Published Ahead of Print on September 14, 2015 as 10.1200IJCO.2015.61.5831
`The latest version is at http:Iljco.ascopubs.orglcgildoil10.1200lJCO.201 5.61.5831
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`ORIGI NAL REPORT
`
`Matthew J Ellis Baylor College Of
`Medicine, Houston, TX, Antonio
`LlombarteCussac, Hospital Arnau de
`Vilanova, Lerida, Spain, Dayld Feltl,
`FNsP Ostrava, OstravaePoruba, Czech
`Republic) John A. Dewar, Ninewells
`Hospital and Medical School, Dundee,
`Nicola Hewson and Yuri Rukazenkov,
`AstraZeneca Pharmaceuticals, Macclese
`field, John F R Robertson, UniverSIty of
`Nottingham, Derby, United Kingdom,
`and MarekJasiOwka, lnstytut im Marii
`SklOdOWSkleFCUrle, KrakOw, Poland
`Published online ahead of print at
`www JCO org on September 14, 2015
`Supported by AstraZeneca.
`Terms in NH" are defined in the glose
`sary, found at the end Of this article
`and online at vwi/w (Georg
`Presented at the 2014 San Antonio
`Breast Cancer Symposuim, San Antoe
`nio, TX, December 913, 2014
`
`Authors' disclosures of potential
`conflicts of interest are found in the
`article online at wwwico org. Author
`contributions are found at the end of
`this article.
`Clinical trial information NCT00274469
`
`Corresponding author Matthew J Ellis,
`MD, Lester and Sue Smith Breast
`Center, One Baylor Plaza, Baylor
`College of Medicme, Houston, TX
`77030, email. Matthew Ellis@locrn edu
`
`© 2015 by American SOCIety of Clinical
`Oncology Licensed undei the Creative
`Commons Attribution 3.0 License
`
`073271813X“ 5/33991/$20 00
`DOI
`1O 'IZOO/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 11 FIRST Study
`
`Matthew]. Ellis, Antonio Llombart—Cussac, David Feltl, Iohn A. Dewar, Mnrek Iasiowka, Nicola Hewson,
`Yuri Rulcazenkov, and John FR. Robertson
`
`ABSTRACT
`
`
`
`Purpose
`To 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—label, 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 [23.4 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 log—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 (fulvestrant 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 08 with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98;
`P = .04; median OS, 54.1 months V484 months). Treatment effects seemed generally consistent
`
`across the subgroups analyz d. No new saf ty issu s W re Obs rvcd.
`
`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 follow—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 (Fulvestrant and Anastrozole Compared in
`Hormonal Therapy Naive Advanced Breast Cancer)
`trial
`(ClinicalTrialsgov identifier:
`NCT01602380).
`
`J Clin Oncol (CD 2075 by American Society of Clinical Oncology. Licensed under the Creative
`Commons Attribution 3.0 License: http://creativecommo‘ns.org/licenses/by/(i.0/
`
`
`
`Emulate .'
`
`Tamoxifen and third—generation aromatase inhibi—
`tors (AIs), 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.1'3 Given the high prevalence Of resis—
`tance tO AI therapy, multiple treatment Options with
`distinct mechanisms Of action are desirable.4
`
`Fulvestrant, a 17B—estradiol analog, is a selec—
`tive ER antagonist that suppresses es’o‘ogen signaling
`by binding tO ER and inducing a conformational
`changeé‘é Dimerization is subsequently blocked,
`triggering accelerated degradation and downregula—
`tion Of the ER protein.5 Fulves‘uant 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.ZS The clinical efficacy Of fulvestrant
`
`© 2015 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at AZ Library on September 14, 2015 from 212.209.42.182
`Copyright ©. 2015 American Society of Clinical Oncology. All rights reserved.
`Copyright 2015 by American Society of Clinical Oncology
`
`1
`
`AstraZeneca Exhibit 2058 p. 1
`InnOPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC V. AstraZeneca AB IPR2017-01910
`
`

`

`Ellis et al
`
`was initially demonsuated 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"m A combined analysis of
`these trials demonstrated that time to progression (TTP) with fulves—
`trant 250 mg was noninferior to anastrozole.11
`Fulvestrant 250 mg was not proven to be superior to tamoxifen in
`a double—blind, randomized trial.12 This findingwas unexpected given
`the superiority of anastrozole over tamoxifenw’ and the comparable
`efficacy of anastrozole and fulvestrant 250 mg as second—line ther—
`apy.11 Pharrnacokinetic modeling, as well as observations made dur—
`ing early clinical studies,L1 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 fulves‘uant 500—mg dose regimen, comparing
`efficacy and safety with anastrozole in the first—line setting. The pri—
`mary end point of clinical benefit rate was noninferior for fulvestrant
`500 mg compared with anastrozole,16 with both treatments demon—
`s‘uating 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 v
`13.1 months). No additional safety issues were reported.17 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.
`
`PATIENTS AND: 'MEIHGII’S
`
`Study Design and Participants
`FIRST was a phase H, randomized, openelabel, multicenter, parallele
`group trial comparing fulvestrant 500 mg with anastrozole 1 mg. Postmenoe
`pausal women with ERepositive 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 come
`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 Harmonisationflood Clinical Practice guide
`lines, and is registered with Clinicfltrialsgov. All patients provided written,
`informed consent Full details. ofthis trial have been reported previouslym‘l7
`
`Random Assignment and Procedures
`Eligible patients were randomly assigned sequentially 1:1 to either fulvese
`trant 500 mg (administered intramuscularly on days 0, 14, 28, and every
`28 days thereafter) or anastrozole 1 mg (administered orally once 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 enteredafolloweup phase after a protocol amendment for
`
`an analysis of TTP. The TTP followeup required a questionnaire to be come
`pleted for each patient 12 months after the patient enteredthe followeup phase
`and every 12 months thereafter for patients continuing to receive randomized
`treatment. After the TTP analysis was performed, a further protocol amende
`ment was developed to enter patients into an optional followeup 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 contribe
`ute additional data to the followeup extension were rightecensored at the last
`known date they were alive, and their data until this point were included in the
`analysis. Sites were invited to request written consent from patients for the
`collection of additional data. Patients were contacted every 3 months until the
`first ofthe following events: death, patientwithdrawal, data cutoffwas reached,
`or the patient was lostto followeup. Patients with a last known survival status of
`alive were contacted within 2 weeks ofdata cutoffto ensure they were 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’”
`The followeup analysis assessed OS, defined as the time from being
`randomlyassign ed to death from any cause. A logeran k test (unadjusted model
`with treatment factor only) was performed for the primary analysis ofOS. HRs
`with 95% CIs were used to compare fiilvestiant 500 mg with anastrozole; no
`adjustments were made for multiplicity. A statistical significance level of .05
`was used to indicate a difference in OS between the treatment groups. For
`patients for whom followeup 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 logrank test 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 and
`progesterone receptor versus positive for both ER and progesterone receptor;
`no visceral involvement versus visceral involvement; no previous chemothere
`apy versus previous. adjuvant chemothelapy; no measurable disease versus
`measurable disease; and no previous endocrine therapyversus previous endoe
`crine therapy.
`Two sensitivity analyses were performed to examine any potential
`impact ofnonparticipation on OS results: a KaplaneMeier 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 followeup
`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 offulvestrant 500 mg
`or for 30 days after the last dose of anastrozole.
`
`
`
`In total, 205 patients were randomly assigned to receive fulvestrant
`500 mg (n = 102) or anastrozole 1 mg (n = 103) at 62 centers in 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 fulvesUant 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 (1 6 in the fulvestrant
`500 mg group and 19 in the anastrozole group) did not participate in
`
`Z
`
`© 2015 by American Seeiety of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at AZ 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 Exhibit 2058 p. 2
`
`

`

`(h =10)
`
`l—l—l
`
`Fulvestrant 500 mg
`(n = 102,)
`
`Anastrozole 1 mg
`in = 103)
`
`Fulvestrant 500 mg: Overall Survival Versus Anastrozole
`
`Enrolled
`(N = 233)
`
`Not randomlyéalloeated
`Incorrect enrollment
`Death
`Adverse event
`Volu ntary patient disco nti n‘uatio n
`Other
`
`(n=28-)
`(n=20)
`.(n=1l
`ln=1)
`ln=4l
`(n=2)
`
`Randomly allocated
`(n = 205)
`
`Fig 1. Study overview. (*) These patients
`were right censored at the time of their last
`known date alive, and data until this point
`were used in the overall survival (08) analysis.
`
`am cutoff for analysis cf overall survival
`Alive
`(n = 23)
`Dead
`(n = 63)
`Did not contribute additional data
`(n = 16,)
`during OS follow-up extension*
`Patient declined to participate
`Site declined to participate
`
`(n=6)
`
`Data cutoff for analysis of OVerall survival
`Al hie
`(n =10)
`Dead
`(n=74)
`Did not contribute additional data
`(n =19)
`during OS follow-up extensi0n*
`Patient declined to participate
`Site declined to participate
`
`(n =9)
`(13:10)
`
`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 08
`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 in 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% Cl, 0.50 to
`0.98; log—rank test P = .04; median 08, 54.1 months v 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).
`
`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 Heat—
`ment. Two SAEs considered to be treatment related were documented
`
`(one case ofhypertension and one case of pulmonary embolism,both
`in the fulvestrant 500 mg treaUnent group).
`
`Dis" 1153!“
`
`This study reports improved 08 with fulvestrant 500 mg treatment
`compared with anastrozole in the first—line setting for ER—positive
`
`— Fulvestrant 500 mg
`----Anastrozo|e 1 mg
`
`
`
`
`
`OverallSurvival
`
`.0 07
`
`(proportion) 52
`
`.0 N
`
`Median overall survival:
`Fulvestrant 500 mg: 54.1 months
`Anastrozole 1 mg: 48.4 months
`Hazard ratio, 0.70; 95% Cl, 0.50 to 0.98; P: .04
`
`6 1218 2430 36 42 48 54 60 66 72 78 84 90 96102
`
`No. at risk
`Fulvestrant 500 mg 102
`Anastrozole 1 mg
`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.
`
`WWW.jammy
`
`© 2015 by American ‘Socrety of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at AZ Library on September 14, 2015 from 212.209.42.182
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`
`3
`
`AstraZeneca Exhibit 2058 p. 3
`
`

`

`Ellis et al
`
`Fulvestrant Anastrozole
`Hazard ratio
`500 mg
`1 mg
`
`events (n)events (n) (95% CI)
`
`Hazard ratio and 95% CI
`0.70 (0.50 to 0.98)
`.
`i
`All patients
`63 (102)
`74 (103)
`Age, years
`< 65
`2 65
`
`0.73 (0.44 to 1.24)
`0.68 (0.44 to 1.06)
`
`29 (45)
`34 (57)
`
`Favors fulvestrant 500 mg
`
`Both ER+ and PgR+
`No
`Yes
`
`Visceral involvement
`No
`Yes
`
`Prior chemotherapy
`No
`Yes
`Measurable disease
`
`Prior endocrine therapy
`No
`Yes
`
`14 (24)
`49 (78)
`
`29 (54)
`34 (48)
`
`43 (73)
`20 (29)
`
`11 (13)
`52 (89)
`
`44 (73)
`19 (29)
`
`26 (45)
`48 (58)
`
`57 (78)
`17 (25)
`
`7 (10)
`67 (93)
`
`NC
`—o— i
`
`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)
`
`g
`.
`0.63 (0.42 to 0.93)
`59 (80)
`—.— 1.01 (0.51 to 1.99)
`15 (23)
`_l—l—l—l—
`0.25
`0.50
`1.00
`2.00
`
`Favors anastrozole
`
`Fig 3. Overall survival subgroup analy-
`sis. ER+, estrogen receptor positive;
`NC, not calculable; PgR+, progesterone
`receptor positive.
`
`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.15 The effect offulvestrant 500 mg on OS was gener—
`ally consistent across all prespecified subgroups (Fig 3). Furthermore,
`
`no new safety or tolerability issues were reported from the OS
`follow—up phase of this study, consistent with previously reported
`safety data.16’17
`The improved OS with fulvestrant 500 mg (54.1 months) relative
`to anastrozole (48.4 months) was observed although the median OS
`for the anashrozole 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 g 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
`ot both ER+ and PgR+
`Both ER+ and PgR+
`Visceral involvement
`0
`Yes
`Previous chemotherapy
`o
`Yes
`Measurable disease at diagnosis
`0
`Yes
`Previous endocrine therapy
`8 (80.0)
`18 (78.3)
`3 (68.4)
`11 (68.8)
`0
`
`Yes 2 (20.0) 5 (31 .3) 6 (31.6) 5 (21.7)
`
`
`
`
`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)
`
`7 (3.6.8)
`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)
`
`
`
`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)
`
`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)
`
`
`
`
`
`Abbreviations: DCO, data cutoff; ER+, estrogen receptor—positive; PgR+, progesterone receptor—positive.
`
`4
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2015 by American Socrety of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at AZ Libraw on September 14, 2015 from 212.209.42.182
`Copyright © 2015 American Society of Clinical Oncology. All rights resen/ed.
`
`AstraZeneca Exhibit 2058 p. 4
`
`

`

`Fulvestrant 500 mg: Overall Survival Versus Anastrozole
`
`
`
`Table 2. Incidence of SAEs and Deaths
`
`Fulvestra nt
`Anastrozole
`500 mg
`1 mg
`
`SAE
`(n : 101)
`(n : 103)
`
`No. of Patients (%)
`
`22 (21.4)
`5 (4.9)
`18 (17.5)
`0
`
`24 (23.8)
`3 (3.0)
`21 (20.8)
`2 (2.0)
`
`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
`1 (1.0)
`1 (1.0)
`Atrial fibrillation
`0
`2 (2.0)
`Cardiac failure
`2 (1.9)
`0
`Death
`0
`2 (2.0)
`Decreased appetite
`O
`2 (2.0)
`Dehydration
`O
`2 (2.0)
`Dyspnea
`2 (1.9)
`1 (1.0)
`Femur fracture
`1 (1.0)
`1 (1.0)
`Neuralgia
`
`Transient ischemic attack 2 (1.9) 0
`
`
`Abbreviation: SAE, serious adverse event.
`
`in a combined analysis of two phase III studies,18 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?0 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 fulvestrant 500 mg as first—line therapy will be further
`defined by the ongoing phase III, double—blind FALCON (Fulvestrant
`and Anastrozole Compared in Hormonal Therapy Naive Advanced
`Breast Cancer) trial (ClinicalTrialsgov identifier: NCT01602380). The
`FALCON trialwill assess the efficacy offulvestrant 500 mg versus anastro—
`zole in women 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—naive 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, in unscreened populations and in 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
`patientsm’mfl 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, only3 had received AI previously (2 in 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 fulvestrant 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 ‘urea‘unents.l7 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 in 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 in the
`extended follow—up for OS was made solelyby the 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 includedin the OS analysis, and similar censoring patterns
`were seen in the two Heatment groups. The sensitivity analyses support
`the main findings, that is, the differences in OS between Heatment arms
`were unrelated to differences in censoring patterns. All—cause mortality
`was used to determine OS in this analysis because it is regarded as the most
`unbiased and objective end point used in oncology.25‘ 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 uials with the cyclin—dependent ki—
`nase 4/6 (CDK4/6) inhibitor palbociclib are also pertinent to the
`discussion. PALOMA—l (Palbociclib Ongoing Trials in the Manage—
`ment of Breast Cancer), a phase II trial of letrozole plus palbociclib
`versus letrozole alone, provided provisional US Food and Drug Ad—
`ministration approval for palbocich in the first—line setting on the
`basis of PFS.23 No positive OS data have been reported to date; the
`results ofaphase III Urial ofthis comparison are pending (PALOMA—2,
`NCT01740427). Data from the phase III PALOMA—3 trial, comparing
`fulves‘urant 500 mg plus palbociclib versus fulvestrant 500 mg alone in
`the second—line or subsequent setting in postmenopausal women (or
`pre— or perirnenopausal women receiving goserelin), reported a
`marked PFS advantage for the combination, but OS data were also
`pending at the time of publication?6 The median PFS for fulvestrant
`500 mg alone was shorter in PALOMA—3 than in 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
`fulves‘urant 500 mg as a first—line treatment option given the potential
`for survival benefits, particularly in 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 ESRI—
`mutant breast cancer provides further rationale for this population,
`because improvements in TTP or OS could be caused by suppression
`of ESRl—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.jco.01’g
`
`© 2015 by American ‘Socrety of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at AZ Libraw on September 14, 2015 from 212.209.42.182
`Copyright © 2015 American Society of Clinical Oncology. All rights reserved.
`
`5
`
`AstraZeneca Exhibit 2058 p. 5
`
`

`

`Ellis et al
`
`improved efficacy compared with a third—generation Al. The phase III
`FALCON trial may provide confirmation for these 08 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 ER. Robertson
`Provision of study materials or patients: Matthew J, Ellis, John ER.
`Robertson
`Collection and assembly of data: Matthew J. Ellis, David Feltl, John ER.
`Robertson
`
`Data analysis and interpretation: Matthew J. Ellis, Antonio
`LlombaIteCussac, John A. Dewar, Marek Jasi’éwka, Nicola Hewson, Yuri
`Rulcazenkov, John ER. Robertson
`Manuscript writing: All authors
`Final approval of manuscript: All authors
`
`
`
`
`
`
`
`endocrine treatment. J Clin Oncol 20:3396-3403,
`21]. Mouridsen H, Gershanovich M, Sun Y, et al:
`2002
`Phase III study of
`letrozole versus tamoxifen as
`11. Robertson JFR, Osborne CK, Howell A, et al:
`first—line therapy of advanced breast cancer in post—
`Fulvestrant versus anas rozole for the treatment of
`1. Cardoso F, Costa A, Norton L, et al: ESO»
`menopausal women: Analysis of survival and update
`ESMO 2nd International Consensus Guidelines for
`advanced breast carcinoma
`in postmenopausal
`of efficacy from the International Letrozole Breast
`advanced breast cancer (ABC2). Ann Oncol 25:1871-
`women: A prospective combined analysis of two
`Cancer Group. J Clin Oncol 21:2101-2109, 2003
`1888, 20 4
`multicenter trials. Cancer 98:229-238, 2003
`21. Paridaens RJ, Dirix LY, Beex LV, et al: Phase
`12. Howell A, Roberson JFR, Abram P, et al:
`2. Cardoso F, Costa A, Norton L, et al: ESO—
`III study comparing exemestane with tamoxifen as
`ESMO 2nd International Consensus Guidelines for
`Comparison of fulvestrant versus tamoxifen for the
`first-line hormonal treatment of metastatic breast
`advanced breast cancer (ABCZ). Breast J 23:489-
`treatment of advanced breast cancer in postmeno»
`cancer in postmenopausal women: The European
`502, 2011
`pausal women previous y untreated with endocrine
`Organisation for Research and Treatment of Cancer
`3. Burstein HJ, Temin S, Anderson H, et al:
`therapy: A multinationa , double-blind, randomized
`Breast Cancer Cooperative Group. J Clin Oncol
`trial. J Clin Oncol 22:1605-1613, 2004
`Adjuvant endocrine therapy for women with hor-
`2848834890, 2008
`13. -lowe|| A, Cuzick J, Baum M, et al: Results of
`mone receptor—positive breast cancer: American
`22. Bergh J, Jonsson PE, Lidbrink EK, et al: FACT:
`the ATAC (Arimidex, Tamoxifen, Alone or in Combi-
`Society 0 Clinical Oncology Clinical Practice Guide—
`An open-label randomized phase III study of fulves»
`line Focused Update. J Clin Oncol 322255-2269,
`nation) trial after comp etion of 5 years' adjuvant
`trant and anastrozole in combination compared with
`2014
`treatment for breast cancer. Lancet 365:60—62, 2005
`anastrozole alone as first-line therapy for patients
`14. Di Leo A, Jerusa em G, Petruzelka L, et al:
`4. Ma CX, Reinert T, Chmielewska I, et al: Mech-
`with receptor-positive postmenopausal breast can-
`anisms o aromatase inhibitor resistance. Nat Rev
`Results of the CONFIR
`Phase III trial comparing
`cer. J Clin Oncol 30:1919—1925, 2012
`Cancer 15:261-275, 2015
`fulves rant 250 mg with fulvestrant 500 mg‘
`in
`23. Finn RS, Crown JP, Lang I, et al: The cyclin»
`postmenopausal women with estrogen receptor—
`5. Wa xeling AE, Dukes M, Bowler J: A potent
`dependent kinase 4/6 inhibitor palbociclib in combi—
`positive advanced breast cancer. J Clin Oncol 28:
`specific pure antiestrogen with clinical potential.
`nation with letrozole versus letrozole alone as first-
`4594-4‘600, 2010
`Cancer Res 5i :3867-3873, 1991
`line
`treatment
`of oestrogen receptor—positive,
`15. Di Leo A, Jerusalem G, Petruzelka L, et al:
`6. Wa eling AE: Similarities and distinctions in
`HER2-negative, advanced breast cancer (PALOMA—
`the mode of action of different classes of antioes-
`Final overall survival: Fulvestrant 500mg vs 250mg
`1/TRIO—18): A randomised phase 2 study. Lancet
`in the randomized CONFIRM trial. J Natl Cancer Inst
`trogens. Endocr Relat Cancer 7:17-28, 2000
`Oncol 16:25-35, 2015
`106:dj 337, 2014
`7. Osborne CK, Wakeling A, Nicholson RI: Ful—
`24. Martin VI, Loibl S, Von Minckwitz G, et al:
`16. Robertson JF, Llombart-Cussac A, Rolski J, et
`vestrant: An oestrogen receptor antagonist with a
`Phase III trial evaluating the addition of be