D0|:10.1093/jnci/djt337
`Advance Access publication December 7, 2013
`
`N
`
`©The Author 2013. Published by Oxford University Press.
`This is an Open Access article distributed under the terms of the Creative Commons Attribution
`Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/), which permits
`non-commercial re—use, distribution, and reproduction in any medium, provided the original
`work is properly cited. For commercial re—use, please contact journa|s.permissions@oup.com
`
`Final Overall Survival: Fulvestrant 500 mg vs 250mg in the
`
`Randomized CONFIRMTrial
`
`Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka, Roberto Torres, Igor N. Bondarenko, Rustem Khasanov, Didier Verhoeven,
`José L. Pedrini, lya Smirnova, Mikhail R. Lichinitser, Kelly Pendergrass, Luca Malorni, Sally Garnett, Yuri Rukazenkov, Miguel Martin
`
`Manuscript received May 15, 2013; revised October 7, 2013; accepted October 18, 2013.
`
`Correspondence to: Angelo Di Leo, MD, PhD, "Sandro Pitigliani" Medical Oncology Unit, Hospital of Prato, Piazza dell Ospedale 2, 59100 Prato, Italy (e—mail:
`adileo@usl4.toscana.it).
`
`Background
`
`Methods
`
`At the time of the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic
`Breast Cancer (CONFIRM) randomized, double-blind, phase III trial, approximately 50% of patients had died.
`A final analysis of OS was subsequently planned for when 75% of patients had died.
`
`Patients were randomly assigned 1:1 to fulvestrant 500 mg administered as two 5-mL intramuscular injections on
`days 0, 14, and 28 and every 28 (:3) days thereafter or fulvestrant 250 mg administered as two 5-mL intramuscular
`injections (one fulvestrant and one placebo [identical in appearance to study drug]) on days 0, 14 (two placebo
`injections only), and 28 and every 28 (:3) days thereafter. OS was analyzed using an unadjusted log-rank test. No
`adjustments were made for multiplicity. Serious adverse events (SAEs) and best response to subsequent therapy
`were also reported. All statistical tests were t\No-sided.
`
`Results
`
`In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500mg (n = 362) or 250mg
`(n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median 08 was 26.4 months for
`fulvestrant 500 mg and 22.3 months for 250 mg (hazard ratio = 0.81; 95% confidence interval: 0.69-0.96; nominal
`P= .02).There were no clinically important differences in SAE profiles between the treatment groups; no cluster-
`ing of SAEs could be detected in either treatment group.Type of first subsequent therapy and objective responses
`to first subsequent therapy were well balanced between the two treatment groups.
`
`Conclusions
`
`In patients with locally advanced or metastatic estrogen receptor—positive breast cancer, fulvestrant 500mg is
`associated with a 19% reduction in risk of death and a 4.1-month difference in median OS compared with fulves-
`trant 250mg. Fulvestrant 500 mg was well tolerated, and no new safety concerns were identified.
`
`JNCI J Natl Cancer Inst (2014) 106(1): djt337
`
`Fulvestrant is a pure estrogen receptor (ER) antagonist devoid of
`the agonistic properties displayed by tamoxifen in some tissues
`(1-4). After phase III studies, which demonstrated similar efficacy
`and an acceptable safety profile for fulvestrant 250mg compared
`with anastrozole (1,5), fulvestrant 250mg was approved as treat-
`ment in postmenopausal women with advanced hormone recep—
`tor—positive breast cancer that had progressed or recurred after
`prior antiestrogen therapy. However, previous preoperative stud-
`ies showed that short—term exposure to fulvestrant was associated
`With a dose—dependent reduction in the levels ofER, progesterone
`receptor, and the cell proliferation—related antigen K167 (6,7) for
`fulvestrant doses up to 2 50 mg. Other phase I and phase III stud-
`ies also suggested a dose—response effect for fulvestrant (1,5,8).
`The phase III Comparison of Faslodex in Recurrent or Metastatic
`Breast Cancer (CONFIRM) trial compared the then—approved dose
`and dosing schedule of fulvestrant (2 50mg every 28 days) with a
`higher—dose regimen (5 00mg every 28 days plus an additional
`5 00mg on day 14 of the first month only) in postmenopausal women
`jnci.oxfordjourna|s.org
`
`with locally advanced or metastatic ER—positive breast cancer that
`had recurred or progressed after prior endocrine therapy. The ini-
`tial results showed that fulvestrant 5 00mg was associated with a
`statistically significant increase in progression—free survival (PFS)
`without increased toxicity, therefore corresponding to a clinically
`meaningful improvement in benefit vs risk compared with fulves-
`trant 250mg
`Based on these data, the 500—mg dose of fulves-
`trant is now the approved dose in the European Union (approved in
`March 2010), United States (approved in September 2010), Japan
`(approved in November 2 01 1), and other countries worldwide.
`In the CONFIRM study, the assessment of the therapeutic effi-
`cacy of both doses of fulvestrant was evaluated by several secondary
`outcome measures, including overall survival (OS). At the time of
`the initial analysis, approximately 5 0% of patients had died. After
`the reporting of the 50% survival data, which showed a trend in
`favor of 500mg over 250mg, it was agreed to perform a final sur-
`vival analysis after 75% of patients had died. Here we report the
`results of this final OS analysis.
`
`JNCI
`
`| Article 1of7
`
`Astrazeneca Ex. 2005 p. 1
`Mylan Pharms. Inc. V. Astrazeneca AB IPR2016-01324
`
`

`
`Methods
`
`Study Design and Patients
`The CONFIRM study design, including eligibility criteria, exclu-
`sion criteria, and the calculation of sample size, has been described
`in detail elsewhere
`Briefly, CONFIRM was a randomized,
`phase III, double—blind trial that evaluated two different doses
`of fulvestrant (500mg vs 250mg) in postmenopausal patients
`who had either locally advanced or metastatic ER—positive breast
`cancer
`(ClinicalTrials.gov identifier: NCT000994-37; http://
`www.clinicaltrials.gov/ct2/show/NCTO0099437). The primary
`study endpoint was PFS (the time elapsing between the date of
`randomization and the date of earliest evidence of objective dis-
`ease progression or death from any cause). Secondary endpoints
`included objective response rate, clinical benefit rate, duration of
`response, duration of clinical benefit, OS, tolerability, and quality
`of life (9).
`After initial analysis, all patients, regardless of whether they
`were still receiving randomized treatment, entered a survival fol-
`low—up phase. Patients remaining on randomized treatment during
`this follow—up phase continued on blinded randomized treatment
`until progression and were assessed for serious adverse events
`(SAEs) and survival status. Patients who had discontinued rand-
`omized treatment were assessed for their survival status and best
`
`response to their first subsequent systemic breast cancer therapy
`received after treatment discontinuation.
`
`Ethics
`
`The study was performed in accordance with the Declaration
`consistent with International Conference
`on
`of Helsinki,
`Harmonisation/Good Clinical Practice requirements. All patients
`gave written informed consent before study entry, and the study
`protocol was approved by the institutional review board of each
`participating institution.
`
`Randomization and Masking
`Patients were randomly assigned to treatment in balanced blocks
`using a computer—generated randomization schedule; all study per-
`sonnel were blinded to randomized treatment. Eligible patients were
`randomly assigned 1:1 to either fulvestrant 500mg administered as
`two 5 —mL intramuscular injections on days 0, 14, and 28 and every
`28 (i 3) days thereafter or fulvestrant 250mg administered as two
`5 —mL intramuscular injections (one fulvestrant and one placebo
`[identical in appearance to study drug]) on days 0, 14- (two placebo
`injections only), and 28, and every 28 (1 3) days thereafter
`Fulvestrant was supplied in the form of a single dose in a pre-
`filled syringe. Each active prefilled syringe contained 250mg of
`fulvestrant at a concentration of 5 0mg/mL in a volume of 5 mL,
`designated fulvestrant 5% weight/volume injection. The placebo
`prefilled syringe was identical to the active prefilled syringe and
`also had a volume of 5 mL.
`
`Survival analysis
`OS was defined as the number of days from randomization to death
`from any cause. Patients who died after the data cutoff or who were
`known to be alive after the data cutoff were right—censored at the
`date of the data cutoff. Patients who were last known to be alive
`
`before the data cutoff or who were lost to follow—up before the
`
`data cutoff were right—censored at the date they were last known
`to be alive.
`
`After the initial analysis, patients on fulvestrant 250mg were
`permitted to switch to 500mg before entering the survival follow-
`up phase. Irrespective of whether they were still receiving rand-
`omized treatment, all patients in the follow—up phase continued to
`have their survival status monitored every 12 :2 weeks until cutoff
`for the final 75% OS analysis (October 31, 2011).
`
`Best Response to First SubsequentTherapy
`Details of the first subsequent systemic breast cancer therapy
`received after discontinuation of randomized treatment, and of the
`best response (complete response, partial response, stable disease,
`progressive disease, not evaluable) to this therapy were collected.
`
`Tolerability
`SAEs were reported to the Patient Safety Database and collated
`during the survival follow—up phase for those patients still receiving
`randomized treatment.
`
`Statistical Analysis
`OS was first analyzed in 2009, in parallel with the primary analysis
`of PFS, after the proportion of reported deaths exceeded 50% of
`the total number of patients randomized across the two treatment
`groups. The analysis was performed using an unadjusted log—rank
`test. An additional exploratory analysis, which used a Cox propor-
`tional hazards model adjusting for six predefined covariables (age at
`baseline, response to last endocrine therapy received before fulves-
`trant, receptor status at diagnosis, visceral involvement at baseline,
`last therapy before fulvestrant, and measurable disease at baseline)
`was also performed to assess the robustness of the unadjusted OS
`result.
`
`An updated analysis is presented here of more mature survival
`data, performed after the proportion of reported deaths exceeded
`75% of the total number of patients randomized across the two
`treatment groups. The data were analyzed using log—rank statistics,
`confirmed by Cox proportional hazards model, and summarized
`by the method of Kaplan—Meier. P values presented are nominal
`without adjustment for multiplicity, and no alpha was retained for
`this analysis (the 5% error was used at the initial OS analysis). All
`statistical tests were two—sided.
`
`For SAEs, summaries and analyses were prepared according to
`the treatment actually received.
`
`Results
`
`Patients
`
`In total, 736 women (median age = 61.0 years) were randomly
`assigned between February 2005 and August 2007 from 128 cent-
`ers in 17 countries (Belgium, Brazil, Chile, Colombia, Czech
`Republic, Hungary, India, Italy, Malta, Mexico, Poland, Russia,
`Slovakia, Spain, the United States, Ukraine, and Venezuela) (ful-
`vestrant 500 mg: n = 362; fulvestrant 250 mg: n = 374-) (Figure 1).
`Baseline patient and tumor characteristics, reported previously,
`were comparable between the treatment groups
`At the tirne
`of the final analysis, 63 patients (8.6%) were lost to follow—up, 16
`patients (2.2%) had withdrawn consent, 103 patients (14.0%) were
`
`20f7 Article
`
`|
`
`JNCI
`
`Vol. 106, Issue 1
`
`| djt337 | January 1, 2014
`
`Astrazeneca Ex. 2005 p. 2
`
`

`
`still being followed up (n = 21 [2.9%] on treatment; n = 82 [11.1%]
`not on treatment), and 554 patients (75.3%) had died.
`For 34 of the 736 patients (4.6%), fulvestrant dose Was unblinded
`after progression to the study drug.
`Eight patients (2.1%) crossed over from fulvestrant 250mg to
`fulvestrant 500mg.
`
`Survival Analysis
`At the initial data cutoff, 378 of 736 patients (51.4%) had died
`(11 = 175 [48.3%] in the fulvestrant 500mg group; n = 203 [54.3%]
`in the fulvestrant 250mg group) (Table 1). There Was a trend for
`improved OS for patients in the fulvestrant 5 00mg group com-
`pared With those in the fulvestrant 25 0mg group (25.1 months vs
`22.8 months, respectively; hazard ratio (HR) = 0.84, 95% confi-
`dence interval (Cl) = 0.69 to 1.03, P = .09 for the unadjusted analy-
`sis; HR = 0.81, 95% C1 = 0.66 to 1.00, P = .049 for the retrospective
`adjusted analysis) (Table 1; Figure 2A).
`At the final survival update, 554 of 736 patients (75.3%) had
`died (n = 261 [72.1%] in the fulvestrant 500mg group; n = 293
`[78.3%] in the fulvestrant 250mg group) (Table 1). There Was
`continued separation of the survival curves for fulvestrant 500mg
`compared With fulvestrant 25 0mg. The median time to death for
`
`patients in the fulvestrant 500 mg group vs the fulvestrant 25 0mg
`group Was 26.4 months vs 22.3 months, respectively (HR = 0.81,
`95% C1 = 0.69 to 0.96, nominal P = .02 for the unadjusted analy-
`sis; HR = 0.79, 95% C1 = 0.67 to 0.94, nominal P = .007 for the
`adjusted analysis) (Table 1; Figure 2B).
`No statistically significant interaction was observed between the
`six predefined variables indicated in the Method section and fulves-
`trant activity (global interaction test P = .62), indicating that the over-
`all treatment effect Was consistent across the predefined covariables.
`
`Best Response to First Subsequent Therapy
`Information on first subsequent therapies Was available for 230
`(63.5%) and 239 (63.9%) patients treated with fulvestrant 500mg
`or 250mg, respectively Best response to subsequent therapy is
`detailed in Table 2. For those randomized patients Who had sub-
`sequent
`therapy, response to subsequent
`therapies Was similar
`between treatment groups: 8.3% vs 8.4% of patients had either
`complete response or partial response in the fulvestrant 5 00mg vs
`250mg groups, respectively; 24.8% and 32.2% ofpatients had sta-
`ble disease in the fulvestrant 500mg vs 250mg groups, respectively;
`and 33.5% and 28.5% of patients had progressive disease in the
`fulvestrant 5 00 mg vs 25 0 mg groups, respectively.
`
`Randomized
`n = 736
`
`Fulvestrant 500 mg
`n = 362
`
`h = 374
`
`Not ongoing study treatment at DCO
`i1 = 349
`Ongoing in survival follow—up,
`but not on treatment
`Lost to follow—up
`Dead at DCO
`Withdrawn consent
`
`45
`33
`261
`10
`
` Fulvestrant 250 mg
`
`Not ongoing study treatment at DCO
`n = 366
`Ongoing in survival follow—up,
`but not on treatment
`Lost to follow—up
`Dead at DCO
`Withdrawn consent
`
`7
`30
`293
`
`63
`
`Ongoing study
`treatment at DCO
`h = 13
`
`Ongoing study
`treatment at DCO
`n = 8
`
`Figure 1. CONSORT diagram. DCO = data cutoff.
`
`Table 1. Summary of overall survival*
`
`Information on overall survival
`No. died (%)
`Median time to death, mo
`Median time to death, d
`"ime to death, mo: 25% percentile
`"ime to death, mo: 75% percentile
`
`* NC = not calculable.
`
`jnci.oxfordjourna|s.org
`
`Initial analysis (50% survival analysis)
`Fulvestrant
`Fulvestrant
`500 mg (n = 362)
`250 mg (n = 374)
`175 (48.3)
`203 (54.3)
`25.1
`22.8
`764
`693
`12.2
`11.5
`NC
`41.7
`
`Update (75% survival analysis)
`Fulvestrant
`Fulvestrant
`250 mg (n = 374)
`500 mg (n = 362)
`293 (78.3)
`261 (72.1)
`26.4
`22.3
`805
`679
`11.7
`11.5
`51.1
`41.7
`
`JNCI
`
`| Article 3of7
`
`Astrazeneca Ex. 2005 p. 3
`
`

`
`
`
`— Fulvestrant 500 mg
`I Fulvestrant 250 mg
`
`Hazard ratio (95% CI)
`
`0.84 (O.69to1.03)
`
`P
`
`.09
`
`
`
`-9
`
`1
`
`1-0 _'
`
`
`
`o_a—
`
`0.6 —
`
`0.4 —
`
`0.2 —
`
`M
`2
`.9
`E
`‘:6o.
`"6
`
`8E
`
`oo.
`9n.
`
`0-0
`
`0
`
`I
`4
`
`I
`8
`
`I
`12
`
`I
`16
`
`I
`20
`
`I
`24
`
`I
`28
`
`362
`374
`
`330
`338
`
`285
`299
`
`251
`260
`
`223
`222
`
`165
`157
`
`116
`107
`
`74
`61
`
`Time (months)
`
`Patients at risk:
`500 mg
`250 mg
`
`B
`
`I
`32
`
`46
`34
`
`I
`36
`
`29
`18
`
`I
`40
`
`16
`10
`
`I
`44
`
`I
`48
`
`6
`2
`
`0
`0
`
`— Fulvestrant 500 mg
`—r Fulvestrant 250 mg
`
`Hazard ratio (95% CI)
`
`0.81 (0.69 to 0.96)
`
`P
`.02*
`
`
`
`
`0-6 —
`
`0.4 m
`
`0-2 —
`
`.2.
`
`
`
`-g
`9
`.5
`‘:6o.
`"6
`
`E.
`
`EE
`
`oo.
`90.
`
`0‘0IIIIIIIIIIIIIIIIIIII
`O
`4 8121620242832364044485256606468727680
`
`Patients at risk:
`500mg
`250mg
`
`362 333 288 254 227 202 178 163 141 123 114 98
`374 338 299 261223191164137112 96
`87
`74
`
`81
`64
`
`64
`48
`
`47
`37
`
`30
`22
`
`26
`14
`
`15
`8
`
`8
`3
`
`1
`2
`
`0
`0
`
`Time (months)
`
`Figure 2. Overall survival from date of randomization. A) Overall survival for when 50% of patients had died. B) Overall survival for when 75%
`of patients had died. Analysis by log-rank test. Pvalues are two-sided. *No adjustments for multiplicity were made.Tick marks indicate censored
`observations. CI = confidence interval. © 2010 American Society of Clinical Oncology. All rights reserved (9).
`
`Tolerability
`A summary of patients with an SAE during the entire treatment
`period (main trial plus folloW—up phase) is shown in Table 3‘.
`During the entire treatment period, a total of 35 (9.7%) and 27
`(7.2%) patients had at least one SAE in the fulvestrant 500mg
`and fulvestrant 250mg groups, respectively. SAEs that Were caus-
`ally related to study treatment Were reported for eight (2.2%)
`
`and four (1.1%) patients, and SAES with an outcome of death
`Were reported for five (1.4%) and seven (1.9%) patients in the
`fulvestrant 5 00 mg and fulvestrant 25 0mg groups, respectively,
`during the entire treatment period. Overall, there Were no clini-
`cally important differences in the profiles of SAES between the
`treatment groups, and no clustering of SA3s could be detected in
`either treatment group.
`
`40f7 Article
`
`|
`
`JNCI
`
`Vol. 106, |ssue1 | djt337 | January 1, 2014
`
`Astrazeneca Ex. 2005 p. 4
`
`

`
`Table 2. Best response to subsequent therapy*
`
`Fulvestrant 500mg (n = 362)
`
`Fulvestrant 250mg (n = 374)
`
`Available information on first subsequent therapy
`
`230
`
`Category of subsequent therapy, No.
`Radiotherapy
`Endocrine therapy
`Chemotherapy
`HER2 directed
`Unknown/other
`Fulvestrantt
`Best response to subsequent therapv, No. (%)
`Complete response
`Partial response
`Stable disease
`Progressive disease
`Not evaluable
`
`8
`80
`135
`0
`3
`4
`
`2 (0.9)
`17 (7.4)
`57 (24.8)
`77 (33.5)
`77 (33.5)
`
`239
`
`8
`74
`142
`1
`5
`9
`
`0
`20 (8.4)
`77 (32.2)
`68 (28.5)
`74 (31.0)
`
`Subsequent endocrine therapy included. anastrozole, exemestane, letrozole, medroxy progesterone, megestrol acetate, and tamoxifen. HER2 = human epidermal
`growth factor receptor 2.
`T Fulvestrant was either given at a dose of 250 mg or the dose was not specified.
`
`Table 3. Summary of patients experiencing SAEs during the treatment period*
`
`Available information on SAEs
`
`Patients with at least 1 SAE during the whole trial
`Any SAE
`Any SAE with outcome other than deatht
`Any causally related SAE
`SAEs occurring in >1 patient
`Acute myocardial Infarction
`Anemia
`Bronchitis
`Dyspnea
`Femur fracture
`Hyperglycemia
`Pneumonia
`Vomiting
`SAEs with outcome of death, preferred term
`Acute myocardial infarction
`Acute renal failure
`Aspiration
`Cardiopulmonary failure
`Suicide
`Death, cause unl<nown
`Dyspnea
`Hypertension
`lntestinal adenocarcinoma
`Meningitis
`
`* SAES : serious adverse events.
`
`Fulvestrant 500mg (n = 361)
`
`Fulvestrant 250mg (n = 374)
`
`No. of patients (%)
`
`35 9.7)
`32 8.9)
`8 2.2)
`
`O C)
`3 C.8)
`2 C.6)
`2 C6)
`1 C.3)
`2 CG)
`2 CG)
`2 0.6)
`
`O C)
`O C)
`0 0)
`1 C.3)
`0 C)
`1 C.3)
`2 C6)
`0 C)
`1 CS)
`0 C)
`
`27 (72)
`22 (5.9)
`1 (1.1)
`
`2 (0.5)
`(0.3)
`0(0)
`(0.3)
`2 (0.5)
`0(0)
`0(0)
`(0.3)
`
`2 (0.5)
`(0.3)
`(0.3)
`0(0)
`(0.3)
`0(0)
`0(0)
`(0.3)
`0(0)
`(0.3)
`
`T All patients experiencing an SAE with nonfatal outcome (regardless of whether they later had a fatal SAE).
`
`Discussion
`
`Preclinical and preliminary clinical data prompted the activation of
`the CONFIRM trial comparing fulvestrant 5 00mg With fulvestrant
`250mg in postmenopausal patients With ER—positive advanced
`breast cancer (1 ,5,6,10). The PFS analysis (primary study endpoint
`of the CONFIRM trial) demonstrated the superiority of 500mg
`over 2 50mg (9).At the time of the PFS analysis, a first OS analysis
`was also performed, and approximately 5 0% of events had been
`reported. The OS analysis suggested a numerical trend in favor
`of 500 mg over 250mg despite the lack of a statistically significant
`
`This observed numerical trend favoring fulvestrant
`difference
`500 mg led to a decision by the study Steering Committee to plan
`for a second OS analysis at 75% maturity.
`This article reports the results of the final 75% OS analysis and
`suggests that fulvestrant 500 mg is superior to fulvestrant 250mg,
`with a 19% relative reduction in the risk of death and a 4.1—month
`
`increase in median OS. However, a limitation of this study is that
`the 75% OS analysis is considered exploratory because it Was
`planned after the results of the PFS and 50% OS events analyses
`Were available; accordingly, no alpha was retained for this analysis
`
`jnci.oxfordjourna|s.org
`
`JNCI
`
`| Article 5of7
`
`Astrazeneca Ex. 2005 p. 5
`
`

`
`and no adjustment for multiplicity was possible. Nevertheless, the
`reported results are consistent with the previously reported PFS
`and 50% OS events results
`In the attempt to rule out the hypothesis that the observed dif-
`ference in OS in favor of fulvestrant 5 00 mg was mainly the con-
`sequence of an imbalance in subsequent therapies delivered after
`progression on the study drug, an investigation of first subse-
`quent therapies after progression on fulvestrant was carried out.
`Information on first subsequent therapies was available for approx-
`imately two—thirds (64%) of the study population, with 15 3 and 165
`patients treated with fulvestrant 5 00 mg and 250mg, respectively,
`evaluable for best response. The findings show that there was no
`imbalance in type of first subsequent therapies given after progres-
`sion on fulvestrant. Last but not least, the analysis shows that the
`objective response rate and stable disease rate for first subsequent
`therapies are very similar between the two treatment groups. In
`summary, the analysis on first subsequent therapies suggests that
`the observed improvement in OS in favor of the 500mg dose was
`not due to an imbalance in subsequent treatments delivered after
`progression on fulvestrant.
`An additional investigation carried out in this study focused on
`the cross—over rate for patients initially treated with 2 50mg. The
`study design did not initially allow for a cross—over after progres-
`sion on fulvestrant 250mg. However, when the PFS results were
`available, the study protocol was amended, and patients on treat-
`ment with 2 50mg were offered the option to cross over to 500mg.
`Most patients had already progressed on fulvestrant by the time
`the PFS results were available and the study protocol had been
`amended. Accordingly, fulvestrant dose was unblinded after pro-
`gression to the study drug for only 34- of the 736 patients. Twenty-
`four patients were eligible for crossover (per protocol amendment),
`but the actual cross—over rate was low, with only eight of 374-
`patients (2.1%) receiving fulvestrant 500mg after prior treatment
`with 25 0 mg. Considering that there is no clinical evidence on the
`activity of fulvestrant 5 00mg in patients pretreated with 250mg,
`it seems unlikely that the suggested OS benefit of 500mg over
`250mg is due to the low cross—over rate in this trial.
`V1/"rth regard to the safety profile, the reported results do not sup-
`port any clinically relevant difference either in the rate or causality
`of related SAEs between the two treatment groups. Furthermore,
`the nurnber of SASS with an outcome of death was very similar
`between the two groups (five events for the 500 mg group vs seven
`events for the 250mg group). In addition, the 5 00—mg safety profile
`reported in this article is comparable with the safety profile of the
`same dose observed at the time of the PFS analysis.
`The results of this study raise a number of questions that need to
`be addressed in future trials. Is fulvestrant given at the 5 00mg dose
`a better option than aromatase inhibitors as a first—line therapy for
`postmenopausal patients with ER—positive advanced breast cancer?
`Results from a phase II randomized trial appear to suggest that this
`might be the case (11,12). A phase III trial (the FALCON trial) is
`currently ongoing (ClinicalTrials.gov identifier: NCT01602380)
`in an attempt to address this question.
`A trial recently reported by the Southwest Oncology Group
`(SWOG) has suggested that a poly—endocrine therapy approach,
`consisting of the combination of fulvestrant 250mg with an aro-
`matase inhibitor, is superior to single—agent treatment with the
`
`same aromatase inhibitor (13). No clinical data on the compari-
`son between the poly—endocrine therapy and fulvestrant 5 00mg
`are available. Ideally, it would be important to have markers driv-
`ing our treatment decisions when a first—line endocrine therapy
`approach has to be started. Unfortunately, no markers are cur-
`rently available to support our treatment strategies. Interestingly,
`a subgroup analysis run in the context of the SWOG trial seems
`to suggest that most of the benefit from poly—endocrine therapy is
`observed in patients with no prior exposure to endocrine therapy,
`either in the adjuvant or in the advanced setting (13). This sub-
`group analysis might explain the contradictory results reported
`in another poly—endocrine therapy trial
`(the Fulvestrant and
`Anastrozole Combination Therapy [FACT] trial) whose design
`completely overlaps with the SWOG trial but where a signifi-
`cantly higher proportion of patients were previously exposed to
`endocrine therapies (14,15).
`Last but not least, our results provide a rationale that if fulves-
`trant is to be combined with other nonendocrine agents targeting
`molecular pathways involved in the induction of primary or secondary
`endocrine resistance, then the dose should be 5 00mg. Results of the
`Breast Cancer Trials of Oral Everolimus 2 (BOLERO—2) show that
`the combination of an endocrine treatment with a compound target-
`ing the PI3K pathway can improve the antitumor activity of single—
`agent endocrine therapy (16). Fulvestrant might be an ideal partner
`for future combination studies considering that its unique mechanism
`of action leads to ER downregulation, thus preventing not only the
`ER—mediated transcription of several genes but also the cross—tall<s
`between cytoplasmic ER and several downstream effectors ofmolecu-
`lar pathways involved in resistance to endocrine therapies (17,18).
`In surnmary, based on the final results of the CONFIRM trial,
`which suggest an OS benefit for fulvestrant 500mg over 250mg,
`and taking into account that the previously reported PFS results
`were statistically significantly in favor of fulvestrant 500mg, we
`believe that whenever treatment with fulvestrant should be initi-
`
`ated, this should be at the dose of 500 mg, according to the sarne
`schedule of this trial.
`
`References
`
`1. Howell A, Robertson]FR, Quaresma Albano J, et al. Fulvestrant, formerly
`ICI 182,780, is as effective as anastrozole in postrnenopausal women with
`advanced breast cancer progressing after prior endocrine treatInent.]7 Clin
`Oncol. 2002;20(16):3396—3403.
`2. Cano A, Matallin P, Legua V, Tortajada M, Bonilla-Musoles F. Tamoxifen
`and the uterus and endometrium. Lomcet. 1989,1(8634-):376
`3. Ewer MS, Gliick S. A woman’s heart: the impact of adjuvant endocrine
`therapy on cardiovascular health. Cflflffl”. 2009; 1 15 (9): 1813-1826.
`4. Santen R]. Clinical review: effect of endocrine therapies on bone in breast
`cancer patients] Clin Endocrinol Metab. Z011,96(2):308—319.
`5. Osborne CK, Pippen J, Jones SE, et al. Double-blind, randomized trial
`comparing the efficacy and tolerability of fulvestrant versus anastrozole
`in postrnenopausal women with advanced breast cancer progressing on
`prior endocrine therapy: results of a North American trial. 7 Clin Omal.
`2002,-20(16);3386—3395.
`6. DeFriend D], Howell A, Nicholson RI, et al. Investigation of a new pure
`antiestrogen (ICI 182780) in women with primary breast cancer. Cancer
`Res. 1994,54(2):408—414.
`7. Robertson]F, Nicholson RI, Bundred N], et al. Comparison of the short-
`term biological effects of 7alpha—[9—(4,4,5,5,5—pentafluoropentylsulfinyl)—
`nonyl]estra-1,3,3, (10)-triene-3,17beta-diol (Faslodex) versus tamoxifen
`in postmenopausal women with primary breast cancer. Canter Rex.
`2001;61(18):6739—6746.
`
`60f7 Article
`
`|
`
`JNCI
`
`Vol. 106, Issue 1
`
`| djt337 | January 1, 2014
`
`Astrazeneca Ex. 2005 p. 6
`
`

`
`8. Addo S, Yates RA, Laight A. A phase I trial to assess the pharmacology of
`the new oestrogen receptor antagonist fulvestrant on the endometrium in
`healthy postmenopausal volunteers. Br} Cancer. 2002,87(12):l3 54-13 59.
`9. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM
`phase TH trial comparing fulvestrant 250 mg with fulvestrant 500 mg in
`postmenopausal women with estrogen receptor—positive advanced breast
`cancer.] (71257 OMLVIZ. 20l0,28(30):4-594-4600.
`10. Robertson Osborne CK, Howell A, et al. Fulvestrant versus anastro-
`zole for the treaurient of advanced breast carcinoma in postmenopausal
`women: a prospective combined analysis of two multicenter trials. Cmieer.
`2003,98(2):229—238.
`11. Robertson
`Llombart-Cussac A, Rolski J, et al. Activity of ful-
`vestrant 500 mg versus anastrozole 1mg as first—line treatment for
`advanced breast cancer: results from the FIRST study. }’ Clm Omol.
`2009,27(27);4530_4535.
`12. Robertson 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 C/meer
`Rex Treat. Z01Z,l36(Z):503—511.
`13. Mehta RS, Barlow VVE, Albain KS, et al. Combination anastrozole and
`fulvestrant in metastatic breast cancer. NEngZj’ Zvled. 2012;367(5):43 5-444-.
`14. Bergh J,J6nsson PE, Lidbrink EK, et al. FACT: an open-label randomized
`Phase HT study of fulvestrant and anastrozole in combination compared
`with anastrozole alone as first-line therapy for patients with receptor-pos-
`itive postmenopausal breast cancer.] Clm Oneal. Z012;30(16):1919—1925.
`15. Di Leo A, Malorni L. Polyendocrine treatinent in estrogen receptor-positive
`breastcancer: a“FACT”yet to be proven._7 Clin Omal. Z012;30(16):l897-1900.
`16. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopau-
`sal hormone—receptor—positive advanced breast cancer. N Engl ] Med.
`2012,366(6):520—529.
`17. Massarweh S, Schiff R. Unraveling the mechanisms of endocrine resist-
`ance in breast cancer: new therapeutic opportunities. Clin Cmzeer Res.
`2007;13(7);1950—1954.
`18. Robertson JFR. Fulvestrant (FaslodeX)—how to make a good drug better.
`Oncologist. 2007,l2(7):774—784.
`
`Funding
`This study was designed and funded by Astrazeneca Pharmaceuticals,
`Macclesfield, UK, which was involved in the reviewing and interpreta-
`tion of data, the writing of the manuscript, and the decision to submit for
`publication.
`
`Notes
`
`A. Di Leo, S. Garnett, and M. Martin were responsible for conception and design
`of the study. A. Di Leo, G.Jerusalem, L. Petruzelka, R. Torres, 1. N. Bondarenko,
`R. Khasanov, D. Verhoeven, J. L. Pedrini, I. Smirnova, M. R. Lichinitser,
`K. Pendergrass, and M. Martin were responsible for provision of study mate-
`rials or patients. S. Garnett and Y. Rukazenkov were responsible for collec-
`tion and assembly of data. A. Di Leo, G. Jerusalem, L. Petruzelka, R. Torres,
`1. N. Bondarenko, R. Khasanov, D. Verhoeven, J. L. Pedrini, I. Smirnova,
`M. R. Lichinitser, K. Pendergrass, L. Malorni, S. Garnett, Y. Rukazenkov, and
`M. Martin were responsible for data analysis and interpretation, manuscript
`writing, and final approval of the manuscript.
`S. Garnett and Y. Rukazenkov are employed or have leadership posi-
`tions at AstraZeneca and have stock ownership in AstraZeneca. A. Di
`Leo has a consultant or advisory role at and has received honoraria and
`research funding from AstraZeneca, Pfizer, and Novartis. M. Martin has
`a consultant or advisory role and has receive honoraria from AstraZeneca.
`T. Smirnova and M. R. Lichinitser have a consultant or advisory role at
`AstraZeneca. G. Jerusalem has received honoraria and research funding
`from AstraZeneca.
`Medical writing assistance was provided by DrVarinia Munoz from Complete
`Medical Communications Ltd, funded by AstraZeneca.
`Data were presented previously at the 35th Annual San Antonio Breast Cancer
`Symposium, San Antonio, Texas, December 4-8, 2012.
`
`"Sandra Pitigliani" Medical Oncology Unit,
`Affiliations of authors:
`ltaly (ADL, LM); Medical Oncology, Centre
`iospital of Prato, Prato,
`iospitalier Universitaire Sart Tilman and Liege University, Liege, Belgium
`(GJ); Department of Oncology, First Faculty of Medicine of Charles
`Jniversity, Prague, Czech Republic (LP); Clinical Oncology,
`lnstituto
`acional del Cancer, Santiago, Chile (RT); Dnipropetrovsk Municipal Clinical
`-lospital, Dnipropetrovsk, Ukraine (INB); Republican Clinical Oncological
`Center, Kazan, Russia (RK); AZ Klina, Brasschaat, Belgium (DV); Mastology,
`-lospital Nossa Senhora da Conceigao, Porto Alegre, Brazil (.JLPl; Thoracal
`Department, Medical Radi