DOK10.1093/jnci/djt337
`Advance Access publication December 7, 2013
`
`©The Author 2013. Published by Oxford University Press.
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`Final Overall Survival: Fulvestrant 500mg vs 250mg in the
`Randomized CONFIRM Trial
`
`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.
`
`Correspondenceto: Angelo Di Leo, MD, PhD, “Sandro Pitigliani” Medical Oncology Unit, Hospital of Prato, Piazza dell Ospedale 2, 59100 Prato,Italy (e-mail:
`adileo@us|4. toscana.it).
`
`Background
`
`Methods
`
`Atthe timeof the initial analysis of overall survival (OS) for the Comparison of Faslodex in Recurrent or Metastatic
`Breast Cancer (CONFIRM) randomized, double-blind, phaseIll 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 250mg
`(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% confidenceinterval = 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 IIT studies, which demonstrated similar efficacy
`and an acceptable safety profile for fulvestrant 250mg compared
`with anastrozole (1,5), fulvestrant 250mg was approvedas 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-dependentreduction in thelevels of ER, progesterone
`receptor, and the cell proliteration—-related antigen Ki67 (6,7) for
`fulvestrant doses up to 250mg. Other phase I and phase ITT stud-
`ies also suggested a dose-responseeffect for fulvestrant (1,5,8).
`‘The phase II] Comparison ofFaslodex in Recurrent or Metastatic
`Breast Cancer (CONFIRM)trial compared the then-approved dose
`and dosing schedule of fulvestrant (250mg every 28 days) with a
`higher-dose regimen (00mg every 28 days plus an additional
`500mgon day 14 of thefirst 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 offulves-
`trant is now the approved dose in the European Union (approved in
`March 2010), United States (approved in September 2010), Japan
`(approved in November 2011), and other countries worldwide.
`In the CONFIRM study, the assessment of the therapeutic effi-
`cacy of both dosesof 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 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.
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`Methods
`
`Study Design and Patients
`‘The CONFIRM study design, including eligibility criteria, exclu-
`sion criteria, and the calculation of samplesize, has been described
`in detail elsewhere (9). Briefly, CONFIRM was a randomized,
`phase HI, double-blind trial that evaluated two different doses
`of fulvestrant (SOOmg vs 250mg) in postmenopausal patients
`whohadeither locally advanced or metastatic ER-positive breast
`eancer
`(ClinicalTrials.gov identifier: NCT00099437; http://
`www.clinicaltrials.gov/ct2/show/NCT00099437). The primary
`study endpoint was PHS (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
`oflife (9).
`After initial analysis, all patients, regardless of whether they
`werestill 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 theirfirst 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 approvedby 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
`randomlyassigned 1:1 to either fulvestrant 500mg administered as
`two 5-mL intramuscular injections on days 0, 14, and 28 and every
`28 (+ 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 (+ 3) days thereafter (9).
`Fulvestrant was supplied in the form ofa single dose in a pre-
`filled syringe. Each active prefilled syringe contained 250mg of
`fulvestrant at a concentration of 50mg/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 numberof days from randomization to death
`from any cause. Patients who diedafter 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 bealive
`
`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% OSanalysis (October 31, 2011).
`
`Best Responseto 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 thosepatientsstill receiving
`randomized treatment.
`
`Statistical Analysis
`OSwasfirst 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 forsix predefined covariables (age at
`baseline, response to last endocrine therapy received before fulves-
`trant, receptor status at diagnosis, visceral involvementat 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 treatinentactually 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.
`For34 ofthe 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
`(n = 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 500mg 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 250mg
`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).
`Nostatistically significant interaction was observed between the
`six predefined variables indicated in the Method section and fulves-
`trantactivity (global interaction test P = .62), indicating that the over-
`all treatment effect was consistent across the predefined covariables.
`
`Best Responseto 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 500mg vs
`250mg groups, respectively; 24.8% and 32.2% of patients 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 500mg vs 250mg groups, respectively.
`
`Randomized
`n=736
`
` Fulvestrant 500 mg
`
`Fulvestrant 250 mg
`
`n= 362
`
`n=374 Not ongoing study treatment at DCO
`
`Not ongoing study treatment at DCO
`n=349
`Ongoing in survival follow-up,
`but not on treatment
`Lost to follow-up
`Dead at DCO
`Withdrawn consent
`
`n = 366
`Ongoing in survival follow-up,
`but not on treatment
`Lost to follow-up
`Dead at DCO
`Withdrawn consent
`
`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
`Information on overall survival 250 mg (n = 374) 500mg (n = 362) 500 mg (n = 362) 250 mg (n = 374)
`
`
`
`No. died (%)
`175 (48.3)
`203 (54.3)
`261 (72,1)
`293 (78,3)
`Median time to death, mo
`25.1
`22.8
`26.4
`92.8
`Median time to death, d
`764
`693
`805
`679
`Time to death, mo: 25% percentile
`WZ2
`WS
`Tad
`11.5
`
`Time to death, mo: 75% percentile
`NC
`A
`51.1
`41.7
`
`* NC = not calculable.
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`
`
`
`
`
`
`
`— Fulvestrant 500 mg
`— Fulvestrant 250 mg
`
`
`Hazard ratio (95% Cl)
`0.81 (0.69 to 0.96)
`P
`.02*
`
`7
`
`,
`
`06-
`
`0-4 =
`
`0-2 =
`
`1.0 Fe,
`
`
`
`0.8 4
`
`— Fulvestrant 500 mg
`— Fulvestrant 250 mg
`
`
`
`Hazard ratio (95% Cl)
`0.84 (0.69 to 1.03)
`
`.09
`
`o =
`
`a 2 S
`
`6=
`
`3a
`2o
`
`&S 06-
`oa.
`Oo
`
`0.4 -
`
`0.2
`
`0.0
`
`Patients at risk:
`500 mg
`250 mg
`
`0
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`28
`
`32
`
`36
`
`40
`
`44
`
`48
`
`Time (months)
`
`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
`
`a
`=
`
`6 £ &
`
`@a
`Oo
`6
`FS
`3a
`9o
`
`B
`
`9:0 roto Toto
`O
`4
`8
`12 16 20 24 28 32
`36
`40 44 48 52 56 60 64 68
`72
`76 80
`
`Patients at risk:
`500 mg
`250 mg
`
`362 333 288 254 227 202 178 163 141
`374 338 299 261 223 191 164 137 112
`
`123 114
`96
`87
`
`98
`74
`
`81
`64
`
`64
`48
`
`47
`37
`
`30
`22
`
`26
`14
`
`15
`8
`
`8
`3
`
`1
`2
`
`O
`O
`
`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. P values are two-sided. *No adjustments for multiplicity were made. Tick marks indicate censored
`observations. Cl = 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 500mg and fulvestrant 250mg 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 SAEs could be detected in
`either treatment group.
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`Table 2. Best response to subsequent therapy*
`
`
`Available information onfirst subsequent therapy
`230
`239
`
`Fulvestrant 500mg (n = 362)
`
`Fulvestrant 250mg (n = 374)
`
`Category of subsequent therapy, No.
`Radiotherapy
`Endocrine therapy
`Chemotherapy
`HER2 directed
`Unknown/other
`Fulvestrantt
`Best response to subsequenttherapy, No. (%)
`0
`2 (0.9)
`Complete response
`20 (8.4)
`17 (74)
`Partial response
`
`FF B22)
`57 (24.8)
`Stable disease
`68 (28.5)
`Ti (3.5)
`Progressive disease
`
`Not evaluable 74 (31.0) 77 (33.5)
`
`
`8
`74
`142
`1
`5
`¢
`
`8
`80
`135
`0
`3
`4
`
`Subsequent endocrine therapy included: anastrozole, exemestane, letrozole, medroxy progesterone, megestrol acetate, and tamoxifen. HER2 = human epidermal
`growth factor receptor2.
`Tt 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 500 mg (n = 361) Fulvestrant 250mg (n = 374)
`
`
`
`
`
`
`
`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
`Cardiopulmonaryfailure
`Suicide
`Death, cause unknown
`Dyspnea
`Hypertension
`Intestinal adenocarcinoma
`Meningitis
`
`35 (9.7)
`32 (8.9)
`8 (2.2)
`
`0 (0)
`3 (0.8)
`2 (0.6)
`2 (0.6)
`1
`(0.3)
`2 (0.6)
`2 (0.6)
`2 (0.6)
`
`0 (0)
`0 (0)
`0 (0)
`1
`(0.3)
`O (0)
`1
`(0,3)
`2 (0.6)
`O (0)
`1 (0.3)
`0 (0)
`
`27 (72)
`22 Ie.2
`2 (1.1)
`
`2 (0/5
`1
`(0.3
`@(Q)
`1 8
`2 (0.5
`G (0)
`G (0)
`1
`(0.3
`
`2 (0,5
`103
`1
`(0.3
`G (0)
`1
`(0.3
`Q (0)
`G (0)
`1
`(0.3
`G (0)
`1
`(Gis
`
`* SAEs = serious adverse events.
`
`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 CONFIRMtrial comparing fulvestrant 500 mg 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 250mg (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 ofa statistically significant
`
`difference (9). This observed numerical trend favoring fulvestrant
`500mgled 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% OSanalysis and
`suggests that fulvestrant 500mg 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
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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 500mg 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 wasavailable for approx-
`imately two-thirds (64%) of the study population, with 153 and 165
`patients treated with fulvestrant 500mg and 250mg, respectively,
`evaluable for best response. The findings show that there was no
`imbalancein type offirst 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 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 250mg 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 wereeligible for crossover (per protocol amendment),
`but the actual cross-over rate was low, with only eight of 374
`patients (2.1%) receiving fulvestrant 500mg aiter prior treatment
`with 250mg. Considering that there is no clinical evidence on the
`activity of fulvestrant 500mg in patients pretreated with 250mg,
`it seems unlikely that the suggested OS benefit of 500mg over
`250mgis due to the low cross-over rate in thistrial.
`Withregard to the safety profile, the reported results do not sup-
`port anyclinically relevant difference either in the rate or causality
`of related SAEs between the two treatment groups. Furthermore,
`the number of SAFs with an outcome of death was very similar
`between the two groups(five events for the 500mg group vs seven
`events for the 250mg group). In addition, the 500-mgsafety profile
`reported in this article is comparable with the safety profile of the
`same dose observed at the time of the PFS analysis.
`Theresults of this study raise a numberof questions that need to
`be addressedin futuretrials. Is fulvestrant given at the 500mg dose
`a better option than aromatase inhibitorsas a first-line therapy for
`postmenopausal patients with ER-positive advanced breast cancer?
`Results from a phase II randomized trial appearto suggest that this
`might be the case (11,12). A phase II trial (the FALCONtrial) 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 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 treatmentstrategies. Interestingly,
`a subgroup analysis run in the context of the SWOGtrial 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 SWOGtrial 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 compoundtarget-
`ing the PI3K pathway can improve the antitumoractivity 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 transeription of several genes but also the cross-talks
`between cytoplasmic ER and several downstream effectors ofmolecu-
`lar pathways involvedin 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 500mg, we
`believe that whenever treatment with fulvestrant should be initi-
`ated, this should be at the dose of 500mg, according to the same
`schedule of this trial.
`
`References
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`6o0f7 Article
`
`|
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`JNCI
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`Vol. 106, Issue 1
`
`| djt337 | January 1, 2014
`
`AstraZeneca Exhibit 2005 p. 6
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`

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`Funding
`This study was designed and funded by AstraZeneca Pharmaceuticals,
`Macclestield, 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, I. 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-
`tials or patients. $. Garnett and Y. Rukazenkov were responsible for collec-
`tion and assembly of data. A. Di Leo, G. Jerusalem, L. Petruzelka, R. Torres,
`I. 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 ot 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.
`
`Medical writing assistance was provided by Dr Varinia Munoz from Complete
`Medical Communications Ltd, funded by AstraZeneca.
`Data were presented previously at the 35th Annual San Antonio Breast Cancer
`Symposium, San Antonio, ‘lexas, December 4-8, 2012.
`
`
`
`“Sandra Pitigliani” Medical Oncology Unit,
`Affiliations of authors:
`Italy (ADL, LM); Medical Oncology, Centre
`Hospital of Prato, Prato,
`Hospitalier Universitaire Sart Tilman and Liége University, Liége, Belgium
`(GJ); Department of Oncology, First Faculty of Medicine of Charles
`University, Prague, Czech Republic (LP); Clinical Oncology,
`Instituto
`acional del Cancer, Santiago, Chile (RT); Dnipropetrovsk Municipal Clinical
`Hospital, Dnipropetrovsk, Ukraine (INB); Republican Clinical Oncological
`Center, Kazan, Russia (RK); AZ Klina, Brasschaat, Belgium (DV); Mastology,
`Hospital Nossa Senhora da Conceicdo, Porto Alegre, Brazil (JL