VOLUME 28 ~ NUMBER 30 ~
`
`OCTOBER 20 2010
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`
`
`O R I G I N A L
`
`R E P 0 R T
`
`Results of the CONFIRM Phase III Trial Comparing
`Fulvestrant 250 mg With Fulvestrant 500 mg in
`Postmenopausal Women With Estrogen Receptor—Positive
`Advanced Breast Cancer
`
`Angelo Di Leo, Guy Jerusalem, Lubes Petruzelka, Roberto Torres, Igor N. Bondarenko, Rustem Khasanov,
`Didier V€Tl10€1/€71,
`Jose L. Peclrini, Iya Smirnoi/a, Mikhail R. Lichinitser, Kelly Pendergrass, Sally Garnett,
`Justin P. O. Linclemann, Francisco Sapunar, and Miguel Martin
`
`See accompanying editorial 4548
`
`ABSTRACT
`
`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, phase III study. Patients were randomly assigned to fulvestrant 500 mg
`(500 mg intramuscularly [lM] 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 of life (OOL).
`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% v10.2%,
`respectively). CBR was 45.6% for fulvestrant 500 mg and 39.6% for fulvestrant 250 mg. DOCB and OS
`were16.6 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.
`
`_
`__
`_
`_
`_
`_
`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. © 2070 by American Society of Clinical Oncology
`
`
`Fulvestrant is an estrogen receptor (ER) antagonist
`without known agonistic properties that downregu-
`lates cellular levels of ER in a dose—dependent
`manner.” Two phase III trials comparing fulves-
`‘urant 250 mg with anastrozole in posnnenopausal
`patients with endocrine—sensitive advanced breast
`cancer pretreated with tamoxifen showed that both
`‘ureatments 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 Ueatment of
`
`posunenopausal patients with endocr'ine—sensit:ive
`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 proljferation—related antigen
`Ki—67 were downregulated in a dose—dependent
`manner after treatment with fulvestrant.“ In addi-
`
`tion, a pooled analysis of the two trials comparing
`fulvestrant 250 mg with anastrozole suggested that a
`
`:rom the Hospital of Prato, Prato, Italy,
`Centre Hospitalier Universitaire Sart
`Tilman, Liege, AZ Klina, Brasschaat,
`3elgium, Charles University, Prague,
`Czech Republic, lnstituto Nacional del
`Cancer, Santiago, Chile, Dnipropetrovsk
`unicipal Clinical Hospital, Dniprope—
`trovsk, Ukraine, Republican Clinical
`Oncological Center, Kazan, Medical
`Radiological Science Center, Obninsk,
`Russian Cancer Research Centre,
`Moscow, Russia, Hospital Nossa
`Senhora da Conceicao, Porto Alegre.
`3razi|, Kansas City Cancer Center,
`ansas 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
`rint at www JCO org on September 20,
`2010
`
`Written on behalf of the Comparison of
`Faslodex in Recurrent or Metastatic
`3reast Cancer (CONFIRM) investigators
`Supported by AstraZeneca Pharmaceu—
`ticals, Macclesfield, United Kingdom
`>resented in part at the 32nd Annual
`San Antonio Breast Cancer Symposium,
`ecember 9-13, 2009, San Antonio, TX
`Authors’ disclosures of potential con—
`licts of interest and author contribu—
`tions are found at the end of this
`article
`
`Clinical Trials repository link available on
`C0 org
`Corresponding author Angelo Di Leo,
`MD, PhD, “Sandro Pitigliani” Medical
`Oncology Unit, Hospital of Prato, Piazza
`e||'Ospeda|e 2, 59100 Prato, Italy.
`e—mail adi|eo@usl4 toscana it
`
`© 2010 by American Society of Clinical
`Oncology
`0732—183X/10/28804594/$20 00
`DOI 101200/JCO 2010 28 8415
`
`4594
`
`© 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 Ex. 2004 p. 1
`Mylan Pharms. Inc. v. AstraZeneca AB IPR2016-01324
`
`

`
`Fulvestrant 500 mg in Advanced Breast Cancer
`
`dose—response effect might exist because the two trials initially in-
`cluded a fulvestrant lower dose arm (125 mg) ,4“ which was discon-
`tinued after a first interim analysis because it failed to meet the
`minimum efficacy requirements.7 More recently, the results of a phase
`II randomized neoadjuvant study testing two different doses offulves-
`trant (ie, 250 1/ 500 mg) have also suggested that the higher dose might
`be associated with increased clinical and biologic activity.8
`Such observations prompted the design of a phase III 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 mg every 28 days) and a
`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 (P FS) results ofthe
`CONFIRM trial.
`
`
`
`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 advanced diswse, eligibility required a previous treatment with 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 were eligible.9 Main exclusion criteria were 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 of each participating institution,
`and all patients gave written informed consent before study entry.
`The trial 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 (i 3) days thereafter; or
`fulvestrant 250 mg given as atwo 5—mL IM injections (one fulvestrant injection
`plus one placebo injection), 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 was stratified by institution site.
`Disease staging at baseline included physical examination, chest x—ray or
`computed tomography scan, and bone scan or skeletal survey. RECIST tumor
`assessment was scheduled every 12 (i 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
`any of the criteria for early treatment discontinuation, such as patient’s with—
`drawal ofconsent or severe toxicity, were met first. Subsequent lines oftherapy
`were at the investigator’s discretion. No crossover from 250 mg to 500 mg was
`allowed at the time of disease progression.
`
`Screened
`(N = 834)
`
`Randomly assigned
`(n = 736)
`
`l—l—l
`
`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. CONSORT diagram. RECIST, Re-
`sponse Evaluation Criteria in Solid Tu-
`mors; DCO, data cutoff.
`
`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)
`in = 258)
`(n = 5)
`(n =13)
`(n =3)
`(n = 2)
`(n :8)
`
`(n = 20)
`
`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
`
`(n=343)
`(n=4)
`ln=6)
`(n =273)
`(n=5)
`(n=1l)
`(n=1)
`(n=2)
`(n=13)
`ln=23)
`
`Ongoing study
`treatment at DCO
`(n :41)
`
`Ongoing study
`treatment at DCO
`(n=3’|)
`
`www.jcc.0rg
`
`© 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
`
`Astrazcneca Ex. 2004 p. 2
`
`

`
`Di Leo et al
`
`The study primary end point was a comparison between the two treat-
`ment arms in terms ofPFS, which was defined as the time elapsing between the
`date of random assignment and the date of the earliest evidence of objective
`disease progression or death from any cause before documented disease pro-
`gression. Secondary end points were the comparisons between the two treat-
`ment arms in terms ofobjective 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 oflife (QOL).
`The sample size calculation was based on the p rimary variable ofPFS and
`assumed exponential progression times. The sample size was driven by the
`number of required events. To detect a hazard ratio (HR) of S 0.8 (or 2 1.25)
`for fiilvestrant 500 mg compared with 250 mg, at a two-sided significance level
`of 5%, with 80% power, approximately 632 events were required to have
`occurred in the study. The median PFS for fulvestrant 250 mg in this patient
`population was estimated to be 5.5 months,7 and an HR of0.8 would equate to
`a prolongation in median PFS for fulvestrant 500 mg over fulvestrant 250 mg
`of 1.58 months. If 720 patients were recruited over a period of 36 months, it
`was anticipated that the required 652 events would be observed approximately
`6 months after the end of recruitment
`
`For the primaryend point ofPFS, the primary analysis was an unadjusted
`log-rank test. The treatment effect was estimated using the HR of fulvestrant
`500 mg versus fiilvestrant 250 mg, together with the corresponding 95% CI
`and P value. Kaplan-Meier plots were presented with estimates ofthe median
`for each treatment group. The secondary analysis of PFS was a Cox propor-
`tional hazards model, which was adjusted for the following predefined covari-
`ates: progesterone receptor status (positive 1/ negative or unknown), visceral
`involvement (no 1/ yes), last endocrine therapy before fulvestiant (antiestrogen 1/
`aromatase inhibitor), age (< V Z 65 years), measurable disease (no vyes), 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 responsive to last endocrine therapy before fulvestrant if recurrence
`occurred after 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 the first 2 years on adjuvant endocrine therapy or ifstable disease for less
`than 24 weeks or disease progression was the best response to first-line endo-
`crine therapy for advanced disease.
`Objective response and clinical benefit rates were summarized and ana-
`lyzed using a logistic regression model. Results were expressed as the odds ratio
`(OR) together with the corresponding 95% CI and P value. Durations of
`response and clinical benefit were summarized, and Kaplan-Meier plots were
`produced with estimates ofthe median for each treatment group. Duration of
`response was calculated either from the date of random assignment or from
`the date of first documented response to the date of progression. Duration of
`clinical benefit was calculated from the date ofrandom assignment to the date
`ofdisease progression. A summary oftime to response was also 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 had died, and this occurred at the time ofthe
`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). 10 A compar-
`ison between the two study arms in the incidence of certain prespecified
`categories of adverse 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).
`Adverse events 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 reported to the
`study sponsor.
`
`
`
`Patients
`
`A total of 736 patients were recruited from 128 centers across
`17 countries (Fig 1). The first patient was randomly assigned on
`February 8, 2005, and the last patient was randomly assigned 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. N0 relevant imbalances are observed between the two
`study arms.
`Table 1 divides patients bythe setting ofendocrine therapy 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 de novo advanced disease 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
`Patients
`Patients
`
`%
`
`Characteristic
`
`%
`
`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 on first-
`line endocrine therapy for
`advanced disease
`Patients presenting with de
`novo advanced disease
`and experiencing
`progression on first—line
`endocrine therapy
`Other
`
`61
`
`100
`
`66.6
`25.4
`8
`1.1
`98.9
`66
`
`362
`
`241
`92
`29
`4
`358
`239
`
`2
`1-6
`
`60.5
`0.9—3386
`
`61
`
`1OO
`
`71.1
`25.7
`3.2
`2.9
`97.1
`62
`
`374
`
`266
`96
`12
`11
`363
`232
`
`2
`0-7
`
`59.9
`1.9—418.4
`
`175
`
`48.3
`
`16
`
`4.4
`
`169
`
`27
`
`45.2
`
`7.2
`
`36
`
`9.9
`
`52
`
`13.9
`
`130
`5
`
`35.9
`1.4
`
`125
`1
`
`33.4
`0.3
`
`Abbreviations: ER, estrogen receptor; PgR, progesterone reoeptor.
`
`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 or CLINICAL ONCOLOGY
`
`Astrazeneca Ex. 2004 p. 3
`
`

`
`Fulvestrant 500 mg in Advanced Breast Cancer
`
`(I)
`4"
`5 Q;
`-4: S
`cu Ll_
`0- C
`“5 .3C to0 <1)
`-— L
`‘E 51O OQ Q
`o O.L
`
`1-0
`
`0_8
`
`— Fulvestrant 500 mg
`Fulvestrant 250 mg
`
`.
`Hazard ratio (95% Cl): 0.80 (0.68 to 0.94)
`P=.006
`
`D. 0
`
`4812162024283236404448
`
`Time (months)
`No. of patients at risk
`U
`2
`3
`7
`12
`30
`54
`37
`13
`113
`163
`215
`Fulvestra nt 500 mg 362
`
`
`
`
`
`
`
`
`
`S0 35 25 12 4 3 l 185144199Fulvestra nt 250 mg 374 0
`
`
`
`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% of patients.
`Percentages of patients 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.
`
`Efficacy
`Figure 2 shows the PFS curves by treatment arm. Fulvestrant 500
`mg significantly prolongs PFS over fulvestrant 250 mg (HR = 0.80;
`95% CI, 0.68 to 0.94; P = .006). This observation is based on a total of
`618 progression events, of which 297 (82.0%) were in the 500—mg
`group and 321 (85.8%) were in the 250—mg group. Median PFS times
`were 6.5 and 5.5 months in the 500- and 250—mg groups, respectively.
`At 12 months, 34% and 25% of patients remained alive and progres-
`sion free on fulvestrant 500 and 250 mg, respectively, these figures
`were 16% and 11%, respectively, at 24 months.
`
`Table 2. Objective Response Rates and Clinical Benefit Rates
`Fulvestrant 500
`Fulvestrant 250
`mg (n : 362)
`mg (n : 374)
`No. of
`No. of
`Patients
`Patients
`4
`1
`29
`37
`33
`38
`132
`110
`165
`148
`47
`52
`140
`167
`10
`7
`
`%
`1.1
`8
`9.1
`36.5
`45.6
`13
`38.7
`2.8
`
`%
`0.3
`9.9
`10.2
`29.4
`39.6
`13.9
`44.7
`1.9
`
`Response
`Complete response
`Partial response
`Objective response“
`Stable disease 2 24 weeks
`Clinical benefitt
`Stable disease < 24 weeks
`Progressive disease
`Not evaluable
`
`*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.
`T Clinical benefit defined as complete response + partial response + stable
`disease 2 24 weeks.
`
`The PFS analysis adjusted bypredefined covariates resulted in an
`HR of 0.78 (95% CI, 0.67 to 0.92; P = .003). Figure 3 shows the PPS
`forest plot according to the predefined covariates and shows that the
`treatment effect seems to be consistent across all subgroups.
`Objective response and clinical benefit rates are listed in Table
`2. Fulvestrant 500 mg was not associated with an increase in objec-
`tive response and clinical benefit rates (OR for objective response
`rate = 0.94; 95% CI, 0.57 to 1.55; P = .795; OR for clinical benefit
`rate = 1.28; 95% CI, 0.95 to 1.71; P = .100; OR > 1 favors
`fulvestrant 500 mg).
`The time to response analysis reveals that within the first 12
`weeks of treatment, seven (18.4%) of the 38 responders had already
`responded in the 250—mg arm; this percentage was 9.1% in the
`500—mg group (three of33 patients). At week 24, 22 (58%) ofthe 38
`responders and 18 (55%) of the 33 responders had an objective
`response to fulvestrant 250 and 500 mg, respectively. Median du-
`rations of response were 19.4 and 16.4 months for the 500- and
`
`Receptor status
`
`Visceral involvement
`
`Response to last endocrine
`therapy prior to fulvestrant
`Measurable disease
`
`ER+ and PgR-i-
`ER+ and PgR-
`or unknown
`No
`Yes
`
`Responsive
`Poorly responsive
`or unknown
`No
`Yes
`
`Age, years
`
`<65
`265
`
`Last endocrine therapy
`prior to fulvestrant
`
`Aromatase inhibitor
`Anti-estrogen
`
`All patients
`
`<— Favors fulvestrant 500 mg
`
`0.60
`
`0.80
`
`1.00
`
`1.25
`
`1.50
`
`1.75
`
`Hazard ratio (fulvestrant 500 mg vfulvestrant 250 mg) and 95% Cl
`
`Favors fulvestrant 250 mg —>
`
`Fig 3. Progression-free survival by pre-
`defined oovariates. ER, estrogen receptor;
`PgR, progesterone receptor.
`
`www.jcc.0rg
`
`© 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 Ex. 2004 p. 4
`
`

`
`Di Leo et al
`
`ous adverse events reported in 2 two patients were as follows: bron-
`chitis (n = 2; 0.6%), dyspnea (n = 2; 0.6%), and vomiting (11 = 3;
`0.8%) in the 500—mg group; no cases were reported in the 250—mg
`group. Casually related serious adverse events included one patient
`with interstitial lung disease m the 500—mg group and one patient with
`blood hypertension m 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 A1 (online only) shows the comparison between the two study
`arms in terms of QOL evaluated as TOI, which is the main outcome
`measure of FACT—B. The TOI score is a summary score of the follow-
`ing subscales: physical well—being, functional well—being, and breast
`cancer subscale. No significant difference was detected between the
`two study arms.
`
`ELIS-GUSSION
`
`The present randomized trial demonstrates that fulvestrant 500 mg
`produces a statistically significant and clinically relevant prolongation
`ofPFS over fulvestrant 250 mg. The PFS improvement seems to be the
`consequence of a modest increase in the rate of disease stabilization
`and a substantial prolongation ir1 duration of disease 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 the basis of data presented
`here, the independent data monitoring committee has advised to
`offer crossover to 500 mg for ongoing 250—mg patients. At the time
`ofdata cutoff, 31 (8.3%) of374 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 crossover rate will not impact significantly on
`the planned 75% survival analysis.
`The safety and QOL analyses do not raise any concern related
`to fulvestrant 500 mg compared with 250 mg. However, because of
`
`— Fulvestrant 500 mg
`Fulvestrant 250 mg
`Hazard ratio (95% Cl): 0.84 (0.69 to 1.03)
`P: .091
`
`
`
`1-0
`
`0.8
`
`ProportionofPatientsAlive
`
`0.4
`
`0.2
`
` 0.6
`
`o
`
`4
`
`8
`
`12
`
`16
`
`2o
`
`24
`
`28
`
`32
`
`36
`
`4o
`
`44
`
`43
`
`Time (months)
`No.atrisk
`0
`5
`16
`28
`45
`223
`165
`116
`74
`251
`285
`330
`Fu|Vestrant500i'ng 362
`
`
`
`
`
`
`
`
`
`222 157 107 61 34 18 10 2260299338Fu|vestrant250n1g 374 0
`
`
`
`Fig 4. Overall survival cun/es 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 months for 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 m 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-
`
`Table 3. Prespecified Adverse Events by Treatment Arm
`Fulvestrant 500 mg (n : 361)
`Grade 1-4
`2 Grade 3
`
`Fulvestrant 2'50 mg (n : 374)
`Grade 14
`2 Grade 3
`
`Adverse Event
`
`No. of Patients
`
`Endometrial dysplasia
`GI disturbances
`Hot flashes
`Injection site reactions
`lschemic cardiovascular disorders
`Joint disorders
`Osteoporosis
`Thromboembolic events
`Urinary tract infection
`Vaginitis
`Weight gain
`
`O
`73
`30
`49
`5
`68
`1
`3
`8
`3
`1
`
`%
`
`O
`20.2
`8.3
`13.6
`1.4
`18.8
`0.3
`0.8
`2.2
`0.8
`0.3
`
`No. of Patients
`
`O
`8
`0
`1
`O
`8
`O
`2
`1
`O
`O
`
`%
`
`O
`2.2
`0
`0.3
`O
`2.2
`0
`0.6
`0.3
`0
`0
`
`No. of Patients
`
`O
`76
`23
`50
`7
`70
`0
`6
`8
`1
`1
`
`%
`
`O
`20.3
`6.1
`13.4
`1.9
`18.7
`0
`1.6
`2.1
`0.3
`0.3
`
`No. of Patients
`
`O
`1
`0
`0
`3
`8
`0
`4
`1
`0
`0
`
`%
`
`0
`0.3
`0
`O
`0.8
`2.1
`0
`1.1
`0.3
`0
`0
`
`4593
`
`JOURNAL or 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 Ex. 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 not allow ruling out the hypothesis
`that the magnitude of benefit fiom fulvestrant 500 mg could be mod-
`ulated by some of the investigated covariates.
`The study population, although selected according to well-
`defined eligibility criteria, remains heterogeneous in terms of some
`clinical and biologic characteristics. In particular, it is expected that
`approximately 10% of patients might have tumors carrying activation
`of the growth factor receptors pathway, and this could ultimately lead
`to an intrinsic form ofresistance to hormone tl1erapy.11’12 In addition,
`length of exposure to prior endocrine therapy and interval between
`date of last hormone therapy treatment and date of fulvestrant start
`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 hormone therapy (ie, > 2 years) and
`who received fulvestrant immediately after progression to endocrine
`therapy could have an acquired form of resistance to hormonal treat-
`ment.12 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.13'16 Given these considerations, we hypothesize that
`the present study population might include a certain proportion of
`patients with an intrinsic or an acquired form of resistance to hor-
`mone therapy. These patients are not expected to derive clinical ben-
`efit from fulvestrant at 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 tumor level 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 in a
`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 mg is associated with a
`statistically significant and clinically relevant increase in PFS, the
`study primary end point. Increasing fulvestrant dose is not associ-
`ated with any safety 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 ir1 current
`medical practice.
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated afinancial or other interest thatis relevant to the subject
`matterunder consideration in this article. Certain relationships marked
`with a “U” are thosefor 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 of interest policy, 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, AstraZe11eca; 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
`
`AUTHOR CONTRIBUTIONS
`
`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, Iya 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 Leo, 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, Iya Smirnova, Mikhail R. Lichinitser,
`Kelly Pendergrass, Sally Garnett, Justin P.O. Lindemann, Francisco
`Sapun