VOLUME 28 -
`
`NUMBER 30 - OCTOBER 20 2010
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`NAL REPORT
`
`Results of the CONFIRM Phase III Trial Comparing
`Fulvestrant 250 mg With Fulvestrant 500 mgin
`Postmenopausal Women With Estrogen Receptor—Positive
`Advanced Breast Cancer
`
`Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka, Roberto ‘Torres, Igor N. Bondarenko, Rustem Khasanov,
`Didier Verhoeven, José L. Pedrini, Iya Smirnova, Mikhail R. Lichinitser, Kelly Pendergrass, Sally Garnett,
`Justin P.O, Lindemann, Francisco Sapunar, and Miguel Martin
`
`See accompanying editorial 4548
`
`A
`
`B
`
`$
`
`T
`
`R
`
`A
`
`T
`
`Purpose
`We compared fulvestrant 500 mg regimen with the approved dose of fulvestrant 250 mg per
`
`month for treatment of postmenopausal women with estrogen receptor—positive advanced breast
`cancer who experienced progression after prior endocrine therapy.
`Patients and Methods
`Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) is a double-blind,
`parallel-group, multicenter, phaseIII study. Patients were randomly assigned to fulvestrant 500 mg
`(500 mg intramuscularly [IM] on day 0, then 500 mg IM on days 14 and 28 and every 28 days
`thereafter) or 250 mg every 28 days. Primary end point was progression-free survival
`(PFS).
`Secondary end points included objective response rate, clinical benefit rate (CBR), duration of
`clinical benefit (DoCB), overall survival (OS), and quality oflife (QOL).
`Results
`PFS was significantly longer for fulvestrant 500 mg (n = 362) than 250 mg (n = 374) (hazard ratio
`[HR] = 0.80; 95% Cl, 0.68 to 0.94: P = .006), corresponding to a 20% reduction in risk of
`progression. Objective response rate was similar for fulvestrant 500 mg and 250 mg (9.1% v 10.2%,
`respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DoCB and OS
`were 16.6 and 25,1 months, respectively, for the 500-mg group, whereas DoCB and OS were 13.9 and
`22.8 months, respectively,
`in the 250-mg group. Fulvestrant 500 mg was well tolerated with no
`dose-dependent adverse events. QOL was similar for both arms.
`
`a
`Conclusion
`increase in PFS and not
`Fulvestrant 500 mg was associated with a statistically significant
`associated with increased toxicity, corresponding to a clinically meaningful improvement in benefit
`versus risk compared with fulvestrant 250 mg.
`
`J Clin Oncol 28:4594-4600. © 2010 by American Society of Clinical Oncology
`
`
`From the Hospital of Prato, Prato,Italy;
`Centre Hospitalier Universitaire Sart
`Tilman, Ligge; AZ. Klina, Brasschaat,
`Belgium; Charles University, Prague,
`Czech Republic; Instituto Nacional del
`Cancer, Santiago, Chile; Dnipropetrovsk
`Municipal Clinical Hospital, Dniprope-
`trovsk, Ukraine; Republican Clinical
`Oncological Center, Kazan; Meclical
`Radiological Science Center, Obninsk;
`Russian Cancer Research Cenitre,
`Moscow, Russia; Hospital Nossa
`Senhora da Conceigao, Porto Alegre,
`Brazil; Kansas City Caneer Center,
`Kansas City, KS; AstraZeneca Pharma-
`ceuticals, Macclesfield, United King-
`dom; and Hospital Universitario
`Gregorio Maranon, Madrid, Spain.
`Submitted February 24, 2010; accepted
`July 9, 2010; published online ahead of
`print at www jco.org on September 20,
`2010.
`
`Written on behalf of the Comparison of
`Faslodex in Recurrent or Metastatic
`Breast Cancer (CONFIRM) investigators
`
`Supported by AstraZeneca Pharmaceu-
`tieals, Macclesfield, United Kingdom.
`Presented in part at the $2nd Annual
`San Antonio Breast Cancer Symposium,
`December 9-13, 2009, San Antonio, TX
`Authors’ disclosures of potential con-
`flicts of interest and author contribu-
`tions are found at the end of this
`article.
`
`Clinical Trials repository link available on
`JCO.org.
`Corresponding author: Angelo Di Leo,
`MD, PhD, “Sandro Pitigliani? Medical
`Oncology Unit, Hospital of Prato, Piazza
`dell’Ospedale 2, 59100 Prato,Italy;
`e-mail: adileo@usl4toscana it
`
`© 2010 by American Society of Clinical
`Oncology
`0732-183X/10/2830-4594/$20.00
`
`DOL 10.1200/JCO.2010.28.8415
`
`
`
` |
`
`To
`
`|
`
`Fulvestrant is an estrogen receptor (ER) antagonist
`without known agonistic properties that downregu-
`lates cellular levels of ER in a dose-dependent
`manner.’* Two phaseIII trials comparing fulves-
`trant 250 mg with anastrozole in postmenopausal
`patients with endocrine-sensitive advanced breast
`cancer pretreated with tamoxifen showed that both
`treatments have similar efficacy and an acceptable
`safety profile with a low incidence ofwithdrawals.*”
`These results led to the registration offulvestrant 250
`mg as an additional option for the treatment of
`
`postmenopausal patients with endocrine-sensitive
`advanced breast cancer.
`
`Observations from previously reported studies
`raised. the hypothesis that a higher dose of fulves-
`trant might be associated with increased efficacy.
`Indeed, results from two preoperative studies, in
`which patients were exposed short term to different
`doses offulvestrant, indicated that ER, progesterone
`receptor, and the cell proliferation—related antigen
`Ki-67 were downregulated in a dose-dependent
`mannerafter treatment with fulvestrant.*° In addi-
`tion, a pooled analysis of the twotrials comparing
`fulvestrant 250 mg with anastrozole suggested that a
`
`4594
`
`© 2010 by American Society ofClinical Oncology
`Downloadedfrom jco.ascopubs.org on October 20, 2015. For personal use only. No other uses without permission.
`Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2004 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`Fresenius-Kabi USA LLCv. AstraZeneca AB IPR2017-01912
`
`€
`

`

`Fulvestrant 500 mg in Advanced Breast Cancer
`
`dose-response effect might exist because the twotrials initially in-
`cluded a fulvestrant lower dose arm (125 mg),**” which was discon-
`tinued after a first interim analysis because it failed to meet the
`minimum efficacy requirements.” Morerecently,the results ofa phase
`I randomized neoadjuvantstudytesting two different doses offulves-
`trant (ie, 250 v 500 mg) have also suggested that the higher dose might
`be associated with increased clinical and biologicactivity.
`Such observations prompted the design of a phaseII trial, the
`Comparison of Faslodex in Recurrent or Metastatic Breast Cancer
`(CONFIRM)trial, in which two different doses of fulvestrant were
`evaluated—the currently approved dose (250 mgevery 28 days) anda
`higher dose regimen that incorporates a day 14 loading element (500
`mg on days 0, 14, and 28, and every 28 days thereafter). The present
`article reports the mature progression-free survival (PFS) results ofthe
`CONFIRMtrial.
`
`
`
`Eligible patients were postmenopausal and had either locally advanced or
`metastatic ER-positive breast cancer. No centralized confirmation ofER status
`was performed.Patients who experienced relapse on adjuvant endocrine ther-
`apy or within 1 year from completion of adjuvant endocrine therapy were
`eligible. For patients who experienced relapse after more than 1 year from
`completion of adjuvant endocrine therapy or for patients presenting with de
`
`novo advanceddisease,eligibility required a previous treatmentwith either an
`antiestrogen or an aromatase inhibitor as a first-line therapy. Patients with
`measurable or evaluable disease according to Response Evaluation Criteria in
`Solid Tumors (RECIST)criteria wereeligible.? Main exclusioncriteriawere as
`follows: presence of extensive liver and/or lung involvement, previous or
`current history ofbrain-leptomeningeal metastases, and more than one chem-
`otherapy or endocrine therapy for advanced disease. The study protocol was
`approved by the institutional review board. ofeach participating institution,
`andall patients gave written informed consent before study entry.
`Thetrial had a double-blind, placebo-controlled design.Eligible patients
`were randomly assigned 1:1 to one of the two following treatment arms:
`fulvestrant 500 mg given as two 5-mL intramuscular (IM) injections, one in
`each buttock, on days 0, 14, and 28 and every 28 (+ 3) days thereafter; or
`fulvestrant 250 mg given as. atwo 5-mLIM injections(one fulvestrant injection
`plus one placeboinjection), one in each buttock, on days 0, 14 (two placebo
`injections only), and 28 and every 28 (+ 3) days thereafter. The study treat-
`ment had to be administered by a health care professional at the participating
`institution site. The random assignment wasstratified by institutionsite.
`Disease staging at baseline included physical examination, chest x-ray or
`computed tomography scan, and bone scan orskeletal survey. RECIST tumor
`assessment was scheduled every 12 (+ 2) weeks from the baseline visit until
`progression. Adverse events were recorded every 4 weeks until 8 weeks from
`the last injection. Treatment was continued until disease progression unless
`anyof the criteria for earlytreatment discontinuation, such as patient’s with-
`drawal ofconsentorsevere toxicity, were metfirst. Subsequentlines oftherapy
`were at the investigator's discretion. No crossover from 250 mg to 500 mg was
`allowed at the time ofdisease progression.
`
`Screened
`(N = 834)
`
`Randomly assigned
`(n = 736)
`
`—
`
`Fulvestrant 500 mg
`(n = 362)
`
`Fulvestrant 250 mg
`(n= 374)
`
`Did not receive
`treatment
`(n = 1, eligibility criteria
`not fulfilled)
`
`Did not receive
`treatment
`(n = 0)
`
`Received
`fulvestrant 500 mg
`(n = 361)
`
`Received
`fulvestrant 250 mg
`(n= 374)
`
`Fig 1. CONSORTdiagram. RECIST, Re-
`sponse Evaluation Criteria in Solid Tu-
`mors; DCO, data cutoff.
`
`treatment at DCO
`
`Discontinued study treatment
`Eligibility criteria not fulfilled
`Adverse event
`Objective progression of disease
`Not willing to continue treatment
`Not willing to continue study
`Lost to follow-up
`Protocol noncompliance
`Death
`Other (eg, disease progression
`judged by evaluations other than
`RECIST,initiation of radiation
`treatment, subject moving abroad)
`
`(n = 320)
`(n=3)
`(n=8)
`(n = 258)
`(n= 5)
`(n= 13)
`(n= 3)
`(n= 2)
`(n=8)
`
`(n= 20)
`
`Discontinued study treatment
`Eligibility criteria notfulfilled
`Adverse event
`Objective progression of disease
`Not willing to continue treatment
`Not willing to continue study
`Lost to follow-up
`Protocol noncompliance
`Death
`Other
`
`(n = 343)
`{n= 4)
`(n =6)
`(n = 278)
`{n= 5)
`(n= 11)
`{n=1)
`{n = 2)
`(n = 13)
`in = 23)
`
`Ongoing study
`treatment at DCO
`(n= 41)
`
`Ongoing study
`
`(n=31)
`
`www.jco.org
`
`© 2010 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 20, 2015. For personal use only. No other uses without permission.
`Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
`
`4595
`
`AstraZeneca Exhibit 2004 p. 2
`
`

`

`Di Leo et al
`
`The study primary end point was a comparison between the two treat-
`ment armsin terms ofPFS, which was defined asthe time elapsing between the
`date of random assignment and the date ofthe earliest evidence of objective
`disease progression or death from any cause before documented disease pro-
`gression. Secondary end points were the comparisons between the twotreat-
`ment armsin termsofobjective response rate (complete and partial response),
`clinical benefit rate (complete response,partial response, and disease stabiliza-
`tion for at least 24 weeks), duration of response and clinical benefit, overall
`survival (OS), tolerability, and quality of life (QOL).
`The sample size calculation was based on the primary variable ofPFS and.
`assumed exponential progression times. The sample size was driven by the
`numberofrequired events. To detect a hazard ratio (HR) of < 0.8 (or = 1.25)
`for fulvestrant 500 mg compared with 250 mg, atatwo-sided significancelevel
`of 5%, with 80%power, approximately 632 events were required to have
`occurredin the study. The median PFS for fulvestrant 250 mgin this patient
`population wasestimated to be 5.5 months,’ andan HR of0.8 would equateto
`a prolongation in median PFS for fulvestrant 500 mgoverfulvestrant 250 mg
`of 1.38 months. If 720 patients were recruited over a period of 36 months,it
`was anticipated that the required 632 events would be observed approximately
`6 monthsafter the endofrecruitment.
`
`For the primary end point ofPFS,the primary analysis wasan unadjusted
`log-rank test. The treatmenteffect was estimated using the HR of fulvestrant
`500 mg versus fulvestrant 250 mg, together with the corresponding 95% CI
`and P value. Kaplan-Meierplots were presented with estimates ofthe median
`for each treatment group. The secondary analysis of PFS was a Cox propor-
`tional hazards model, which was adjustedfor the following predefined covari-
`ates: progesterone receptorstatus (positive y negative or unknown), visceral
`involvement(no v yes), last endocrine therapy before fulvestrant (antiestrogen v
`aromatase inhibitor), age (< v = 65 years), measurable disease (no v yes), and
`level of responsiveness to last endocrine therapy before fulvestrant (respon-
`sive v poorly responsive or unknown). For the latter covariate, a tumor was
`defined as responsiveto last endocrine therapybefore fulvestrant ifrecurrence
`occurredafter 2 or more years on the previous adjuvant endocrine therapy or
`if complete response, partial response, or disease stabilization for at least 24
`weeks was recorded on first-line endocrine therapy for advanced disease.
`Conversely, a tumor was defined as poorly responsive if recurrence occurred
`within thefirst 2 years on adjuvant endocrine therapyorifstable diseaseforless
`than 24 weeks or disease progression wasthe best response to first-line endo-
`crine therapy for advanceddisease.
`Objective response and clinical benefit rates were summarized and ana-
`lyzed usinga logistic regression model. Results were expressed.as the oddsratio
`(OR) together with the corresponding 95% CI and P value. Durations of
`response andclinical benefit were summarized, and Kaplan-Meierplots were
`produced with estimates ofthe median for each treatment group. Duration of
`response wascalculated either from the date of randomassignmentor from
`the date offirst documented response to the date of progression. Duration of
`clinical benefit was calculated from the date ofrandom assignmentto the date
`ofdisease progression. A summary oftimeto response wasalso produced. OS
`was analyzed using an unadjusted log-rank test as described for the PFS
`analysis. The log-rank test was to be performed when approximately 50% of
`the randomly assigned patients haddied,and this occurred at the time of the
`present PFS analysis. Incidence of each adverse event by treatment arm was
`reported. Adverse events were graded according to National Cancer Institute
`Common Terminology Criteria ofAdverse Events (version 3.0).'° A compar-
`ison between the two study arms in the incidence ofcertain prespecified
`categories ofadverse events was also performed using a two-sided Fisher’s
`exact test at nominal significance ofP = .05.
`The Functional Assessment of Cancer Therapy—Breast (FACT-B) ques-
`tionnaire was the instrument used to assess QOL. A subgroup of the trial
`population completed questionnaires at scheduled clinical visits at. baseline
`and at each 4-week visit for 24 weeks or until progression. The main QOL
`variable was Trial Outcome Index (TOI).
`Adverseevents and laboratory abnormalities were summarized by treat-
`ment actually received, whereas efficacy and QOL analyses were carried out
`according to the randomly assigned treatment. The study was sponsored. by
`AstraZeneca (Macclesfield, United Kingdom). Data monitoring was per-
`
`formed by an independent data monitoring committee, which reportedto the
`study sponsor.
`
`SUMEy
`
`Patients
`A total of 736 patients were recruited from 128 centers across
`17 countries (Fig 1). Thefirst patient was randomly assigned on
`February 8, 2005, and the last patient was randomlyassigned on
`August 31, 2007. The data cutoff date for the primary analysis
`(February 28, 2009) was chosen based on modeling of the rate of
`known progression events. At this time, 618 events were recorded.
`Table 1 lists main patient and tumor characteristics by treat-
`ment group. No relevant imbalances are observed between the two
`study arms.
`Table 1 divides patients bythe setting ofendocrinetherapy before
`fulvestrant (ie, either adjuvant or for advanced disease). It is worth
`noting that the most represented subgroups were patients who expe-
`rienced relapse on adjuvant endocrine therapy and patients who pre-
`sented with denovo advanceddisease and experienced progression on
`
`
`
`Table 1. Main Patient and Tumor Characteristics
`Fulvestrant
`Fulvestrant
`500 mg
`250 mg
`
`(n = 362)
`(n = 374)
`No. of
`No. of
`
`Characteristic
`Patients
`%
`Patients
`%
`
`61
`
`100
`
`66.6
`254,
`8
`14
`98.9
`66
`
`362
`
`241
`92
`29
`4
`358
`239
`
`Z
`16
`
`60.5
`0.9-338.6
`
`61
`
`100
`
`Ad
`25.7
`3.2
`29
`97.1
`62
`
`374
`
`266
`96
`(2
`11
`363
`282
`
`2
`0-7
`
`59.9
`1.9-418.4
`
`Median age, years
`ER positive
`PgR status
`Positive
`Negative
`Unknown
`Locally advanced disease
`Metastatic disease
`Visceral involvement
`No. of disease sites
`Median
`Range
`Time from diagnosis to random
`assignment, months
`Median
`Range
`Relapse/progression
`During adjuvant endocrine
`therapy
`0-12 months after
`completion of adjuvant
`endocrine therapy
`> 12 months after
`completion of adjuvant
`endocrine therapy and
`after progression onfirst-
`liné endocrine therapy for
`advanced disease
`Patients presenting with de
`nove advanced disease
`and experiencing
`progression on first-line
`33.4
`125
`25.9
`130
`endocrine therapy
`
`Other O38 5 la 1
`
`
`
`
`175
`
`48.3
`
`169
`
`45.2
`
`16
`
`AA
`
`ae
`
`12
`
`36
`
`AS:
`
`BZ
`
`39
`
`Abbreviations: ER, estrogen receptor: PgR, progesterone receptor.
`
`4596
`
`© 2010 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 20, 2015. For personal use only. No other uses without permission.
`Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`AstraZeneca Exhibit 2004 p. 3
`
`

`

`Fulvestrant 500 mg in Advanced Breast Cancer
`
`= o
`
`
`
`ProgressionFree °°°&Oooo
`
`9 hD
`
`= Fulvestrant 500 mg
`== Fulvestrant 250 mg
`Hazard ratio (95% Cl): 0.80 (0.68 to 0.94)
`P=,006
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`28
`
`32
`
`36
`
`40
`
`44 48
`
`
`
`Table 2. Objective Response Rates and Clinical Benefit Rates
`Fulvestrant 500
`Fulvestrant 250
`
`mg (n = 362)
`mg (n = 374)
`No. of
`No. of
`
`Response
`Patients
`%
`Patients
`%
`Complete response
`4
`val
`1
`0.3
`Partial response
`29
`8
`37
`@.9
`Objective response*
`33
`9.7
`38
`10.2
`Stable disease = 24 weeks
`132
`36.5
`110
`29.4
`Clinical benefitT
`165
`45.6
`148
`39.6
`Stable disease < 24 weeks
`47
`1é
`52
`13.8
`Progressive disease
`140
`38.7
`167
`44.7
`
`10 2.8 7Not evaluable 1.0
`
`
`
`
`*The complete response plus partial response rate in patients with measur-
`able disease was 13.8% (33 of 240 patients) with fulvestrant 500 mg and
`14.6% (38 of 261 patients) with fulvestrant 250 mg.
`Tt Clinical benefit defined as complete response + partial response + stable
`disease = 24 weeks.
`
`
`4
`
`wnpas
`Cc
`Oo
`eSo
`ae
`oO
`O
`a]L
`a
`oO=
`oO
`
`oQ
`
`co
`
`No.of patients at risk
`Fulvestrant 500mg 362
`Fulvestrant 250mg 374
`
`Time (months)
`
`216
`199
`
`163
`144
`
`113
`85
`
`90
`60
`
`54
`35
`
`37
`25
`
`19
`12
`
`12
`
`Fig 2. Progression-free survival curves by treatment arm.
`
`first-line endocrine therapy. Overall, the last endocrine therapy before
`fulvestrant was an aromatase inhibitor for 42.5% of patients and an
`antiestrogen for the remaining 57.5% ofpatients.
`Percentagesofpatients by level of responsiveness to prior endo-
`crine therapy were as follows: 63.3% and 36.7% were considered as
`responsive and poorly responsive, respectively, in the 500-mg group;
`and 66.6% and 33.4% of patients were defined as responsive and
`poorly responsive, respectively, in the 250-mg group.
`
`The PFSanalysis adjusted by predefined covariates resulted in an
`HRof0.78 (95%CI, 0.67 to 0.92; P = .003). Figure 3 shows the PFS
`forest plot according to the predefined covariates and showsthat the
`treatmenteffect seems to be consistentacross all subgroups.
`Objective response and clinical benefit rates are listed in Table
`2. Fulvestrant 500 mg wasnot associated with an increase in objec-
`tive response and clinical benefit rates (OR for objective response
`Efficacy
`rate = 0.94; 95% CI, 0.57 to 1.55; P = .795; ORforclinical benefit
`rate = 1.28; 95% CI, 0.95 to 1.71; P = .100; OR > 1 favors
`Figure 2 showsthe PFS curves by treatment arm. Fulvestrant 500
`mg significantly prolongs PFS over fulvestrant 250 mg (HR = 0.80;
`fulvestrant 500 mg).
`The time to response analysis reveals that within the first 12
`95% CI, 0.68 to 0.94; P = .006). This observationis based onatotal of
`618 progression events, of which 297 (82.0%) were in the 500-mg
`weeks oftreatment, seven (18.4%) of the 38 responders had already
`group and 321 (85.8%) were in the 250-mg group. Median PFS times
`responded in the 250-mg arm; this percentage was 9.1%in the
`were 6.5 and 5.5 months in the 500- and 250-mggroups,respectively.
`500-mg group(three of 33 patients). At week 24, 22 (58%) of the 38
`At 12 months, 34% and 25% ofpatients remained alive and progres-
`responders and 18 (55%) of the 33 responders had an objective
`sion free on fulvestrant 500 and 250 mg,respectively; these figures
`responseto fulvestrant 250 and 500 mg,respectively. Median du-
`were 16% and 11%,respectively, at 24 months.
`rations of response were 19.4 and 16.4 months for the 500- and
`
` Favors fulvestrant 250 mg —>
`
`Receptor status
`
`Visceral involvement
`
`ER+ and PgR+
`ER+ and PgR-
`or unknown
`No
`Yes
`
`Response tolast endocrine Responsive
`therapy prior to fulvestrant
`Poorly responsive
`or unknown
`Measurable disease
`No
`Yes
`
`Age, years
`
`<65
`265
`
`Last endocrine therapy
`prior to fulvestrant
`
`Aromatase inhibitor
`Anti-estrogen
`
`All patients
`
`Fig 3. Progression-free survival by pre-
`defined covariates. ER, estrogen receptor:
`PgR, progesterone receptor.
`
`0.60
`
`0.80
`
`1.00
`
`1.25
`
`1.50
`
`Hazard ratio (fulvestrant 500 mg v fulvestrant 250 mg) and 95% Cl
`
`«— Favorsfulvestrant 500 mg
`
`www.jco.org
`
`© 2010 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 20, 2015. For personal use only. No other uses without permission.
`Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
`
`4597
`
`AstraZeneca Exhibit 2004 p. 4
`
`

`

`Di Leo et al
`
`= Fulvestrant 500 mg
`== Fulvestrant 250 mg
`Hazard ratio (95% Cl): 0.84 (0.69 to 1,03)
`P=.091
`
`uw OD
`o>
`cs
`oat
`ee Y_ +
`oca ®d
`PsoO
`oO 7
`
`4
`
`8
`
`12
`
`16
`
`20
`
`24
`
`28
`
`32
`
`36
`
`61 4B
`
`No,atrisk
`Fulvestrant 500mg 362
`Fulvestrant 250mg 374
`
`330
`338
`
`285
`299
`
`251
`260
`
`Time (months)
`223
`165
`116
`7A
`222
`157
`107.
`
`46
`
`«(29
`
`Fig 4. Overall survival curves by treatment arm.
`
`250-mg groups,respectively,if duration of response was calculated
`from the date of random assignment. Conversely, if duration of
`response was calculated from the date on which response was
`actually detected, median durations were 8.5 and 12 monthsfor the
`500- and 250-mg groups, respectively. Median durations ofclinical
`benefit were 16.6 and 13.9 months in the 500- and 250-mg
`groups,respectively.
`Figure 4 shows the OS curves. Median times to death were 25.1
`and 22.8 months for fulvestrant 500 mg and 250 mg,respectively
`(HR = 0.84; 95% CI, 0.69 to 1.03; P = .091). A preplanned second
`survival analysis will be performed when approximately 75% of
`patients have had an event, and this is expected to occur in 2011.
`
`Safety
`Median durations of exposure to fulvestrant were 174 days
`(range, 10 to 1,441 days) and 145 days(range, 7 to 1,387 days) in the
`500- and 250-mg groups, respectively. Table 3 lists the incidence of
`prespecified adverse events by treatment group. No substantial differ-
`ence in incidence and severity of adverse events was seen between the
`two treatment groups. No relevant laboratory abnormalities were
`observed, and no differences were reported by fulvestrant dose. Seri-
`
`ous adverse events reported in = two patients were as follows: bron-
`chitis (n = 2; 0.6%), dyspnea (n = 2; 0.6%), and vomiting (n = 3;
`0.8%) in the 500-mg group; no cases were reported in the 250-mg
`group. Casually related serious adverse events included onepatient
`with interstitial lung disease in the 500-mg group and onepatient with
`blood hypertension in the 250-mg group. The latter was the only
`instance of a casually related adverse event leading to death from
`cardiac failure.
`
`QoL
`A total of 145 patients completed a baseline FACT-B question-
`naire, which represented 82.3% ofthe 176 patients randomly assigned
`in the countries that participated in the QOL substudy. Appendix
`Figure Al (online only) shows the comparison between the two study
`arms in terms of QOL evaluated as TOI, which is the main outcome
`measure ofFACT-B. The TOI score is a summary score ofthe follow-
`ing subscales: physical well-being, functional well-being, and breast
`cancer subscale. No significant difference was detected between the
`two study arms.
`
`DISCUSSION
`
`The present randomized trial demonstrates that fulvestrant 500 mg
`producesa statistically significant andclinically relevant prolongation
`of PFS overfulvestrant 250 mg. The PFS improvementseemsto be the
`consequence of a modestincrease in the rate of disease stabilization
`and a substantial prolongation in duration ofdisease stabilization.
`OS data seem to favor fulvestrant 500 mg. Interestingly,at the
`time of this analysis, no crossover from the 250-mg arm to the
`500-mg arm has occurred. However, on thebasis of data presented
`here, the independent data monitoring committee has advised to
`offer crossover to 500 mg for ongoing 250-mgpatients. At the time
`of data cutoff, 31 (8.3%) of 374 patients treated in the 250-mg arm
`were continuing on treatment, and thus, the overall proportion of
`crossover patients is expected to be small. Accordingly, it is ex-
`pected that the low crossoverrate will not impact significantly on
`the planned 75% survival analysis.
`The safety and QOL analyses do notraise any concern related
`to fulvestrant 500 mg compared with 250 mg. However, because of
`
`
`
`Table 3. Prespecified Adverse Events by Treatment Arm
`Fulvestrant 500 mg (n = 361) Fulvestrant 250 mg (n = 374)
`
`
`Grade 1-4
`= Grade 3
`Grade 1-4
`= Grade 3
`
`Adverse Event
`No. of Patients
`%
`No. of Patients
`%
`No. of Patients
`%
`No. of Patients
`%
`
`
`0
`0
`0
`0
`0
`0
`0
`0
`Endometrial dysplasia
`0.3
`1
`20.3
`76
`22
`8
`20.2
`WS
`Gl disturbances
`0
`0
`6.1
`23
`0
`0
`8.3
`30
`Hot flashes
`0
`0
`TA
`50
`0.3
`1
`13.6
`AS
`Injection site reactions
`0.8
`2
`Le
`7
`0
`0
`14
`5
`Ischemic cardiovascular disorders
`Zl
`8
`18.7
`70
`au!
`8
`18.8
`68
`Joint disorders
`0
`0
`0
`0
`0
`0
`0.3
`1
`Osteoporosis
`Lat
`4
`1.6
`6
`0.6
`2
`0.8
`2
`Thromboembolic events
`0.3
`1
`Zi
`8
`03
`1
`22
`8
`Urinary tract infection
`Vaginitis
`3
`0.8
`0
`0
`1
`0.3
`0
`0
`
`Weight gain
`1
`0.3
`0
`0
`1
`0.3
`0
`0
`
`
`4598
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2010 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on October 20, 2015. For personal use only. No other uses without permission.
`Copyright © 2010 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2004 p. 5
`
`

`

`Fulvestrant 500 mg in Advanced Breast Cancer
`
`the inclusion of a placebo injection in the control arm,the present
`study design is not appropriate to assess any potential increase in
`the risk of injection site reactions related to the 500-mg dose. Of
`note, previous investigations into fulvestrant solubility suggest
`that a more concentrated formulation of fulvestrant (ie, > 250
`mg/5 mL) is unlikely to be achieved for slow-release injection (M.
`Harrison, personal communication).
`The results reported in the present article refer to the overall
`study population. The planned subgroup analysis according to six
`predefined covariates suggests that the type of treatment effect
`seems to be consistent across the investigated subgroups (global
`interaction test, P = .801; Fig 3). Nevertheless, it is important to
`mention that the study was not powered to detect interactions
`between the investigated covariates and treatment activity. In ad-
`dition, the study sample size does notallow ruling out the hypothesis
`that the magnitude ofbenefit from fulvestrant 500 mg could be mod-
`ulated by someofthe investigated covariates.
`The study population, although selected according to well-
`definedeligibility criteria, remains heterogeneous in terms of some
`clinical and biologic characteristics. In particular, it is expected that
`approximately 10% of patients might have tumorscarrying activation
`ofthe growth factor receptors pathway, and this could ultimately lead
`to an intrinsic form ofresistance to hormonetherapy.'''* In addition,
`length of exposure to prior endocrine therapy andinterval between
`date of last hormone therapy treatment and date of fulvestrantstart
`might both contribute to modulate the level of sensitivity to an addi-
`tional line of endocrine therapy.” For instance, patients who were
`previously exposed long term to hormonetherapy(ie, > 2 years) and
`whoreceived fulvestrant immediately after progression to endocrine
`therapy could have an acquired form ofresistance to hormonal treat-
`ment.’” Preclinical and early clinical data indicate that in this setting,
`estrogens could paradoxically enhance tumor apoptosis and that, con-
`versely, antihormone agents could lose, at least temporarily,their
`clinical activity.'°"° Given these considerations, we hypothesize that
`the present study population might include a certain proportion of
`patients with an intrinsic or an acquired form ofresistance to hor-
`monetherapy. These patients are not expected to derive clinical ben-
`efit from fulvestrantat either dose or from other endocrine therapies.
`In the attempt to corroborate this hypothesis, we are now running a
`correlative study (ie, Trans-CONFIRM) in which activation of the
`growth factor receptor pathway at the primary tumorlevel and dura-
`tion of exposure to prior hormone therapy will be investigated as
`potential factors predicting the activity of fulvestrant 500 mg.
`In conclusion, the present study has investigated the clinical
`value of increasing the dose of fulvestrant from 250 to 500 mg ina
`population of postmenopausal patients with advanced breast can-
`cer with ER-positive tumors previously exposed to at least one
`endocrine therapy. The results of CONFIRM support previous
`
`data and demonstrate that fulvestrant 500 mgis associated with a
`statistically significant and clinically relevant increase in PFS, the
`study primary end point. Increasing fulvestrant dose is not associ-
`ated with anysafety concern. These results indicate that fulvestrant
`500 mg IM (on days 0, 14, and 28 and every 28 days thereafter)
`should replace the currently approved 250-mg schedule in current
`medical practice.
`
`OF INTEREST
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest thatis relevant to the subject
`matter under consideration in this article. Certain relationships marked
`with a “U” are those for which no compensation was received; those
`relationships marked with a “C” were compensated. For a detailed
`description ofthe disclosure categories, orfor more information about
`ASCO’s conflict ofinterestpolicy, please refer to the Author Disclosure
`Declaration and the Disclosures ofPotential Conflicts ofInterest section in
`Information for Contributors.
`Employment or Leadership Position: Sally Garnett, AstraZeneca (C);
`Justin P.O. Lindemann, AstraZeneca (C); Francisco Sapunar,
`AstraZeneca (C) Consultant or Advisory Role: Angelo Di Leo, Pfizer
`(C), AstraZeneca (C); Miguel Martin, AstraZeneca (C), Pfizer (C)
`Stock Ownership: Sally Garnett, AstraZeneca; Justin P.O.
`Lindemann, AstraZeneca; Francisco Sapunar, AstraZeneca
`Honoraria: Angelo Di Leo, Pzifer, AstraZeneca; Guy Jerusalem,
`AstraZeneca Research Funding: Angelo Di Leo, Pfizer, AstraZeneca;
`Guy Jerusalem, AstraZeneca; Kelly Pendergrass, AstraZeneca Expert
`Testimony: Francisco Sapunar, AstraZeneca (C) Other
`Remuneration: None
`
`UTSOETLONILOES
`
`Conception and design: Angelo Di Leo, Sally Garnett, Miguel Martin
`Financial support: Justin P.O. Lindemann
`Administrative support: Justin P.O. Lindemann
`Provision of study materials or patients: 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, Justin P.O. Lindemann, Miguel Martin
`Collection and assembly of data: Sally Garnett, Justin P.O. Lindemann
`Data analysis and interpretation: Angelo Di Lco, Guy Jerusalem, Lubos
`Petruzelka, Sally Garnett, Justin P.O. Lindemann, Francisco Sapunar,
`Miguel Martin
`Manuscript writing: Angelo Di Leo, Guy Jerusalem, Lubos Petruzelka,
`Sally Garnett, Justin P.O. Lindemann, Francisco Sapunar, Miguel Martin
`Final approval of manuscript: 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, Sally Garnett, Justin P.O. Lindemann, Francisco
`Sapunar, Miguel Martin
`
`REFERENCES
`
`1. Wakeling AE, Dukes M, Bowler J: A potent
`specific pure antiestrogen with clinical potential.
`Cancer Res 5