DOI:10.1093/jnci/djt337
`Advance Access publication December 7, 2013
`
`l
`
`©The Author 2013. Published by Oxford University Press.
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`
`Final Overall Survival: Fulvestrant 500 mg vs 250mg in the
`
`Randomized CONFIRMTriaI
`
`Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka, Roberto Torres, Igor N. Bondarenko, Rustem Khasanov, DidierVerhoeven,
`Jose 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 (08) 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 two-sided.
`
`Results
`
`In total, 736 women (median age = 61.0 years) were randomly assigned to fulvestrant 500 mg (n = 362) or 250 mg
`(n = 374). At the final survival analysis, 554 of 736 (75.3%) patients had died. Median OS was 26.4 months for
`fulvestrant 500mg 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 500 mg is
`associated with a 19% reduction in risk of death and a 41-month difference in median 08 compared with fulves-
`trant 250 mg. 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 of ER, progesterone
`receptor, and the cell proliferation—related antigen Ki67 (6,7) for
`fulvestrant doses up to 250mg. 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 Nletastatic
`Breast Cancer (CONFIRNI) trial compared the then—approved dose
`and dosing schedule of fulvestrant (250mg every 28 days) with a
`higher—dose regimen (5 00 mg every 28 days plus an additional
`5 00mg on day 14- of the first month only) in postmenopausal women
`
`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 500mg 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 (9). 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 50% of patients had died. After
`the reporting of the 5 0% survival data, which showed a trend in
`favor of 5 00mg 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.
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`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 (9). 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: NCT0009943 7; http://
`www.clinicaltrials.gov/ct2/show/NCTO’0099437). 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 (i 3) days thereafter (9.).
`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
`prefille’d syringe was identical to the active prefilled syringe and
`also had a volume of 5mL.
`
`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 fmal 75% OS analysis (October 31, 2011).
`
`Best Response to First Subsequent Therapy
`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 (9). At the time
`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
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`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 5 00mg.
`
`Survival Analysis
`At the initial data cutoff, 378 of 736 patients (51.4%) had died
`(n = 175 [48.3%] in the fulvestrant 500mg group; n = 203 [54.3%]
`in the fulvestrant 25 0mg 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 250mg group (25.1 months vs
`22.8 months, respectively; hazard ratio (HR) = 0.84, 95% confi—
`dence interval (CI) = 0.69 to 1.03, P = .09 for the unadjusted analy—
`sis; HR = 0.81, 95% CI = 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 250mg. The median time to death for
`
`patients in the fulvestrant 500mg group vs the fulvestrant 25 0mg
`group was 26.4 months vs 22.3 months, respectively (HR = 0.81,
`95% CI = 0.69 to 0.96, nominal P = .02 for the unadjusted analy—
`sis; HR = 0.79, 95% CI = 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 00 mg vs
`250mg groups, respectively; 24.8% and 32.2% ofpatients had sta—
`ble disease in the fulvestrant 5 00 mg vs 25 0mg groups, respectively;
`and 33.5% and 28.5% of patients had progressive disease in the
`fulvestrant 5 00 mg vs 2 50mg groups, respectively.
`
`Randomized
`n = 736
`
`Fulvestrant 500 mg
`n = 362
`
`n = 374
`
`Not ongoing study treatment at DCO
`n = 349
`Ongoing in survival follow—up,
`but not on treatment
`Lost to follow—u p
`Dead at DCO
`Withdrawn consent
`
`45
`33
`261
`10
`
`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
`
`87
`30
`293
`6
`
` Fulvestrant 250 mg
`
`Ongoing study
`treatment at DCO
`n = 13
`
`Ongoing study
`treatment at DCO
`n = 8
`
`Figure 1. CONSORT diagram. DCO = data cutoff.
`
`
`Table 1. Summary of overall survival*
`Initial analysis (50% survival analysis) Update (75% survival analysis)
`
`Fulvestrant
`Fulvestrant
`Fulvestrant
`Fulvestrant
`
`500 mg (n = 362)
`Information on overall survival
`250 mg (n = 374)
`250 mg (n = 374)
`500 mg (n = 362)
`
`293 (78.3)
`261 (72.1)
`203 (54.3)
`175 (48.3)
`No. died (%)
`22.3
`26.4
`22.8
`25.1
`Median time to death, mo
`679
`805
`693
`764
`Mediantime to death, 01
`"ime to death, mo: 25% percentile
`12.2
`11.5
`11.7
`11.5
`
`"Ime to death, mo: 75% percentile
`NC
`41.7
`51.1
`41.7
`
`* NC = not calculable.
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`
`
`— Fulvestrant 500 mg
`— Fulvestrant 250 mg
`
`
`
`Hazard ratio (95% CI)
`0.84 (0.69 to 1.03)
`
`P
`.09
`
`
`”IfV
`
`
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`I
`4
`8
`12
`16
`2O
`24
`28
`32
`36
`40
`44
`48
`
`O
`
`362
`374
`
`330
`338
`
`285
`299
`
`251
`260
`
`223
`222
`
`165
`157
`
`116
`107
`
`74
`61
`
`46
`34
`
`29
`18
`
`16
`10
`
`6
`2
`
`0
`0
`
`Time (months)
`
`0-0
`
`Patients at risk:
`500 mg
`250 mg
`
`B
`
`m
`g
`<6
`.9
`.5
`13'o.
`“5
`
`8
`E
`oo.
`90.
`
`
`
`1
`1:,
`
`— Fulvestrant 500 mg
`7 Fulvestrant 250 mg
`
`
`Hazard ratio (95% CI)
`0.81 (0.69 to 0.96)
`
`P
`.02*
`
`0-6 —
`
`0 4
`. _
`
`02 —
`
`
`
`
`
`
`|
`O'OIIIIIIIIIIIIIIIIIII
`048
`12 16 2O 24 28 32
`36
`40 44 48 52 56 6O 64 68
`72
`76 80
`
`
`
`Time (months)
`
`1
`2
`
`O
`0
`
`83
`
`81
`64
`
`64
`48
`
`47
`37
`
`30
`22
`
`26,
`14
`
`15
`8
`
`362 333 288 254 227 202 178 163 141
`374 338 299 261 223 191 164 137 112
`
`123 114
`96
`87
`
`98
`74
`
`Patients at risk:
`500 mg
`250 mg
`
`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 2 50mg 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 500mg and fulvestrant 250mg groups, respectively,
`during the entire treatment period. Overall, there Were no clini—
`cally iInportant differences in the profiles of SAES between the
`treatment groups, and no clustering of SAEs could be detected in
`either treatment group.
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`1'0 “
`
`
`
`
`0.8 _
`
`0.6 —
`
`0 4
`' _
`
`0.2 —
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`

`

`Table 2. Best response to subsequent therapy*
`
`Fulvestrant 250 mg (n = 374)
`Fulvestrant 500mg (n = 362)
`
`Available information on first subsequent therapy
`230
`239
`
`Category of subsequent therapy, No.
`Radiotherapy
`Endocrine therapy
`Chemotherapy
`HER2 directed
`Unknown/other
`Fulvestrantt
`Best response to subsequent therapy, No. (%)
`0
`2 (0.9)
`Complete response
`20 (8.4)
`17 (7—-)
`Partial response
`
`77 (32.2)
`57 (2—-.8)
`Stable disease
`68 (28.5)
`77 (33.5)
`Progressive disease
`
`Not evaluable 74 (31.0) 77 (33.5)
`
`
`8
`74
`142
`1
`5
`9
`
`8
`80
`135
`0
`3
`4
`
`* Subsequent endocrine therapy included: anastrozole, exemestane, letrozole, medroxy progesterone, megestrol acetate, and tamoxifen. HERZ = human epidermal
`growth factor receptor 2.
`T Fulvestrant was either given at a dose of 250mg or the dose was not specified.
`
`Table 3. Summary of patients experiencing SAEs during the treatment period*
`No. of patients (%)
`Available information on SAEs Fulvestrant 250 mg (n = 374) Fulvestrant 500mg (n = 361)
`
`
`
`
`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
`Vomit ng
`SAEs with outcome of death, preferred term
`2 0.5
`0 O)
`Acute myocardial infarction
`Acute renal failure
`1 0.3
`0 O)
`1 0.3
`0 O)
`Aspiration
`0 O)
`1 0.3)
`Cardiopulmonary failure
`Suicide
`1 0.3
`0 O)
`0 O)
`1 0.3)
`Death, cause unknown
`0 O)
`2 0.6)
`Dyspnea
`1 0.3
`0 O)
`Hypertension
`Intestinal adenocarcinoma
`0(0)
`1 (0.3)
`
`0 O)
`1 0.3
`Meningitis
`
`35 9.7)
`32 8.9)
`8 2.2)
`
`0 O)
`3 0.8)
`2 0.6)
`2 0.6)
`1 0.3)
`2 0.6)
`2 0.6)
`2 0.6)
`
`
`
`27 72)
`22 5.9
`4 1.1)
`
`2 0.5
`1 0.3
`0 O)
`1 0.3
`2 0.5
`0 O)
`0 O)
`1 0.3
`
`
`
`
`
`* SAEs = serious adverse events.
`
`T All patents experiencing an SAE with nonfatal outc0‘ne (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 00 mg with fulvestrant
`25 0mg in postmenopausal patients with ER—positive advanced
`breast cancer (156,10). 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 50% of events had been
`reported. The OS analysis suggested a numerical trend in favor
`of 500mg over 250mg despite the lack of a statistically significant
`
`difference (9). This observed numerical trend favoring fulvestrant
`500mg 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 41—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
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`and no adjustment for multiplicity was possible. Nevertheless, the
`reported results are consistent with the previously reported PFS
`and 50% OS events results (9).
`In the attempt to rule out the hypothesis that the observed dif—
`ference in OS in favor of fulvestrant 500 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 00mg 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 obseived improvement in OS in favor of the 5 00mg 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 250mg. 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 5 00 mg.
`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 (21%) receiving fulvestrant 500 mg after prior treatment
`with 250mg. 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.
`VVith 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 number of SAEs with an outcome of death was very similar
`between the two groups (five events for the 500mg group vs seven
`events for the 2 5 0mg group). In addition, the 5 OO—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 500 mg 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 (ClinicalTrialsgov 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 500mg
`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 ofprimary or secondary
`endocrine resistance, then the dose should be 500mg. 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—talks
`between cytoplasmic ER and several downstream effectors of molecu—
`lar pathways involved in resistance to endocrine therapies (17,18).
`In summary, 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 5 00mg, we
`believe that whenever treatment with fulvestrant should be initi—
`
`ated, this should be at the dose of 500 mg, according to the same
`schedule of this trial.
`
`References
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`60f7 Article
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`|
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`JNCI
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`Vol. 106, Issue 1
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`|djt337 | January 1, 2014
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`AstraZeneca Exhibit 2005 p. 6
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`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 N1. 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, 1. 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,
`1V1. R. Lichinitser, K. Pendergrass, L. Malorni, S. Garnett1 Y. Rukazenkov, and
`M. Martin were responsible for data analysis and inteipretation, manuscript
`writing, and final approval of the manuscript.
`S. Garnett and Y. Rultazenkov 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.
`I. Smirnova and M. R. Lichinitser have a consultant or advisory role at
`AstraZeneca. G. Jerusalem has received honoraria and research funding
`from AstraZeneca.
`
`NIedical writing assistance was provided by DrVarinia Munoz from Complete
`Niedical 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:
`Italy (ADL, LM); Medical Oncology, Centre
`-lospita| of Prato, Prato,
`-lospita|ier 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,
`Instituto
`acional del Céncer, Santiago, Chile (RT); Dnipropetrovsk Municipal Clinical
`-lospita|, Dnipropetrovsk, Ukraine (INB); Republican