responses could not be obtained, data were
`censored at the date the patient was last known to be alive.
`Exploratory subgroup analyses were conducted using the log—ranktest to
`compare OS for the following prespecified patient subgroups:
`less than
`65 years of age versus 65 years of age or greater; not positive for both ER a.nd
`progesterone receptor versus positive for both ER and progesterone receptor;
`no visceral involvement versus visceral involvement; no previous chemother-
`apy versus previous adjuvant chemotherapy; no measurable disease versus
`measurable disease; and no previous endocrine therapy versus previous endo—
`crine therapy.
`Two sensitivity analyses were performed to examine any potential
`impact of nonparticipation on OS results: a Kaplan—Meier OS analysis was
`performed in which the censoring indicator was reversed; and baseline
`covariates were assessed for patients censored greater than 3 months before
`data cutoff and for those censored 3 months or less before data cutoff,
`which corresponds to patients who did not participate in the OS follow—up
`and to those who did, respectively.
`Tolerability was assessed by serious adverse event (SAE) monitoring. All
`SAEs were coded in compliance with the Medical Dictionary for Regulatory
`Activities and recorded in an internal AstraZeneca database for evaluation.
`
`SAEs were monitored for up to 8 weeks after the last dose offiilvestrant 500 mg
`or for 30 days after the last dose of anastrozole.
`
`RESULTS
`
`In total, 205 patients were randomly assigned to receive fulvestrant
`500 mg (n = 102) or anastrozole 1 mg (n = 103) at 62 centers ir1 nine
`countries (Brazil, Bulgaria, the Czech Republic, France, Italy, Poland,
`Spain, the United Kingdom, and the United States).
`Baseline characteristics and patient demographics were similar
`between the treatment groups as reported previously. 16 The propor-
`tion of patients who had not received previous endocrine treatment
`for early disease was similar for the fulvestrant 500 mg and anastrozole
`treatment groups (71.6% and 77.7% of patients at baseline, respec-
`tively). Of those that did, almost all had received tamoxifen exclu-
`sively. Of the 205 randomly assigned patients, 35 (16 m the fulvestrant
`500 mg group and 19 in the anastrozole group) did not participate in
`
`2
`
`© 2015 by American Society of Clinical Oncology
`on September 14, 2015 from 212.209.42.182
`Information downloaded from jco.ascopubs.org and provided by at A2 Library
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL or CLINICAL ONCOLOGY
`
`Astrazeneca Ex. 2058 p. 2
`
`

`
`Fulvestrant 500 mg: Overall Survival Versus Anastrozole
`
`Enrolled
`(N = 233)
`
`Not randomly allocated
`Incorrect enrollment
`Death
`Adverse event
`Voluntary patient discontinuation
`Other
`
`(I‘i =28)
`(n =20)
`(n =1)
`in =1)
`(n =4)
`(n :2)
`
`Randomly allocated
`(n = 205)
`
`IT}
`
`Fulvestrant 500 mg
`(n = 102)
`
`Anastrozole 1 mg
`(n = 103)
`
`Data cutofffor analysis of overall survival
`Alive
`(n = 23)
`Dead
`(n = 63)
`Did not contribute additional data
`in = 16)
`during OS follow-up extension“
`Patient declined to participate
`Site declined to participate
`
`(n=6)
`(n =10)
`
`Data cutoff for analysis. of overall su rvival
`Alive
`(n = 10)
`Dead
`(n =74)
`Did not contribute additional data
`ll) =19)
`during 08 follow-up extension*
`Patient declined to participate
`Site declined to participate
`
`(n=9l
`(n = 10)
`
`(*) These patients
`Fig 1. Study overview.
`were right oensored at the time of their last
`known date alive, and data until this point
`were used in the overall survival (OS) analysis.
`
`Safety
`The occurrence of SAEs during the main study period and the
`follow—up period combined is detailed in Table 2. The majority of
`SAEs were considered by the investigator to be unrelated to the treat-
`ment. Two SAEs considered to be treatment related were documented
`
`(one case of hypertension and one case of pulmonary embolism, both
`in the fulvestrant 500 mg treatment group).
`
`lillSCUSSl0lil
`
`This study reports improved OS with fulvestrant 500 mg treatment
`compared with anastrozole ir1 the first—line setting for ER—positive
`
`— Fulvestrant 500 mg
`----Ariastrozole 1 mg
`
`
`
`L -
`
`Median overall survival:
`Fulvestrant 500 mg: 54.1 months
`Anastrozole 1 mg: 48.4 months
`Hazard ratio, 0.70; 85% Cl, 0.50 to 0.98; P: .04
`
`-1
`
`“"341
`"""'
`
`
`
`OverallSurvival
`
`(proportion)
`
`.0 07
`
`.0 -l>
`
`.0 N
`
`0
`
`6 12 1824303642 48 54606672 78849096102
`
`No. at risk
`Fulvestrant 500 mg
`Anastrozole 1 mg
`
`102
`103
`
`90 84 77
`90 80 72
`
`Time (months)
`47
`39
`31
`39
`29
`21
`
`57
`49
`
`24
`14
`
`Fig 2. Kaplan—Meier plot of overall survival.
`
`the OS follow—up phase and were censored at the date they were last
`known to be alive; for these patients, data until this time are
`included in the OS analysis, and thus all patients contributed data
`to the analysis. The majority of the nonparticipating patients (n =
`20) did not contribute additional data because they attended cen-
`ters that declined to contribute to the OS follow—up phase. An
`additional 15 individual patients from nine participating centers
`did not consent to follow—up. No patients participating in the OS
`phase were lost to follow—up, and the survival status at data cutoff
`was known for all patients consenting to the OS follow— up.
`
`Efficacy
`At the time of the follow—up analysis for OS, 63 of 102 patients in
`the fulvestrant 500 mg group (61.8%) and 74 of 103 patients ir1 the
`anastrozole group (71.8%) were known to have died (Fig 1). The
`primary analysis of OS was improved in the fulvestrant 500 mg group
`compared with anastrozole 1 mg; the HR was 0.70 (95% CI, 0.50 to
`0.98; log—rank test P = .04; median OS, 54.1 months 1/ 48.4 months;
`Fig 2). The HR for fulvestrant 500 mg versus anastrozole was found to
`be generally consistent across all subgroup analyses (Fig 3). At 3 years,
`64% (fulvestrant 500 mg) and 58% (anastrozole) of patients were
`event free; at 5 years, the equivalent Values were 47% and 38%.
`
`Sensitivity Analyses
`There were no important differences between the treatment
`groups in time to censoring (data not shown). Furthermore, when key
`baseline covariates for patients censored within the last 3 months
`before data cutoff and for those censored more than 3 months before
`
`data cutoff were summarized, there were no important differences
`between treatment groups, indicating that the results were not caused
`by differences between patients who did and did not consent to OS
`follow—up (Table 1).
`
`www.jc0.org
`
`© 2015 by American Society of Clinical Oncology
`on September 14, 2015 from 212.209.42.182
`Information downloaded from jco.ascopubs.org and provided by at A2 Library
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`
`3
`
`Astrazeneca Ex. 2058 p. 3
`
`

`
`All patients
`Age, yea rs
`< 65
`2 65
`
`Both ER+ and PgFl+
`No
`Yes
`Visceral involvement
`No
`Yes
`
`Prior chemotherapy
`No
`Yes
`Measurable disease
`No
`Yes
`
`Prior endocrine therapy
`No
`Yes
`
`Fulvestrant Anastrozole
`500 mg
`1 mg
`events (n)
`events (n)
`
`63 (102)
`
`74 (103)
`
`29 (45)
`34 (57)
`
`14 (24)
`49 (78)
`
`29 (40)
`45 (63)
`
`18 (25)
`56 (78)
`
`11 (13)
`52 (89)
`
`44 (73)
`19 (29)
`
`7 (10)
`67 (93)
`
`59 (80)
`15 (23)
`
`0.25
`
`Ellis et al
`
`Hazard ratio and 95% Cl
`
`NC
`—o—
`
`—-:
`
`0.50
`
`I
`1.00
`
`Hazard ratio
`(95% Cl)
`0.70 (0.50 to 0.98)
`
`0.73 (0.44 to 1.24)
`0.68 (0.44 to 1.06)
`
`0.66 (0.33 to 1.32)
`0.72 (0.49 to 1.06)
`
`0.68 (0.40 to 1.18)
`0.86 (0.56 to 1.34)
`
`0.63 (0.43 to 0.94)
`0.93 (0.48 to 1.78)
`
`NC
`0.67 (0.46 to 0.96)
`
`0.63 (0.42 to 0.93)
`1.01 (0.51 to 1.99)
`2.00
`
`Fig 3. Overall survival subgroup analy-
`sis. ER+, estrogen receptor positive;
`NC, not calculable; PgR+, progesterone
`receptor positive.
`
`Favors fulvestrant 500 mg
`
`Favors anastrozole
`
`advanced breast cancer, with an approximately 30% reduction in
`mortality risk The previously reported improvements in TTP have
`translated into an improvement in OS of approximately 6 months
`with fulvestrant 500 mg (54.1 months) compared with anastrozole
`(48.4 months). This OS advantage is consistent with the OS benefit for
`fulvestrant 500 mg versus 250 mg in the second—line setting in the
`CONFIRM trial.” The effect of fulvestrant 500 mg on OS was gener-
`ally consistent across all prespecified subgroups (Fig 3). Furthermore,
`
`no new safety or tolerabflity issues were reported from the OS
`follow—up phase of this study, consistent with previously reported
`safety data. 1817
`The improved OS with fulvestrant 500 mg (54.1 months) relative
`to anastrozole (48.4 months) was observed although the median OS
`for the anastrozole group in this study was higher than has previously
`been reported. For example, OS of 39.2 months was reported for
`anastrozole as first—line endocrine therapy for advanced breast cancer
`
`Table 1. Baseline Covariates and Subgroups by Patients Censored 2 3 Months and S 3 Months Before DCO
`No. of Patients (%)
`
`Censored > 3 Months Before DCO
`
`Censored s 3 Months Before DCO
`
`Subgroup
`
`Fulvestrant 500 mg (n : 16)
`
`Anastrozole 1 mg (n : 19)
`
`Fulvestrant 500 mg (n : 23)
`
`Anastrozole 1 mg (n : 10)
`
`Age, years
`< 65
`2 65
`Receptor status at diagnosis
`Not both ER+ and PgR+
`Both EFH and PgR+
`Visceral involvement
`No
`Yes
`Previous chemotherapy
`No
`Yes
`Measurable disease at diagnosis
`No
`Yes
`Previous endocrine therapy
`N0
`Yes
`
`5 31.3)
`11 68.8)
`
`6 37.5)
`10 62.5)
`
`9 56.3)
`7 43.8)
`
`11 '68.8)
`5 31.3)
`
`1 6.3)
`15 93.8)
`
`11 68.8)
`5 31.3)
`
`7 (36.8)
`2 (63.2)
`
`5 (26.3)
`4 (73.7)
`
`1 (57.9)
`8 (42.1)
`
`3 (68.4)
`6 (31.6)
`
`3 (15.8)
`6 (84.2)
`
`3 (68.4)
`6 (31.6)
`
`11 (47.8)
`12 (52.2)
`
`4 (17.4)
`19 (82.6)
`
`16 (69.6)
`7 (30.4)
`
`19 (82.6)
`4 (17.4)
`
`1 (4.3)
`22 (95.7)
`
`18 (78.3)
`5 (21.7)
`
`4 (40.0)
`6 (60.0)
`
`2 (20.0)
`8 (80.0)
`
`8 (80.0)
`2 (20.0)
`
`8 (80.0)
`2 (20.0)
`
`0
`10 (100.0)
`
`8 (80.0)
`2 (20.0)
`
`Abbreviations: DCO, data cutoff; ER+, estrogen receptor—positive; PgR+, progesterone receptor—positive.
`
`4
`
`© 2015 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at A2 Library on September 14, 2015 from 212.209.42.182
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL or CLINICAL ONCOLOGY
`
`Astrazeneca Ex. 2058 p. 4
`
`

`
`Fulvestrant 500 mg: Overall Survival Versus Anastrozole
`
`Table 2. Incidence of SAEs and Deaths
`
`SAE
`
`Any SAE
`Any SAE related to death
`Any SAE with outcome other than death
`Any causally related SAE
`Most commonly reported (2 two patients)
`SAES
`Atrial fibrillation
`Cardiac failure
`Death
`Decreased appetite
`Dehydration
`Dyspnea
`Femur fracture
`Neuralgia
`Transient ischemic attack
`
`Abbreviation: SAE, serious adverse event.
`
`No. of Patients (%)
`Fulvestra nt
`Anastrozole
`500 mg
`1 mg
`(h : 101)
`(n : 103)
`
`24 (23.8)
`3 (3.0)
`21 (20.8)
`2 (2.0)
`
`22 (21.4)
`5 (1.9)
`18( 7.5)
`0
`
`1 (1.0)
`2 (2.0)
`0
`2 (2.0)
`2 (2.0)
`2 (2.0)
`1 (1.0)
`1 (1.0)
`0
`
`1
`
`I
`
`.0)
`
`0
`2( .9)
`O
`O
`O
`2( .9)
`1
`(
`.0)
`2[ .9)
`
`in a combined analysis of two phase III studies,” and OS of 41.3
`months was reported for the anastrozole monotherapy arm of a phase
`III combination study.” In addition, corresponding median OS val-
`ues of 34.0 months (letrozole)2O and 37.2 months (exemestane)21 have
`been reported for other AIs. It is therefore unlikely that the present
`analysis overestimates the margin of improvement with fulvestrant
`500 mg over anastrozole, which might have been possible had the
`control arm underperformed.
`The role of fulvesurant 500 mg as first—line therapy will be further
`defined by the ongoing phase III, double—bljnd FALCON (Fulvesurant
`and Anastrozole Compared ir1 Hormonal Therapy Naive Advanced
`Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380). The
`FALCON trialwill assess the efficacy offulvestrant 500 mg versus anas‘uro—
`zole inwomen with locally advanced or metastatic breast cancer with strict
`definitions of endocrine therapy—naive disease, including restrictions on
`exposure to hormone replacement therapy.
`Endocrine therapy—na'1've advanced breast cancer is relatively un-
`common in countries with advanced health care, but represents a
`numerically substantial patient population, given the high disease
`prevalence. Furthermore, ir1 unscreened populations and m develop-
`ing countries, metastatic disease at presentation is a significant prob-
`lem. Recent clinical trials reporting on first—line endocrine therapy in
`patients with ER—positive breast cancer have contained a substantial
`proportion, and often a majority, of endocrine therapy—naive
`patients.19’2”4 In FIRST, previous endocrine therapy had been re-
`ceived by 29 (28.4%) of the patients treated with fulvestrant 500 mg
`and 23 (22.3%) of the anastrozole—treated patients. Of these 52 pa-
`tients, only 3 had received AI previously (2 m the anastrozole group and
`1 in the fulvestrant 500 mg group); the remainder had received adjuvant
`tamoxifen. Therefore, AI resistance resulting from previous AI exposure
`cannot account for the observed OS difference. Indeed, hypothetically,
`previous exposure to tamoxifen may bias against fiilvestrant as both
`agents are in the same therapeutic class. Upon disease progression, pa-
`tients were treated according to the standard of care, and therefore, there
`could potentially be imbalances between the two treatment groups that
`
`could have affected the OS analysis. However, response to subsequent
`therapies (systemic chemotherapy or endocrine therapy) has previously
`been shown to be similar between the treatment groups, demonstrating
`that patients with disease progression on fulvestrant retain sensitivity to
`subsequent treatments.” Differential second—line response, therefore, is
`also an unlikely explanation for the observed OS effect.
`There are significant limitations to this report. The sample size was
`relatively small, and the OS analysis was not specified ir1 the original
`protocol but was added as a hypothesis in a protocol amendment after
`TTP results were known. Furthermore, 35 patients did not contribute
`additional data to the OS follow—up; the decision not to participate m the
`extended follow—up for OS was made solelybythe patient or participating
`center and was known at the start ofthe OS follow—up and before the data
`were collected and analyzed. Data from these patients until the time of
`censoring were included m the OS analysis, and similar censoring patterns
`were seen m the two treaunent groups. The sensitivity analyses support
`the main findings, that is, the differences ir1 OS between treatment arms
`were unrelated to differences ir1 censoring patterns. All—cause mortality
`was used to determine OS ir1 this analysis because it is regarded as the most
`unbiased and objective end point used ir1 oncology.” This point is partic-
`ularly relevant to an open—label study like FIRST. A final limitation was
`that the number ofpatients within subgroups was relatively small. There-
`fore, care should be taken when interpreting results.
`Recent results from several trials with the cyclin—dependent ki-
`nase 4/6 (CDK4/6) inhibitor palbociclib are also pertinent to the
`discussion. PALOMA—1 (Palbociclib Ongoing Trials m the Manage-
`ment of Breast Cancer), a phase II trial of leurozole plus palbociclib
`versus letrozole alone, provided provisional US Food and Drug Ad-
`ministration approval for palbociclib in the first—line setting on the
`basis of PFS.” No positive OS data have been reported to date; the
`results of a phase III trial ofthis comparison are pending (PALOMA—2,
`NCT01740427). Data from the phase III PALOMA—3 trial, comparing
`fulvestrant 500 mg plus palbociclib versus fulvestrant 500 mg alone in
`the second—line or subsequent setting in postmenopausal women (or
`pre— or perimenopausal women receiving goserelin), reported a
`marked PFS advantage for the combination, but OS data were also
`pending at the time of publication?“ The median PFS for fulvestrant
`500 mg alone was shorter in PALOMA—3 than ir1 previous studies,
`indicative of the younger, higher—risk, and more heavily pretreated
`population recruited into the PALOMA—3 trial.
`The treatment algorithm for ER—positive advanced breast cancer,
`therefore, is in a state of flux. Currently, it is rational to consider
`fulvestrant 500 mg as a first—line treatment option given the potential
`for survival benefits, particularly ir1 settings where palbociclib is not
`available or palbociclib cost or adverse effects are a significant concern,
`and especially if these results are confirmed in FALCON. These data
`also suggest that a first—line study offulvestrant 500 mg with a CDK4/6
`inhibitor versus fulvestrant 500 mg alone is a logical proposition that
`could lead to further prolonged TTP. Recent preclinical data on the
`efficacy of an ER degrading agent with a CDK4/6 inhibitor in ESR1—
`mutant breast cancer provides further rationale for this population,
`because improvements ir1 TTP or OS could be caused by suppression
`of ESR1—mutant AI—resistant clones.27
`
`In conclusion, we report that fulvestrant 500 mg may be associ-
`ated with improved OS versus anastrozole in the first—line setting for
`ER—positive advanced breast cancer. To our knowledge, this repre-
`sents the first time an endocrine monotherapy has demonstrated
`
`www.jc0.mg
`
`© 2015 by American Society of Clinical Oncology
`on September 14, 2015 from 212.209.42.182
`Information downloaded from jco.ascopubs.org and provided by at A2 Library
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`
`5
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`AstraZeneca Ex. 2058 p. 5
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`Ellis et al
`
`improved efficacy compared with a third—generation Al. The phase III
`FALCON trial may provide confirmation for these OS results; until
`then, the findings reported here should be regarded as preliminary,
`but clinically relevant.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`
`OF INTEREST
`
`Disclosures provided by the authors are available with this article at
`www.jco. org.
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Matthew J. Ellis, John F.R. Robertson
`Provision of study materials or patients: Matthew J. Ellis, Iohn ER.
`Robertson
`Collection and assembly of data: Matthew I. Ellis, David Feltl, Iohn F.R.
`Robertson
`Data analysis and interpretation: Matthew J. Ellis, Antonio
`Llombart-Cussac, Iohn A. Dewar, Marek Iasiowka, Nicola Hewson, Yuri
`Rukazenkov, Iohn F.R. Robertson
`Manuscript writing: All authors
`Final approval of manuscript: All authors
`
`1. Cardoso F, Costa A, Norton L, et al: ESO—
`ESMO 2nd International Consensus Guidelines for
`advanced breast cancer (ABC2). Ann Oncol 25:1871—
`1888, 20 4
`2. Cardoso F, Costa A, Norton L, et al: ESO—
`ESMO 2nd International Consensus Guidelines for
`advanced breast cancer (ABC2). Breast J 23:489-
`502, 2011
`3. Burstein HJ, Temin S, Anderson H, et al:
`Adjuvant endocrine therapy for women with hor-
`mone receptor—positive breast cancer: American
`Society o Clinical Oncology Clinical Practice Guide-
`line Focused Update. J Clin Oncol 32:2255-2269,
`2014
`4. Ma CX, Reinert T, Chmielewska I, et al: Mech-
`anisms o aromatase inhibitor resistance. Nat Rev
`Cancer 15:261-275, 2015
`5. Wa eling AE, Dukes M, Bowler J: A potent
`specific pure antiestrogen with clinical potential.
`Cancer Res 51 :3867-3873, 1991
`6. Wa eling AE: Similarities and distinctions in
`the mode of action of different classes of antioes-
`trogens. Endocr Relat Cancer 7:17-28, 2000
`7. Osborne CK, Wakeling A, Nicholson RI: Ful-
`vestrant: An oestrogen receptor antagonist with a
`novel mechanism of action. Br J Cancer 90:S2-S6,
`2004 (suppl 1)
`8. Robertson JFR, Howell A, Gorbunova VA, et
`al: Sensitivity to further endocrine therapy is
`re-
`tained following progression on first-line fulvestrant.
`Breast Cancer Res Treat 92: 169-174, 2005
`al:
`9. Osborne CK, Pippen J, Jones SE, et
`Double—blind, randomized trial comparing the effi-
`cacy and tolerability of fulvestrant versus anastro-
`zole in postmenopausal women with advanced
`breast cancer progressing on prior endocrine ther-
`apy: Results of a North American trial. J Clin Oncol
`20:3386-3395, 2002
`1D. Howell A, Robertson JFR, Ouaresma 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 203396-3403,
`2002
`11. Robertson JFR, Osborne CK, Howell A, et al:
`Fulvestrant versus anas rozole for the treatment of
`advanced breast carcinoma in postmenopausal
`women: A prospective combined analysis of two
`multicenter trials. Cancer 98:229-238, 2003
`I2. Howell A, Roberson JFR, Abram P, et al:
`Comparison of fulvestrant versus tamoxifen for the
`treatment of advanced breast cancer in postmeno-
`pausal women previousy untreated with endocrine
`therapy: A multinationa, double—blind, randomized
`trial. J Clin Oncol 22:1605—1613, 2004
`I3.
`-Iowell A, Cuzickc, Baum M, et al: Results of
`the ATAC (Arimidex, Tamoxifen, Alone or in Combi-
`nation) trial after competion of 5 years’ adjuvant
`treatment for breast cancer. Lancet 365:6062, 2005
`I4. Di Leo A, Jerusa em G, Petruzelka L, et al:
`Results of the CONFIR
`Phase III trial comparing
`fulves rant 250 mg with fulvestrant 500 mg in
`postmenopausal women with estrogen receptor-
`positive advanced breast cancer. J Clin Oncol 28:
`4594-4600, 2010
`I5. Di Leo A, Jerusalem G, Petruzelka L, et al:
`Final overall survival: Fulvestrant 500mg vs 250mg
`in the randomized CONFIRM trial. J Natl Cancer Inst
`106:dj 337, 2014
`I6. Robertson JF, Llombart—Cussac A, Rolski J, et
`al: Activity of fulvestrant 500 mg versus anastrozole
`1 mg as first-line treatment for advanced breast
`cancer: Results from the FIRST study. J Clin Oncol
`27:4530¢l535, 2009
`I7. Robertson JF, Lindemann J, Llombart—Cussac
`A, et al: Fulvestrant 500 mg versus anastrozole 1 mg
`for the first-line treatment of advanced breast can-
`cer: Follow—up analysis from the randomized ‘FIRST’
`study. Breast Cancer Res Treat 136:503—5i 1, 2012
`I8. Nabholtz JM, Bonneterre J, Buzdar A, et al:
`Anastrozole (Arimidex) versus tamoxifen as first-line
`therapy for advanced breast cancer in postmeno-
`pausal women: Survival analysis and updated safety
`results. EurJ Cancer 39:1684—1689, 2003
`19. Mehta RS, Barlow WE, Albain KS, et al: Com-
`bination anast