VOLUME
`
`26
`
`NUMBER 10
`
`APRIL
`
`1
`
`2008
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`
`
`R I G I N A L
`
`R E P 0 R T
`
`From the Division of Medical Oncology,
`British Columbia Cancer Agency,
`University of British Columbia, Vancou—
`ver, British Columbia, Canada, Division
`of Hematology and Medical Oncology,
`Feinberg School of Medicine, North-
`western University, Chicago, lL, Depart—
`ment of Medical Oncology, lnstrtut
`Bergonié, Bordeaux, Department of
`Medical Oncology, CRLC Val d’ Aurel|e—
`Paul Lamarque, Montpellier, France,
`Medical Oncology, lnstituto National de
`Cancer, Rio de Janeiro, Departmento
`de Radiologia, Faculdade de Medicina
`da USP, University of Sao Paulo, Sao
`jaulo, Brazil, Division of Gynecologic
`Oncology, Department of Obstetrics
`and Gynecology, University Hospitals
`Leuven, Leuven, Medicine Department,
`Jules Bordet Institute, Brussels,
`Selgium, lnvestigacion Clinica, Centro
`Oncologico de Bosario, Rosario, Argen—
`tina, The M D Anderson Cancer Center,
`University of Texas, Houston, TX,
`Drofessorial Unit of Surgery, Notting—
`am City Hospital, Nottingham, Clinical
`evelopment, AstraZeneca Pharmaceu—
`ticals, Macclesfield, Cheshire, United
`ingdom, Division of Hematology/
`Oncology, University of Pittsburgh
`School of Medicine, Pittsburgh, PA,
`epartment of Oncology and Haematol-
`ogy, Charite Campus Mitte, Universite
`tsmedizin, Berlin, Germany, and Clinical
`evelopment, AstraZeneca Pharmaceu—
`ticals, Wilmington, DE
`Submitted July 26, 2007, accepted
`ecember 5, 2007, published online
`ahead of print at www ico org on
`March 3, 2008
`>resented in part at the 29th Annual
`San Antonio Breast Cancer Symposium
`ecember 14—17, 2006, San Antonio,
`Texas
`
`Authors’ disclosures of potential con—
`flicts of interest and author oontribu—
`tions are found at the end of this
`article
`
`Corresponding author Stephen Chia,
`MD, Division of Medical Oncology, Brit-
`ish Columbia Cancer Agency, University
`of British Columbia, 600 West 10“
`Avenue, Vancouver, B C Canada, V5Z
`4E6, email 5chia@bccancer bc ca
`© 2008 by American Society of Clinical
`Oncology
`073Z—183X/08/26104664/$20 00
`DOI 101200/JCO 2007 13 5822
`
`Double—Blind, Randomized Placebo Controlled Trial of
`
`Pulvestrant Compared With Exemestane After Prior
`Nonsteroidal Aromatase Inhibitor Therapy in
`Postmenopausal Women With Hormone
`Receptor—Positive, Advanced Breast Cancer: Results
`From EFECT
`
`Stephen Chia, William Gradishar, Louis Mauriac, Jose Bines, Frederic Amant, Miriam Federico, Luis Fein,
`Gilles Romieu, Aman Buzdar, John F.R. Robertson, Adam Brufsky, Kurt Possinger, Pamela Rennie,
`Francisco Sapunar, Elizabeth Lowe, and Martine Piccart
`
`ABSTRACT
`
`Purpose
`The third—generation nonsteroidal aromatase inhibitors (Als) are increasingly used as adjuvant and
`first—line advanced therapy for postmenopausal, hormone receptor—positive (HR+) breast cancer.
`Because many pa ients subsequently experience progression or relapse, it is important to identify
`agents with efficacy after Al failure.
`Materials and Methods
`is a randomized, double—blind,
`Evaluation of Fas ode>< versus Exemestane Clinical Trial (EFECT)
`placebo controlled, multicenter phase III trial of fulvestrant versus exemestane in postmenopausal
`women with HR-- advanced breast cancer (ABC) progressing or recurring after nonsteroidal Al.
`The primary end point was time to progression (TTP). Afulvestrant loading—dose (LD) regimen was
`used: 500 mg in ramuscularly on day 0, 250 mg on days 14, 28, and 250 mg every 28 days
`thereafter. Exemestane 25 mg orally was administered once daily.
`Results
`A total of 693 wocnen were randomly assigned to fulvestrant (n = 351) or exemestane (n = 3-2)
`Approximately 60% of patients had received at least two prior endocrine therapies. Median "TP
`was 3.7 months "n both groups (hazard ratio = 0.963; 95% CI, 0.819 to 1.133; P = .6531). "he
`overall response rate (7.4% i/6.7%; P = .736) and clinical benefit rate (32.2% i/31.5%; P = .853)
`were similar between fulvestrant and exemestane respectively. Median duration of clinical benefit
`was 9.3 and 8.3 'nonths, respectively. Both treatments were well tolerated, with no significant
`differences in the incidence of adverse events or quality of life. Pharmacokinetic data confirm that
`steady—state was reached within 1 month with the LD schedule of fulvestrant.
`Conclusion
`Fulvestrant LD and exemestane are equally active and well—tolerated in a meaningful proportion of
`postmenopausal women with ABC who have experienced progression or recurrence during
`treatment with a nonsteroidal Al.
`
`J Clin Oncol 26.'1664—7670. © 2008 by American Society of Clinical Oncology
`
`Hormone receptor—positive (HR+) breast cancer is
`the most common presentation of breast cancer to-
`day} In postmenopausal HR+ breast cancer, there
`are several hormonal therapeutic options available,
`of which the classes of selective estrogen receptor
`modulators (SERMS) and aromatase inhibitors
`(Als) have been studied extensively and are standard
`therapeutic options in breast cancer.
`
`The third—generation Als consists of both non-
`steroidal (anastrozole, letrozole) and steroidal (ex-
`emestane) inhibitors. The nonsteroidal inhibitors
`block the peripheral conversion of androgens to
`estrogens by inhibiting the heme porphyrin por-
`tion of aromatase. In contrast, the steroidal Als
`act by binding irreversibly to the androgen bind-
`ing site and are structurally different from the
`nonsteroidal Als. As first—line therapy in HR+,
`postmenopausal advanced breast cancer (ABC),
`
`1554
`
`© 2008 by American Society of Clinical Oncology
`Information downloaded from jco.ascopubs.org and provided by at AZ Library
`on September29, 2010 from 193.132.159.169
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Ex. 2062 p. 1
`Mylan Pharms. Inc. v. AstraZeneca AB IPR2016-01324
`
`

`
`Randomized Trial of Fulvestrant v Exemestane in Advanced Breast Cancer
`
`the AIs have demonstrated superiority to tamoxifen for response rates
`and time to progression.“ Furthermore, the AIs, either up front or
`after tamoxifen, have been clearly established as adjuvant hormonal
`options in early—stage HR+ postmenopausal breast cancer.5’1° Unfor-
`tunately, the vast majority of patients diagnosed with ABC will even-
`tually progress during treatment with a specific therapy, and a
`significant proportion of patients with early stage—breast cancers will
`relapse. Thus, additional therapeutic agents are required to continue
`to treat the disease at time of progression/relapse.
`Fulvestrant is a novel estrogen—receptor (ER) antagonist that,
`unlike tamoxifen, is devoid of any agonist activity.‘11 On binding to the
`ER, fulvestrant induces a rapid degradation and loss of ER and the
`progesterone receptor (PgR).12'13 Several large phase III trials have
`demonsfirated significant activity for fulvestrant in the treannent of
`HR+ ABC, with similar efficacy to that of anastrozole and
`tamoxifen.14’16 Furthermore, activity has been seen in phase II trials of
`fulvestrant after progression during treatment with a nonsteroidal AI,
`with clinical benefit rates (CBRs) of 30% to 35°/0.1748
`Exemestane is a steroidal—based AI, with modest androgenic ac-
`tivity.” Exemestane has been studied in a phase II trial after docu-
`mented progression during treatment with a nonsteroidal AI, and
`showed a 20% clinical benefit rate.2° Because of the lack of random-
`ized clinical trial data and the prevalence of patients exposed to non-
`steroidal AIs, the Evaluation of Faslodex versus Exemestane Clinical
`Trial (EFECT) was undertaken to address this specific question of
`which hormonal agent to consider first after progression during treat-
`ment with a nonsteroidal AI.
`
`
`
`Study Design
`EFECT is a randomized, double blind, doi1ble—dummy, phase III inter-
`national trial designed to compare the efficacy and tolerability of a loading-
`dose (LD) schedule of fulvestrant to exemestane in postmenopausal women
`with HR+ ABC with disease progression after prior nonsteroidal AI therapy.
`
`Patient Population
`All patients were postmenopausal women with incurable locally ad-
`vanced or metastatic breast cancer whose disease had relapsed during
`treatment with (or within 6 months of discontinuation OD an adjuvant
`nonsteroidal AI, or whose advanced disease progressed during treatment
`with a nonsteroidal AI. Patients were categorized as Al sensitive if the
`investigator determined that the patient had a complete response (CR),
`partial response (PR), or stable disease (SD) for at least 6 months during
`treatment with the AI for ABC. All other patients, including all those who
`received the AI as adjuvant therapy, were defined as AI resistant.
`Inclusion onto the trial required women to be postmenopausal (2 60
`years old, or age 2 45 years with amenorrhea for > 12 months or follicle
`stimulating hormone levels within postmenopausal range, or prior bilateral
`oophorectomy). Other inclusion criteria included HR+ (ER and/or PgR)
`disease as determined locally, WHO performance status of 0 to 2, life expect-
`ancy of at least 3 months and the presence of at least one measurable or
`assessable (nonmeasurable) lesion. Initially, the protocol required that all
`patients have at least one measurable lesion by Response Evaluation Criteria in
`Solid Tumors (RECIST) criteria, but subsequently the protocol was amended
`to include patients with bone only (lytic or mixed) metastatic lesions. Up to
`one prior chemotherapy regimen for the treatment ofABC was allowed.
`Exclusion criteria included life threatening metastatic visceral disease,
`brain or leptomeningeal metastases, prior exposure to either fulvestrant or
`exemestane, extensive radiation or cytotoxic therapywithin the last 4 weeks, or
`a history of bleeding diathesis or need for long—term anticoagulation.
`
`All women provided written informed consent before registration on
`trial. The study was conducted in accordance with the ethical principles that
`originated in the Declaration ofHelsinki and with local Research Ethics Board
`approval at each participating center.
`Trial Treatments
`Fulvestrant 250 mg/5 mL (X 2) as an intramuscular injection or a match—
`ing 5 mL (X 2) oily excipient placebo was injected into each buttock (500 mg or
`matching placebo) on day 1, followed by a single injection of 250 mg fulves-
`trant/placebo at day 14 and again on day 28. Treatment after day 28 was every
`28 days ( : 3 days) thereafter. Exemestane 25 mg and a matching placebo were
`to be taken orally once daily.
`Patients continued treatment until objective disease progression or other
`events that required withdrawal. There was no built in crossover design in this
`trial. Thereafter, patients were followed up until death. Patients who withdrew
`from trial treatment before progression were followed up for response until
`progression and death.
`All patients were seen by a physician monthly until month 6, and every 3
`months thereafter. Tumor assessment was performed every 8 weeks from
`baseline until month 6, and then every 3 months until disease progression.
`In a subset of 60 patients (30 in each treatment group) pharmacokinetic
`samples were collected at specified time intervals to confirm whether the LD
`regimen would achieve steady—state earlier than that seen previously with a
`dose of fulvestrant 250 mg every 28 days.
`
`Statistical Analysis
`The primary end point of the study was time to disease progression
`(TTP). Secondary end points included objective response (OR) rate, CBR,
`duration of response, time to response, overall survival, and tolerability. The
`trial was designed to detect superiority offulvestrant compared with exemes-
`tane in terms of TTP. The final analysis was scheduled to take place when 580
`progression events (ie, objective disease progression or death) had occurred
`across both treatment groups This would provide 90% power to detect a
`hazard ratio of 1.31 or greater, or of 0.76 or less for fulvestrant treatment
`compared with exemestane treatment, at a two—sided significance level of5%.
`To achieve the required number of events, it was planned to recruit 660
`patients (330 in each treatment group). Data for the efficacy parameters were
`analyzed and summarized on an intention—to—treat basis.
`TTP
`
`TTP was defined as the number of days from the date of random assigr
`ment until the date ofobjective disease progression, as per RECIST criteria If
`the patient died without documented disease progression, and the date of
`death was no more than 6 months from the last disease assessment per RE—
`CIST, then death was regarded as a progression event. For patients who had
`not experienced disease progression at the time of data cutoff, data were right
`censored to the date ofthe last RECIST assessment.
`The primary analysis for TTP was the unstratified log—rank test. The
`secondary analysis used the Cox proportional hazards regression model and
`included the following six baseline covariates: age (< 65 1/ 2 65 years), number
`ofprior hormonal therapies (1 v 2 2), receptor status (both ER+ and PgR+ 1/
`only one receptor positive), visceral involvement (yes 1/ no), presence of mea—
`surable disease compared with nonmeasurable disease, and AI sensitive versus
`AI resistant. The treatment effect was estimated using the hazard ratio of
`fulvestrant to exemestane, together with the 95% CI and P value. A global
`interaction test using a 1% significance level was performed to determine
`whether the overall treatment benefit was consistent across each of the six
`covariates. TTP was also summarized using Kaplan—Meier curves for each
`treatment group and the median TTP was calculated.
`Overall Survival
`Time to death was to be analyzed when more than 50% ofthe patients
`had died across both treatment groups. At the time of data analysis, only
`34% of patients had died, and therefore no formal statistical analyses
`were conducted.
`
`Best OR and CBR
`An OR was defined as a patient having a best overall response of either
`CR or PR with confirmation criteria as per RECIST. A patient with clinical
`
`www.jcc.0rg
`
`© 2008 by American Society of Clinical Oncology
`on September 29, 2010 from 193.132.159.169
`Information downloaded from jco.ascopubs.org and provided by at AZ Library
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`1665
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`AstraZeneca Ex. 2062 p. 2
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`

`
`Chia et al
`
`benefit (CB) was defined as a patient having a best overall response ofa CR, PR,
`or SD for at least 24 weeks. SD was defined, as per RECIST criteria, as neither
`achieving a PR nor progressive disease at week 24 or later.
`
`Duration of Response
`Duration ofresponse (DOR) was evaluated only for patients who had an
`OR, and was defined as the nuinber Ofdays from date of raiidoiii assignniciit
`until the day On which disease progression or death resulting from any cause
`was first observed.
`
`Quality of Life
`Quality of life (QOL) was assessed using the Functional Assessment of
`Cancer Therapy—Endocrine Symptom (FACT—ES) instrument. The analysis
`was undertaken using both the FACT—ES and Trial Outcome Index (TOI). The
`difference between the two treatment groups in FACT—ES and T01 over time
`was compared using a generalized linear mixed model, with the Restricted
`Maximum Likelihood option, including the same six covariates as for TTP.
`
`Tolerability
`All safety data were listed a.nd summarized according to the treatment
`received. Adverse events (AEs) were presented using MedDRA terminology.
`Eight AE categories considered relevant to endocrine therapy were predefined
`for statistical analysis. The analysis ofthe predefined AEs was performed using
`a two—sided Fisher’s exact test at the 5% significance level.
`
`Patients
`
`A total of693 women across 138 centers worldwide were randomly
`assigned to either fulvestrant (n = 351) or exemestane (n = 342) from
`August 2003 to November 2005. The accountability of all patients
`randomly assigned is seen in Figure A1 (online only). Baseline char-
`acteristics between the two randomly assigned treatments are outlined
`in Table 1. Overall, the groups were well balanced, except that the
`fulvestrant cohort had a slightly greater number of women with ER+
`and PgR+ tumors (67.5%) versus the exemestane cohort (56.4%).
`Approximately 60% of participants had two or more prior lines of
`hormonal therapy. Approximately 60% ofpatients in both groups had
`either a response (CR or PR) or SD lasting at least 6 months during
`treatment with the prior nonsteroidal A1 for ABC (termed AI sensi-
`tive) as determined by the individual investigator. Only 10% of
`Women enrolled received their previous AI as adj uvant therapy. The
`median follow—up for all patients alive is approximately 13 months.
`
`Efficacy
`The primary end point of this study was TTP. At the time of analy-
`sis, 821% (n = 288) ofthe fulvestrant group and 87.4% (n = 299) of
`the exemestane group had experienced a defined progression event.
`The median time to progression (Fig 1) in both groups was 3.7 months
`(P = .65) with a hazard ratio of 0.93 (95% CI, 0.819 to 1.133). The
`adjusted hazard ratio for the specified covariates was 0.968 (P = .70)
`with the 95% CI at 0.822 to 1.141. In an investigation of the consis-
`tency of treatment effect across the predefined covariates, there were
`no statistically significant differences (Fig 2).
`
`OR Rate and CBR
`
`A total of 540 patients (270 in each arm) had measurable disease
`by RECIST criteria at trial entry. Overall, 20 patients in the fulvestrant
`arm (7.4%) and 18 patients in the exemestane arm (6.7%) had a doc-
`umented response (odds ratio = 1.12; 95% CI, 0.578 to 2.186;
`P = .736). The CBR was 32.2% and 31.5% in the fulvestrant and
`
`exemestane arms, respectively (odds ratio = 1.03; 95% CI, 0.72 to
`1.487; P = .853). Of note, in the cohort of patients with visceral
`involvement, the CBR was 29% and 27% in the fulvestrant and ex—
`emestane arms, respectively.
`The median DOR, as measured from the date of random assign-
`ment, was 13.5 months in the fulvestrant group and 9.8 months in the
`exemestane group (Fig 3); median DOR as measured from the date of
`first response was 7.5 months for fulvestrant compared with 5.5
`months for exemestane.
`
`Pharmacokinetics
`
`The pharmacokinetic (PK) substudy results mirrored those from
`modeling studies and demonstrated a much faster time to steady—state
`levels with the LD schedule of fulvestrant, compared to prior PK
`studies of the 250 mg monthly dose. Median time to steady state was
`achieved within 28 days with the LD regimen, compared with 3 to 6
`months with the 250—mg monthly dose” (Fig 4).
`
`Tolerability
`Both fulvestrant and exemestane were well tolerated in this study
`(Table 2), with only 2% of fulvestrant—treated patients and 2.6% of
`exemestane—treated patients withdrawing because of an adverse event
`(AE). Drug—related serious AEs (SAEs) were rare, occurring in 1.1%
`and 0.6% of each arm, respectively. No patient died as a result of a
`drug—related AE. The incidence of venous thromboembolic events in
`the fulvestrant and exemestane arms was 1.1% and 0.9%, respectively.
`
`QOL
`
`QOL was measured with two instruments in this study, the
`FACT—ES and TOI. A graph Of the mean TOI Over time is shown in
`Figure A2 (online only). The mean difference across both instruments
`was not significant, demonstrating that QOL was not statistically dif-
`ferent between either treatment arms.
`
`DISCUSSION
`
`EFECT is not only one ofthe largest published trials to date comparing
`hormonal therapies in HR+ ABC, but also one of the first to specifi-
`cally address the optimal agent to use in sequence immediately after
`progression of a nonsteroidal AI. EFECT confirmed efficacy for both
`fulvestrant and exemestane in this setting, with clinical benefit rates of
`approximately 32% and a median TTP of 3.7 months for both agents.
`The observed durations of response with fulvestrant and exemestane
`(13.5 V 9.8 months, respectively) and durations of clinical benefit (9.3
`v 8.3 months, respectively), are encouraging for a population of pa-
`tients with relapsed disease after AI treatment. Furthermore, results
`from EFECT support the concept that patients achieving SD lasting at
`least 24 weeks have similar outcomes compared with patients obtain-
`ing a response (Fig A3, online only), even in this previously horrnon—
`ally treated population.
`It is interesting, that for more than 60% ofwomen in EFECT, the
`treating oncologist identified the patient as A1 sensitive, but this was
`neither confirmed centrally or by RECIST criteria. Yet by 6 months,
`approximately 70% of trial subjects had experienced disease progres-
`sion. This indicates that approximately two thirds of patients did not
`benefit from either hormonal agent, implying that the majority of
`
`1666
`
`© 2008 by American Society of Clinical Oncology
`on September 29, 2010 from 193.132.159.169
`Information downloaded from jco.ascopubs.org and provided by at AZ Library
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`Astrazeneca Ex. 2062 p. 3
`
`

`
`Randomized Trial of Fulvestrant v Exemestane in Advanced Breast Cancer
`
`Table 1. Baseline Patient and Disease Characteristics
`
`Fulvestrant (n : 351)
`
`Exemestane (n : 342)
`
`Characteristic
`
`Age, years
`Median
`Range
`Age group, years
`< 65 (adult)
`2 65 (elderly)
`Prior treatments
`Adluvant endocrine therapy*
`Endocrine therapy for advanced diseaset
`1 prior endocrine therapy
`> 1 prior endocrine therapy
`Adluvant chemotherapy
`Chemotherapy for advanced disease
`Adluvant radiotherapy
`Radiotherapy for advanced disease
`Other breast cancer treatment
`Al—sensitive disease
`Al—resistant disease
`Disease stagei
`Locally advanced
`Metastatic
`Sites of metastases§
`Bone
`Lung
`Liver
`Lymph nodes
`Skin/soft tissue
`Other
`Visceral involvement
`Yes
`No
`Hormone receptor status
`ER+ and/or PgR+
`ER+ and PgR+
`Otherll
`WHO performance status
`0 (normal activity)
`1 (restricted activity)
`2 (in bed 2 50% of the time)
`Measurable disease
`Yes
`No
`
`No.
`
`89
`62
`
`217
`313
`45
`206
`47
`87
`90
`29
`35
`224
`27
`
`8
`342
`
`236
`121
`109
`104
`71
`48
`
`197
`154
`
`345
`237
`6
`
`194
`133
`24
`
`270
`81
`
`63
`3888
`
`%
`
`53.8
`46.2
`
`61.8
`89.2
`41.3
`58.7
`41.9
`24.8
`54.1
`36.8
`10.0
`63.8
`36.2
`
`2.3
`97.4
`
`67.2
`34.5
`31.1
`29.6
`20.2
`13.7
`
`56.1
`43.9
`
`98.3
`67.5
`1.7
`
`55.3
`37.9
`6.8
`
`76.9
`23.1
`
`No.
`
`94
`48
`
`99
`294
`47
`95
`68
`74
`71
`42
`29
`210
`32
`
`10
`332
`
`227
`24
`10
`17
`58
`56
`
`98
`44
`
`336
`93
`6
`
`81
`49
`12
`
`270
`72
`
`63
`32—91
`
`%
`
`56.7
`43.3
`
`58.2
`86.0
`43.0
`57.0
`49.1
`21.6
`50.0
`41.5
`8.5
`61.4
`38.6
`
`2.9
`97.1
`
`66.4
`36.3
`32.2
`34.2
`17.0
`16.4
`
`57. 9
`42.1
`
`98.2
`56.4
`1.8
`
`52.9
`43.6
`3.5
`
`78.9
`21.1
`
`Abbreviations: ER, estrogen receptor; PgR, progesterone receptor; Al, aromatase inhibitor.
`*Thiity—eight patients (10.8%) in the fulvestrant group and 48 (14.0%) patients lh the exemestane group received their last non—steroidal /-\l therapy as adjuvant therapy.
`tThree hundred ten patients (88.3%) in the fulvestrant group and 293 (85.7%) in the exemestane group received their last non—steroidal Al therapy for advanced disease.
`iDisease stage was unknown in one patient in the fulvestrant group (patients subsequently classed as a violator).
`§Patients could have > 1 site of metastases.
`llOne patient in the fulvestrant group and five patients lit the exemestane group had no evidence of meeting the criterion for ER of PgR positivity at baseline and
`so were classed as violators. The remaining five patients in the fulvestrant group and one patient in the exemestane group did not meet this criterion at baseline
`but met it previously and so weren't considered violators.
`
`patients enrolled on EFECT had hormone—insensitive disease. In ad-
`dition, in close to 60% of women, the study hormonal agent was
`administered as third—line or greater therapy. All of these factors could
`have contributed to a less—than—optimal clinical eflicacythan had been
`hoped for, and may have undermined the power ofthe study. Indeed,
`in a retrospective analysis looking at TTP in patients who received
`fulvestrant or exemestane as second—line treatment and were deemed
`
`to be sensitive to the prior nonsteroidal Al, the curves do appear to
`
`separate in favor of fulvestrant (hazard ratio = 0.73; 99.8% CI, 0.45 to
`1.19; Fig A4, online only). However, the number of patients contrib-
`uting to this analysis is small (n = 190), and the results are nonsignif—
`icant as well as being retrospectively derived.
`When used earlier in the hormonal treatment sequence of ER+
`ABC, fulvestrant has demonstrated significantly better clinical out-
`comes than those seen here. As first line therapyfulvestrant was shown
`to be similar to tamoxifen, with a clinical benefit rate of 57% and a
`
`www.jcc.0rg
`
`© 2008 by American Society of Clinical Oncology
`on September 29, 2010 from 193.132.159.169
`Information downloaded from jco.ascopubs.org and provided by at AZ Library
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`1667
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`Astrazeneca Ex. 2062 p. 4
`
`

`
`Chia et al
`
`Table Z. Most Commonly Occurring Treatment—Related Adverse Events
`(> 2% incidence in either treatment group)
`Fulvestrant
`(n : 351)
`
`Exemestane
`(n : 340)
`
`Adverse Event
`
`njection-site pain
`-lot flashes
`ausea
`Zatigue
`yalgia
`Arthralgia
`Diarrhea
`Asthenia
`njection-site reaction
`Alopecia
`-leadache
`Anorexia
`Dyspepsia
`Pain in extremity
`
`No.
`
`33
`31
`24
`22
`14
`13
`12
`11
`8
`8
`7
`7
`3
`1
`
`%
`
`9.4
`8.8
`6.8
`6.3
`4.0
`3.7
`3.4
`3.1
`2.3
`2.3
`2.0
`2.0
`0.9
`0.3
`
`No.
`
`28
`39
`27
`34
`14
`19
`10
`7
`7
`5
`10
`7
`7
`8
`
`%
`
`8.2
`11.5
`7.9
`10.0
`4.1
`5.6
`2.9
`2.1
`2.1
`1.5
`2.9
`2.1
`2.1
`2.4
`
`median TTP of 8.2 months.16 In a combined analysis of two multi-
`center trials as either first— or second—line therapy ir1 ABC compared
`with anastrozole, fulvestrant demonstrated a clinical benefit rate of
`43.5% and a median TTP of 5.5 months.“ Interestingly in a relatively
`small phase II trial of fulvestrant administered immediately after pro-
`gression during treatment with an AI, in the subset of patients whose
`only prior hormonal therapy was an Al, the clinical benefit rate was
`52.4% (95% CI, 32.8% to 71.4%).17 Of note, in EFECT, there was no
`difference in either CBR or median TTP between the predefined
`subgroup ofpatients exposed to only one prior hormonal agent or two
`or more prior hormonal agents.
`As a pure ER antagonist, fulvestrant is in a distinct class of its own
`in regard to its mechanism of action. When fulveshrant binds to the
`
`coco..
`“F:
`. 9U3(/3cu..
`cno..
`Q.
`V?a.«:cl:2»:(5Q.-._
`c>
`:o
`'4:..
`oQ.o..
`Q.
`
`? Fulvestrant
`' ' ' ' Exemestane
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`700
`
`800
`
`ER+/PgR+
`Not ER+/PgR+
`With
`Without
`Sensitive
`Resistant
`Yes
`No
`< 65 years
`2 65 years
`1 prior
`2 2 prior
`
`
`
`Receptor status
`
`Visceral involvement
`
`Al sensitive/resistant
`
`Measurable disease
`
`Age
`
`No. of prior hormonals
`
`All patients
`
`1.25 1.51.75
`1
`0.80
`0.60
`0.40
`Hazard ratio (fulvestrant vexemestane) and 95% Cl
`
`
`Fig 2. Forest plot of effect of predefined oovariates on time to progression. ER,
`estrogen receptor; PgFl, progesterone receptor.
`
`ER, it results in reduced nuclear uptake ofthe ER—fulvestrant complex,
`prevention of the ER binding to the estrogen—responsive genes, and,
`ultimately, downregulation of ER levels.23'27 Given a distinctly differ-
`ent mechanism of action, it was rational to assume that a substantial
`degree of clinical activity would be seen with fulvestrant in this setting.
`The clinical activity seen with fulvestrant ir1 EFECT is similar to those
`in a previously published eXperience.13’28’3O
`\/Vhat perhaps was surprising from this study was the clinical
`activity seen with exemestane in this setting: The CBR of 31.5% was
`higher than the 20% CBR reported in a phase II trial, even though the
`median TTP was similar.” EFECT reinforces the notion of incom-
`
`plete resistance between the nonsteroidal and steroidal Als. This in-
`complete cross—resistance is likely not a result of differences in the
`degree of aromatase inhibition between the AIs.31'32 It may be caused
`by the androgenic effects of exemestane.19'2O
`Some questions still remain unanswered today ir1 regard to the
`optimal use of fulvestrant m the treatment of breast cancer. A higher
`dose is currently being investigated in several trials. The combination
`
`1.0
`0.9
`0.8
`0.7
`0.6
`0.5
`0.4
`0.3
`0.2
`0.1
`
`0
`
`
`
`ProportionofPatientsResponding
`
`
`
`j Fulvestrant
`-- - - Exemestane
`
`-------------------- --
`
`100
`
`200
`
`300
`
`400
`
`500
`
`600
`
`700
`
`800
`
`Duration of Response (days)
`
`50 100 150 200 250 300 350 400 450 500 550 600 650 700
`0
`Days
`20
`20
`20
`15
`13
`10
`9
`8
`3
`1
`0
`O
`O
`0
`20
`Fulvestrantatrisk
`Exemestaneatrisk181818171512
`9
`5
`5
`4
`3
`3
`3
`3
`
`2 F
`
`l<aplan—Meier estimates for duration of response (DOR; from random
`ig 3.
`assignment). Estimated median DOR for patients receiving fulvestrant was 13.5
`months, compared with 9.8 months for patients receiving exemestane.
`
`
`
`Time to Progression (days)
`
`50 100 150 200 250 300 350 400 450 500 550 600 650 700
`0
`Days
`351 301 191 127 89 67
`46
`29
`23
`13
`10
`4
`4
`2
`0
`Fulvestrantatrisk
`Exemestaneatrisk 342 305184130 86 56
`37
`24
`21
`13
`10
`8
`8
`6
`2
`
`Fig 1. Kaplan—Meier estimates for time to progression (TTP). Estimated median
`Tl'P for patients receiving fulvestrant was 3.7 months, compared with 3.7
`months for patients receiving exemestane (hazard ratio : 0.963; 95% CI, 0.819
`to 1.133; P: .6531).
`
`1663
`
`© 2008 by American Society of Clinical Oncology
`on September 29, 2010 from 193.132.159.169
`Information downloaded from jco.ascopubs.org and provided by at AZ Library
`Copyright © 2008 American Society of Clinical Oncology. All rights reserved.
`
`JOURNAL or CLINICAL ONCOLOGY
`
`Astrazeneca Ex. 2062 p. 5
`
`

`
`Randomized Trial of Fulvestrant v Exemestane in Advanced Breast Cancer
`
`1 Population predicted
`I Observed
`
`Time (days)
`PredictedConcentration(ng/mL)
`
`
`
`Fig 4. Observed and population—predicted pharmacokinetic profile for the
`fulvestrant loading—dose regimen (500 mg day 0, 250 mg day 14, 250 mg day 28,
`and then 250 mg/month thereafter).
`
`of fulvestrant and an AI compared with an AI alone is another ap-
`proach being studied in several clinical trials. The premise for the
`combination is that fulvestrant may be more effective in a low-
`estrogen environment, which is supported by preclinical data.”
`In conclusion, EFECT has demonstrated clinical activity for both
`LD fulvestrant and exemestane in a meaningful proportion of post-
`menopausal HR+ ABC after progression during treatment with a
`nonsteroidal AI. Both agents were well tolerated, with a similar inci-
`dence of reported adverse events and quality oflife. There were also no
`apparent preliminary differences in the proportion of women receiv-
`ing chemotherapy (approximately 50%) as the first subsequent sys-
`temic therapy after trial treatment failure. The pros and cons of these
`two agents with their different mechanisms of action, costs, and
`modes of delivery should be discussed with patients because there are
`preferences to both intramuscular and oral agents.“
`
`AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS
`
`OF INTEREST
`
`Although all authors completed the disclosure declaration, the following
`author(s) indicated a financial or other interest that is relevant to the subject
`matter under 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: Pamela Rennie, AstraZeneca (C);
`Francisco Sapunar, AstraZeneca (C); Elizabeth Lowe, AstraZeneca (C)
`Consultant or Advisory Role: Stephen Chia, Advisory board for Astra
`Zeneca (C); William Gradishar, AstraZeneca (C), Pfizer (C); Louis
`Mauriac, Novartis (C), AstraZeneca (C); Iohn F.R. Robertson,
`AstraZeneca (C), Pfizer (C); Martine Piccart, AstraZeneca (C), Pfizer
`(C), Novartis (C) Stock Ownership: Pamela Rennie, AstraZeneca;
`Francisco Sapunar, AstraZeneca; Elizabeth Lowe, AstraZeneca
`Honoraria: Stephen Chia, Honoraria for CME talks by Astra Zeneca;
`Louis Mauriac, Novartis, AstraZeneca; lose Bines, AstraZeneca; Aman
`Buzdar, AstraZeneca, Eli Lilly, Roche, Genetech, Pfizer, Taiho; Iohn F.R.
`Robertson, AstraZeneca; Adam Brufsky, AstraZeneca; Kurt Possinger,
`AstraZeneca Research Funding: Stephen Chia, Investigator initiated
`funding with Astra Zeneca; William Gradishar, AstraZeneca; Iohn F.R.
`Robertson, AstraZeneca; Martine Piccart, Novartis, Pfizer Expert
`Testimony: None Other Remuneration: Iohn F.R. Robertson,
`AstraZeneca, Pfizer; Kurt Possinger, AstraZeneca
`
`AUTHOR CONTRIBUTIONS
`
`Conception and design: Stephen Chia, Aman Buzdar, Pamela Rennie,
`Francisco Sapunar
`Provision of study materials or patients: Stephen Chia, William
`Gradishar, Louis Mauriac, lose Bines, Frederic Amant, Miriam Federico,
`Luis Fein, Gilles Romieu, Aman Buzdar, Iohn F.R. Robertson, Adam
`Brufsky, Kurt Possinger, Martine Piccart
`Collection and assembly of data: Stephen Chia