Review
`
`@CI'OSSMaIk
`A Good Drug Made Better: The Fulvestrant
`Dose—Response Story
`
`John ER. Robertson,1 Justin Lindemann,2 Sally Garnett,2 Elizabeth Anderson,3
`Robert 1. Nicholson,4 Irene Kuter,5 Julia M.W. Gee4
`
`Abstract
`
`Sequential use of endocrine therapies remains the cornerstone of treatment for hormone receptor-positive advanced
`breast cancer, before the use of cytotoxic chemotherapy for unresponsive disease. Fulvestrant is an estrogen receptor
`(ER) antagonist approved for the treatment of postmenopausal women with ER+ advanced breast cancer after failure
`of prior antiestrogen therapy. Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was
`revised to 500 mg (500 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progresslon—free
`survival versus fulvestrant 250 mg. We have reviewed the dose—dependent effects of fulvestrant, both from a retro—
`spective combined analysis of dose-dependent reduction of tumor biomarkers in the presurgical setting (3 previously
`reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57)
`and from a review of clinical studies for advanced breast cancer in postmenopausal women. Analysis of presurgical
`data revealed a consistent dose-dependent effect for fulvestrant on tumor biomarkers, with increasing fulvestrant
`dose resulting in greater reductions in ER, progesterone receptor, and Ki67 labeling index. The dose-dependent
`biological effect corresponds with the dose-dependent clinical efficacy observed in the treatment of advanced
`breast cancer after failure of prior antiestrogen therapy. Although it remains to be determined in a phase III trial, cross-
`trial comparisons suggest a dose-dependent relationship for fulvestrant as first-line treatment for advanced breast
`cancer. Overall, biological and clinical data demonstrate a strong dose-dependent relationship for fulvestrant, sup—
`porting the efficacy benefit seen with fulvestrant 500 mg over the 250 mg dose.
`
`
`Clinical Breast Cancer, Vol. 14, No. 6, 381—9 © 2014 Elsevier Inc. All rights reserved.
`
`
`Keywords: Advanced breast cancer, Endocrine therapy, Estrogen receptor, Postmenopausal, Tumor biomarkers
`
`Introduction
`
`Endocrine therapies provide effective and well—tolerated treat—
`ments for postmenopausal women with hormone receptor—positive
`breast cancer (estrogen receptor—positive [ER+] and/or progester—
`one receptor—positive [PgR+]), both in the adjuvant setting1 and for
`the treatment of advanced disease.Z
`
`Aromatase inhibitors (A15), which block production of estrogen
`through their
`interaction with the estrogen—producing enzyme
`
`1Graduate Entry Medicine and Health School (GEMS), University of Nottingham,
`Derby, UK
`2AstraZeneca, Alderley Park, Macclesfield, UK
`5Fornzerly AstraZeneca, Alderley Park, Macclesfield, UK
`4Breast Cancer Molecular Pharmacology Group, School of Pharmacy and
`Pharmaceutical Sciences, Cardiff University, Cardiff, UK
`5Massachusetts General Hospital, Boston, MA
`
`Submitted; Mar 28, 2014', Revised: Jun 10, 2014; Accepted: Jun 17, 2014; Epub:
`Jun 24, 2014
`
`Address for correspondence: John F. R Robertson, MD, Division of Medical
`Sciences 8c Graduate Entry Medicine, School of Medicine, Faculty of Medicine 8x
`Health Sciences, University of Nottingham, Royal Derby Hospital Centre, Derby
`DE22 3DT, UK
`Fax: 744 (0)1332 724880; e-mail contact: john.i‘obertson@nottinghamac.uk
`
`aromatase, have demonstrated increased efficacy compared with the
`ER antagonist tamoxifen in postmenopausal women as firsteline
`endocrine treatment for ERnL advanced breast cancers'6 and as
`
`therapy for postmenopausal women with early breast
`adjuvant
`Canceri’q As such, AIS are now considered the standard of care as
`adjuvant endocrine therapy for postmenopausal women with hor—
`mone receptor-positive breast cancer.
`that
`is an ER antagonist
`Fuivestrant, a 17B—estradiol analog,
`competes with endogenous estrogen for binding to the ER10
`However, unlike
`tamoxifen, which exhibits partial
`estrogen
`agonist activity, fulvestrant has no recognized estrogenic effect. It is
`thought that this is due to the fact that on binding to the ER,
`fulvestrant induces a conformational change, leading to degradation
`of the ER and complete inhibition of ER signaling in animal
`models.“
`
`Unfortunately, resistance to endocrine therapy will eventually
`develop, Although optimal sequencing of appropriate hormone
`therapies is the ideal approach, few randomized controlled trials
`have directly compared the effects of changing the order in which
`2 different agents are given.2 Furthermore, the paucity of data led
`
`1526-8209/3 - see fronfmnlfer © 2014 Elsevier Inc. All rights reserved.
`hilp://dx.doi.org/10.1016/i.c|bc.2014.06.005
`
`Clinical Breast Cancer December 2014
`
`381
`
`AstraZeneca Exhibit 2071 p. 1
`InnoPharrna Licensing LLC v. AstraZeneca AB IPR2017-00904
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01910
`
`

`

`Fulvestrant Dose—Response Story
`
`the authors of a recent review to conclude that no definitive rec—
`
`ommendations could be made regarding the sequencing of endo—
`crine therapies in patients with advanced breast cancer, and that
`patients should receive the most efficacious treatment
`in that
`7
`setting, while also considering specific side effect
`issues for that
`patient.
`Early preclinical data demonstrated a lack of cross—
`reactivity between fulvestrant and tamoxifen, with fulvestrant
`inhibiting the growth of tamoxifen-resistant tumors.12 Similarly in
`the clinical setting, many postmenopausal women with advanced
`breast cancer
`that
`responded to first—line fulvestrant
`remained
`1 "
`4 Furthermore,
`responsive
`to further
`endocrine
`treatment.13 ‘
`tumors that have responded to prior treatment with an anties-
`trogenls‘16 or an A117“18 may retain sensitivity to subsequent
`treatment with fulvestrant.
`
`Presurgical studies provide the opportunity to perform a detailed
`analysis and comparison of biomarker expression and biomarker
`response with various experimental drug treatments. As an example,
`the selective ER modulator tamoxifen was reported to increase PgR
`levels as a result of its partial estrogen agonist activity.” However,
`downregulation of ER with fulvestrant leads to reduction in PgR
`protein levels through disruption of ER—dependent
`transcription
`of the PgR gene, as shown in a randomized comparison with
`tamoxifen, highlighting the distinct mechanisms of action of these
`2 agents.20 Reduction in Ki67 expression, a nuclear antigen and
`marker of cell proliferation, is reported to correlate with treatment
`response to endocrine therapy in ER+ breast cancer,21 and Ki67 in
`short—term neoadjuvant studies has been shown to predict outcome
`in long-term adjuvant trialsll
`Clinical
`efficacy of fulvestrant was demonstrated in post-
`menopausal women with advanced breast cancer that had pro—
`7%1'
`6“" 4 and was
`gressed or recurred on prior antiestrogen therapy1
`originally approved at a monthly dose of 250 mg. However, a dose-
`dependent
`effect was
`subsequently shown, with improved
`progression—free survival (PFS) for fulvestrant 500 mg (500 mg/mo
`intramuscular [1M] injection plus 500 mg on day 14 of month 1)
`versus the 250 mg dose. This led to approval of the 500 mg dose for
`the treatment of postmenopausal women with ERnL advanced breast
`cancer after failure of prior antiestrogen therapy.25
`This review investigates the dose—dependent effects of fulvestrant
`more broadly, in terms of both the reduction of tumor biomarkers
`in the presurgical setting and the clinical efficacy for the treatment
`of breast cancer.
`
`range of 50 to 500 mg administered using the commercially avail—
`able long—acting formulation. Data from Study 18,20 Neoadjuvant
`Endocrine Therapy for Women with Estrogen—Sensitive Tumors
`(NEWEST)? and Trial 5718 were combined in this analysis.
`
`Study Designs
`Study 18
`Study 18 was a randomized, multicenter, partially blinded study
`that compared placebo, tamoxifen, fulvestrant 50 mg, fulvestrant
`125 mg, and fulvestrant 250 mg before surgery in postmenopausal
`women with previously untreated primary breast cancer.20 Patients
`received a single IM dose of fulvestrant 50 mg, 125 mg, 250 mg, or
`tamoxifen 20 mg daily, or tamoxifen placebo daily for 14 to 21 days
`before surgery. Only data from patients whose tumors were ER+ or
`PgR+ have been included in the current analysis, When patients
`had more than 1 tumor, baseline data from only the primary tumor
`Were included.
`
`NEWEST
`
`NEWEST (ClinicalTrialsgov identifier NCT0093002) was a
`randomized, multicenter, open—label, phase II study comparing
`fulvestrant 500 mg (500 mg/mo plus 500 mg on day 14 of
`month 1) with fulvestrant 250 mg/mo for 16 weeks before surgery
`in postmenopausal women with ER+ locally advanced breast
`cancer.27 Tumor biomarker levels at week 4 have been used in the
`
`present analysis for the closest consistency with data from Study 18
`and Trial 57.
`
`Trial 57
`
`Trial 57 (ClinicalTrialsgov identifier NCT00259090) was a
`randomized, multicenter, double-blind, phase II trial comparing
`fulvestrant 500 mg (single 1M dose) plus anastrozole (1 mg orally
`once daily for 14-21 days), fulvestrant 500 mg plus anastrozole
`placebo, or anastrozole plus fulvestrant placebo before surgery in
`postmenopausal women with ER+ primary breast cancer.28 Before
`protocol amendment, Trial 57 included a treatment phase in which
`patients were randomized to receive fulvestrant 250 mg plus anas—
`trozole (n : 6),
`fulvestrant 250 mg plus anastrozole placebo
`(n : 6), or anastrozole 1 mg plus fulvestrant placebo (n : 6).
`Although patient numbers are small and should be interpreted with
`caution, data for this initial treatment phase have been included
`for completeness in this analysis.
`
`Biological Rationale for a
`Dose-Response Relationship
`for Fulvestrant
`
`Dose—dependent reduction of tumor biomarkers after fulvestrant
`treatment was first demonstrated in a short-term presurgical study
`in postmenopausal women with primary breast cancer,26 After daily
`injections of a short—acting formulation of fulvestrant, reductions in
`ER expression and Ki67 labeling index were greater in patients with
`ER+ breast cancer who received a fulvestrant 18 mg daily injection
`compared with those who received a fulvestrant 6 mg daily
`injection,
`\We now extend the study of dose dependency by presenting
`a retrospective analysis of tumor biomarker data extracted from
`3 previously reported presurgical studies over a fulvestrant dose
`
`Tumor Biomarker Expression and
`Statistical Analyses
`ER, PgR, and Ki67 expression were determined in each study by
`immunochemistry on sections of formalin—fixed, paraffin—embedded
`tissue. Study 18 used the following antibodies: ER, H222 (Abbott
`Laboratories, Abbott Park, IL); PgR, KD68 (Abbott); Ki67, MlB-l
`(Coulter Electronics, Luton, UK). In NEWEST,
`the antibodies
`
`used were the following: ER, IDS (Dako Ltd, Carpinteria, CA);
`PgR, 636 (Dako Ltd); Ki67, MIB—l
`(Coulter Electronics). The
`antibodies used in Trial 57 were as follows: ER, 6F11 (Novocastra,
`Newcastle, UK); PgR, 636 (Dako Ltd); Ki67, Clone MIB-1 (Dako
`Ltd). Antigen retrieval methods and secondary detection methods
`varied between the studies and have been described.20’27‘ZS ER, PgR,
`and Ki67 expression levels at pre— and post-treatment (14—21 days
`
`382
`
`Clinical Breasl Cancer December 2014
`
`AstraZeneca Exhibit 2071 p. 2
`
`

`

`Table 1 Change From Baseline in ER H-Score
`
`[01m ER. Robertson et a]
`
`Treatment
`Placebo
`Tamoxifen
`Fulrestrant 50 mg
`Fulrestrant 125 mg
`Fulrestrant 250 mg
`Fuirestrant 500 mg
`Fuirestrant 250 mg plus anasirozole
`Fulrestrant 500 mg plus anastrozole
`Anastrozole
`
`Study 18
`69.5 to 28.9)
`(7
`737.3
`(7
`82.5 to 715.9)
`761.7
`757.5 (783.7 to 735.5)
`(7
`775.2
`87.0 to 752.4)
`784.0 (791.7 to 439.1)
`
`Back-Transformed Least Squares Mean ‘Change From Baseline (9%») (95% Cl)
`Trial 57 Initial Phase
`Trial 57 Main Phase
`
`
`
`710.7 (730.3 to 14.4)
`752.9 (763.0 to 740.1)
`
`721.0 (756.2 to 42.4)
`
`743.2 (768.4 to 2.1)
`
`5.8 (741.0 to 89.?)
`
`744.6 (753.9 to 733.4)
`
`748.9 (758.1 to 737.6)
`714.7 (729.7 to 3.5)
`
`Abbreviations: CI : confidence interval; ER : estrogen; NEWEST : Neoadjuvant Endocrine Therapy for Women with Estrogen—Sensitive Tumors.
`
`post—treatment in Study 18 and Trial 57 and at Week 4 in NEWEST)
`were determined by manual counting under light microscopy. ER
`and PgR expression were determined as the H-score, calculated
`
`as(0.5 ><%::)+(1><%+)+(2><%+i)+(3>< %+++),
`
`where % ::, A) +, % ++, and % +++ represent the overall per—
`centage positivity of very weak, weak, moderate, and strong staining,
`respectively. Ki67 Expression was determined as the labeling index,
`derived from the number of positively stained epithelial cells,
`expressed as a percentage of the total number of cells counted.
`Tumor biomarker expression data were analyzed by study using
`an analysis of covariance (ANCOVA) model (log-transformed ratio
`of post- to pretreatment) with the log-transformed baseline value
`and treatment included as factors, The least squares mean and
`confidence interval
`(CI) values were back—transformed to the
`
`original scale. To assess the impact of fulvestrant dose while
`allowing for between—study variability, a second AN COVA model
`was produced including log—transformed baseline, dose (as
`a.
`continuous variable), and study as factors. The first ANCOVA
`included all
`treatment groups within each trial;
`the second
`AN COVA included only placebo and the fulvestrant 50 mg,
`125 mg, 250 mg, and 500 mg treatment groups. For the placebo
`data to be log-transformed, a dose of 0.5 mg rather than 0 mg was
`used for the purpose of this analysis.
`
`ER H-Score
`
`In Study 18, NEWEST, and Trial 57, a dose—dependent effect
`was seen over the dose ranges investigated for reduction in ER
`expression. In each study, the greatest reduction in ER expression
`was seen with the highest fulvestrant dose, In Study 18, greater
`reduction in ER was observed for fulvestrant 250 mg versus
`tamoxifen, and in Trial 57, greater reduction in ER expression was
`observed for fulvestrant 500 mg versus anastrozole. In Trial 57, no
`additional reduction in ER expression was observed for fulvestrant
`500 mg plus anastrozole compared with fulvestrant 500 mg alone
`(Table 1; Figure 1)..
`
`PgR H-Score
`A consistent dose-dependent effect of fulvestrant was also
`observed in Study 18, NEW/EST, and Trial 57 for reduction in PgR
`expression. The greatest reduction in PgR expression was seen with
`the highest fulvestrant dose Within each study. An increase in PgR
`
`expression was seen in the tamoxifen treatment group in Study 18.
`In'Trial 57, no additional reduction in PgR expression was observed
`for
`the combination of fulvestrant 500 mg plus anastrozole
`compared with fulvestrant 500 mg alone or anastrozole alone.
`Similar reductions in PgR expression were observed for fulvestrant
`500 mg alone and anastrozole alone (Table 2; Figure 2).
`
`Ki67 Labeling Index
`Ki67 labeling index was reduced after treatment in each fulves—
`trant treatment group in each study. In Study 18 and NEW/EST,
`the greatest reduction in Ki67 labeling index was seen with the
`highest fulvestrant dose. In Trial 57, which also included the small
`initial cohort of patients treated with fulvestrant 250 mg (n : 6),
`there were no meaningful differences in Ki67 labeling index
`reduction between the fulvestrant
`treatment groups (Table 3;
`Figure 3).
`Overall results from the ANCOVA model show a consistent
`
`dose-dependent effect for fulvestrant over the dose ranges analyzed
`for ER and PgR H-score and Ki67 labeling index. Results for the
`
`Figure 1 Change From Baseline in ER Expression
`
`Change
`f’°"‘_
`“52"“
`(96)
`
`:itélvfi;
`100
`a Trial 5710
`5°
`6° ATria|57
`40
`20
`o
`-20
`40
`a
`so
`'100
`
`,
`l
`l
`I
`
`i
`
`i
`
`,
`i
`§
`~‘
`
`I
`|
`|
`|
`|
`|
`|
`|
`|
`|
`P
`T
`F50
`F125
`F250
`F500
`F250
`F500
`A
`+A
`+A
`
`7
`
`l
`
`i
`
`Study ill-(n)
`NEWBTm)
`Trial 57(i) (n)
`Trial 57in)
`
`46
`
`31
`
`38
`
`35
`
`40
`92
`6
`
`99
`35
`
`E
`
`31
`
`6
`37
`
`Least squares mean and 95% confidence interval; output from an analysis ofcovariance model
`of ER change from baseline (natural log transformed) with treatment as 3 factor.
`Trial57ii): data from initial patients inTtlal 57. treated with F250. priorta protocol amendment.
`A. anastrozale; ER, estrogen raptor; F5011 25/250600. fulvestrant 5011750501500 mg; P.’ placebo.
`T. tamoxifen.
`
`
`
`Abbreviation: NEWEST : Neoadjuvant Endocrine Therapy for Women With Estrogen—Sensith/e
`Tumors.
`
`Clinical Breast Cancer December 20l4
`
`383
`
`AstraZeneca Exhibit 2071 p. 3
`
`

`

`Fulvestrant Dose—Response Story
`
`Table 2 Change From Baseline in PgR H-Score
`
`Back-Transformed Least Squares Mean ‘Change From Baseline (9%») (95% Cl)
`Trial 57 Initial Phase
`Trial 57 Main Phase
` Treatment
`Study 18
`Placebo
`40.3 (725.8 to 165.4)
`Tamoxifen
`160.1 (27.7 to 429.8)
`Fulvestrant 50 mg
`‘ 762.7 (780.6 to 728.6)
`Fulvestrant 125 mg
`778.8 (788.4 to ~61.3}
`
`67.3 ( 81.0 to
`43.7)
`Fulvestrant 250 mg
`86.4( 92.8 to
`74.2)
`Fulvestrant 500 mg
`Fulvestrant 250 mg plus anaetrozole
`Fulvestrant 500 mg plus anastrozole
`Anastrozole
`
`703.2 (777.2 to 740.6)
`
`758.3 (775.5 to 729.0)
`759.2 (775.0 to 733.6)
`
`791.4 (795.0 to 785.0) 47.5 ( 82.8 to, 60.3)
`
`749.2 (782.9 to 50.9)
`
`765.9 (fees to 4.0)
`
`Abbreviations: CI : confidence interval; NEWEST : Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors; PgR : progesterone.
`
`second ANCOVA, which adjusted for between—study Variability,
`show that increasing fulvestrant dose results in greater reduction in
`ER and PgR H-score and KiG7 labeling index (P < .0001 for the
`dose—response relationship for each biomarker).
`
`Clinical Evidence of a Dose-
`
`Response Relationship for
`Fulvestrant
`
`Fulvestrant Dose—Response in Second—Line Tbempy for
`Advanced Breast Cancer
`
`The clinical elficacy of fiilvestrant at a dose of 250 mg/mo was
`established in the registration trials 0020 and 0021, which
`compared fiilvestrant 250 mg with anastrozole for the treatment of
`postmenopausal women with advanced breast cancer
`that had
`progressed or recurred on prior antiestrogen therapy.25‘24 In a
`combined analysis of data from both studies (fulvestrant, n : 428;
`anastrozole, n : 423), fulvestrant 250 mg was shown to be at least
`as effective as anastrozole with respect to time to progression (TTP).
`Median TTP was 5.5 months for fulvestrant 250 mg compared
`with 4.1 months for anastrozole (hazard ratio [HR], 0.95; 95.14%
`
`CI, 0.82-1.10; P : .48).16 This led to the approval of fulvestrant
`250 mg for the treatment of postmenopausal women with advanced
`breast cancer that had progressed or recurred on prior antiestrogen
`therapy. However, evidence of dose—dependent clinical efficacy with
`fulvestrant had already been suggested in these studies, because an
`initial 125 mg dose was dropped after a planned interim assessment
`that found no evidence for clinical efficacy at the fulvestrant 125 mg
`dose. Given the favorable tolerability profile of fulvestrant 250 mg,
`alternative dosing regimens were investigated.
`The phase III COmparisoN ofFaslodeX In Recurrent or Meta—
`static breast cancer (CONFIRM) trial was designed to compare
`fulvestrant 500 mg with fulvestrant 250 mg in patients with hor—
`mone receptor—positive, pretreated, advanced breast cancer. Ful-
`vestth 500 mg significantly prolonged PFS versus fulvestrant
`250 mg. Median PFS was 6.5 months in the fulvestrant 500 mg
`group compared with 5.5 months in the fulvestrant 250 mg group
`(HR. 0.80; 95% CI, 0.68—0.94; P : .006), demonstrating a clear
`dosedependent
`relationship
`for
`fulvestrant
`in
`this
`setting
`(Table 4).25 Of note, the dose—dependent clinical efficacy seen in
`CONFIRM was not associated with a dose-dependent increase in
`toxicity, with no substantial differences between the treatment
`
`groups in terms of incidence and severity of adverse events. This
`increase in therapeutic index led to fulvestrant 500 mg becoming
`the recommended dose. This benefit was further confirmed in a
`
`followup analysis performed when approximately 75% of patients
`had died. Median overall survival was 26.4 months for fulvestrant
`
`500 mg compared with 22.3 months for fulvestrant 250 mg,
`indicating a clinically relevant difference in overall survival between
`the treatment groups (HR, 0.81; 95% CI, 0.69—0.96; nominal
`P : .016).29
`
`Fulvestrant Dose—Rewanse in First—Line Therapy for
`Advanced Breast Cancer
`
`Cross-trial comparisons also suggest a dose—response relationship
`for fulvestrant as first-line therapy for advanced breast mneer. In
`Trial 25, fulvestrant 250 mg failed to demonstrate noninferiority
`compared with tamoxifen, the standard of care at the time of the
`trial, in postmenopausal women with advanced breast cancer pre—
`viously untreated with endocrine therapy for advanced diseasef"0
`
`Figure 2 Change From Baseline in PgR Expression
`
`22:95 45°
`inninin
`(96)
`
`1 5°
`1 00
`50
`
`I Study 18
`0 NEWEST
`
`°
`-50
`'1 0°
`
`
`
`l
`
`a
`I
`s
`T
`i
`:
`E
`i
`i
`I
`I
`I
`I
`I
`I
`T
`I
`I
`P
`T
`F50
`F125
`F250
`F500
`F250
`F500
`A
`+ A
`+ A
`
`Study 13 in)
`NEWEST (n)
`Trial 570) (n)
`Trial 57 in)
`
`40
`
`32
`
`38
`
`35
`
`40
`92
`6
`
`$9
`35
`
`6
`
`31
`
`6
`37
`
`Least squares m-n one! 95% confidence interval;outputfrom an analysis ofcovariance model
`of Pgllehangefrom baseline (natural log transformed) with treatmentas a factor
`Trial 570): data [mm Initial patients InTrial 57, treated with F250. prior to protocol amendment
`A. anastruzale; Fin/11512501500. fuivestrant 5011 25/2501500 mg; P, placebo; PgR. pregamemne manor;
`1', tamoxifen
`
`
`
`Abbreviation: NEWEST : Neoadjuvant Endocrine Therapy for Women With Estrogen—Sensitive
`Tumors.
`
`384
`
`Clinical Breast Cancer December 20l4
`
`AstraZeneca Exhibit 2071 p. 4
`
`

`

`Table 3 Change From Baseline in Ki67 Labeling Index
`
`john ER. Robertson et a]
`
`Back-Transformed Least Squares Mean ‘Change From Baseline (96) (95% Cl)
`Trial 57 Initial Phase
`Trial 57 Main Phase
` Treatment
`Study 18
`Placebo
`3.7
`18.0 to 31.1)
`(7
`(,
`Tamoxifen
`35.8
`51 .3 to 715.5)
`Fulrestrant 50 mg
`723.3 (740.6 to 70.9)
`(,
`Fulrestrant 125 mg
`e461
`58.6 to 729.7)
`
`28.2)
`79.0( 90.410
`Fulvestrant 250 mg
`46.5 ( 58.1 to
`31.6)
`45.5 ( 58.5 to
`Fuivestrant 500 mg
`Fuivestrant 250 mg plus anastrozole
`Fulvestrant 500 mg plus anastrozole
`Anastrozole
`
`791.2 (785.8 to 775.0) 774.4 (781.5 to 754.5)
`
`53.7)
`
`791.1 (796.0 to 780.2)
`783.4 (788.5 to 776.0)
`
`65.6)
`55.0( 89.1 to
`79.4)
`84.4 ( 92.9 to
`
`Abbreviations: CI : confidence interval; NEWEST : Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors,
`
`shown to demonstrate
`previously
`anastrozole was
`Because
`improvements in efficacy over tamoxifen,3 this was considered a
`surprising outcome for fulvestrant 250 mg. However, with the
`almost immediate separation of the TTP curves in this trial, it was
`hypothesized that the 5 to 6 months to steady state for the fiilves—
`trant 250 mg regimen could have led to the underperformance of
`this treatment group.
`In the phase II Fulvestrant flRst—line Study comparing endocrine
`Treatments (FIRST) study, fulvestrant 500 mg was compared with
`anastrozole in postmenopausal women with advanced breast cancer
`who had not received endocrine therapy for advanced disease. The
`fulvestrant 500 mg dose regimen, which includes a 500 mg dose at
`day 14, was shown to be at least as effective as anastrozole in terms
`of the primary endpoint of clinical benefit rate (fulvestrant, 72.5%;
`anastrozole, 67.0%), and the secondary endpoint of TTP was
`significantly longer for fulvestrant 500 mg compared with anas—
`trozole.31 Safety data indicated that fulvestrant 500 mg has a similar
`tolerability profile compared with anastrozole 1 mg and is well
`tolerated as first-line therapy for advanced breast cancer. In a follow—
`up analysis, which was performed when disease had progressed in
`approximately 75% of patients, median TTP was 23.4 months for
`fulvestrant 500 mg compared with 13.1 months for anastrozole
`(HR, 0.66; 95% CI, 0.47—0.92; P : .01).” This was the first trial
`to indicate that an alternative endocrine therapy may be more
`effective than an A1 in the first—line setting for advanced breast
`cancer and indirectly suggests a dose—response relationship for ful—
`vestrant 500 mg over fulvestrant 250 mg as first—line therapy for
`advanced breast cancer. Given that fiilvestrant 250 mg demon—
`strated noninferiority to anastrozole (in the second-line setting of
`the registration trials 0020 and 0021 “"23 ’24), the significantly longer
`TTP with fulvestrant 500 mg versus anastrozole in the first—line
`setting also was indirect evidence of a dose—response relationship
`for fulvestrant.
`
`tumor response rate at week 4 was 17.4% for the fiilvestrant 500 mg
`group compared with 11.8% in the fulvestrant 250 mg group (odds
`ratio [OR], 1.68; 95% CI, 0.77-3.70; P : .19). At week 16, tumor
`response was 22.9% in the fiulvestrant 500 mg group compared
`with 20.6% in the fiilvestrant 250 mg group (OR, 1.30; 95% CI,
`0.64—2.64; P : .47).”
`
`Fulvestmnt in Combination Therapy
`Together with its distinct mechanism of action and reduced risk
`of cross-resistance with other endocrine treatments, the observa—
`
`in
`tion of incomplete ER reduction with fulvestrant 250 mg,
`the short}0 medium, and long term (Agrawal, in press),51 led to
`combination therapies being developed, aiming to further reduce
`ER activity and improve efficacy. The Fulvestrant and Anastrozole
`Combination Therapy (FACT) study compared the efficacy of a
`combination of anastrozole plus the fulvestrant 250 mg loading
`dose (LD) regimen (fiulvestrant 250 mg + LD: 500 mg day 0, 250
`mg days 14 and 28, 250 mg/mo thereafter) versus anastrozole
`
`Figure 3 Change From Baseline in Ki61 Labeling Index
`
`$2399
`.
`baseline
`(96)
`
`4°
`20
`0
`
`- Study 18
`0 NEWEST
`l Trial 57(i)
`A Trial 57
`
`60
`”8°
`JIM
`
`7i
`J!
`.
`1
`in
`i5:
`i
`9
`
`|
`|
`|
`|
`|
`|
`TI
`|
`|
`P
`T
`F50
`F125
`F250
`F500
`F250
`F500
`A
`+ A
`+ A
`
`Study 1’8 (n)
`NEWBTln)
`Trial 57o) (n)
`Trial 57 (n)
`
`40
`
`31
`
`33
`
`35
`
`40,
`92
`e
`
`99
`35
`
`e
`
`31
`
`6
`37
`
`Fulvestmnt Dose Revonse in the Neoaq'juvant Setting
`NEWEST was the first study to compare the biological and
`clinical activity of the fulvestrant 500 mg dose regimen versus fill-
`vestrant 250 mg. Although the primary endpoint of NEWEST
`was biological (change in Ki67 labeling index from baseline to
`Week 4), the clinical data appeared to correspond with the dose-
`dependent reduction in tumor biomarkers seen at week 4. The
`
`least squaresmean and 95% confidence interval; output from an analysis ofcovariance model
`of Kl67 labelling index change from baseline (natural log transformed) with treatment use fitter.
`Trial 57(1): data from initial patients inTrlal 57, treated with F250, prinrbo protocol amendment.
`A. anastrozole; F5W125/250/500, fulvestrant 50/175/250/500 mg; P. placebn:T. tamoxifen.
`
`
`
`Abbreviation: NEWEST : Neoadjuvant Endocrine Therapy for Women With Estrogen—Sensitive
`Tumors.
`
`Clinical Breast Cancer December 2014
`
`385
`
`AstraZeneca Exhibit 2071 p. 5
`
`

`

`Second-line
`studies
`
`Study 20a
`
`Study 21a
`
`EFECT
`
`FINDER1
`
`FINDER2
`
`CONFIRM
`
`First-line
`studies
`Trial 25
`
`FIRSTh
`
`Phase III; randomized; openelabel,
`parallelagroup, multicenter study:
`fuIvestrant 250 mg, n : 222;
`anastrozole, n : 22923
`Phase III, randomized, doubleeblind;
`parallel—group, doubleedummy;
`multicenter study: fulvestrant 250 mg;
`n : 206; anastrozole, n : 19424
`Phase III, randorrized; double~blind;
`doubleedummy, nulticenter study:
`fulvestrant 250 mg + LD, n : 351;
`exemestane, n : 34218
`Phase I; random‘zed, doubleeblind;
`paralle agroup; mult'center study:
`fulvestrant 500 mg; n : 47;
`fulvestrant 250 rrg W LD, n : 51;
`fulvestrant 250 mg, n : 4542
`Phase I, random'zed; doubleablind,
`paralle agroup; mult'center study:
`fulvestrant 500 rrg, n : 46;
`fulvestraat 250 rrg W LD; n : 51;
`fulvestrant 250 mg, n : 4743
`Phase II, random'zed, doubleeblind;
`paralle agroup, mult'center study:
`fulvestrant 500 mg, n : 362;
`fulvest ant 250 mg, n : 374‘5
`
`
`
`
`
`
`
`
`
`Fulvestrant Dose—Response Story
`
`Table 4
`
`PFS in Fulvestrant Monotherapy Trials for Advanced Breast Cancer
`
`study Design
`
`Fulvestrant
`250 mg
`
`Fulvestrant
`250 mg + LD
`
`Fulvestrant
`500 mg
`
`Tamoxifen Anastrozole Exemestane
`25 mg/d
`
`3.7
`
`Phase II; randomized, doubleeblind;
`parallelegroup, doubleadummy,
`multicenter study: fulvestrant 250mg,
`n : 313; tamoxifen, n : 27430
`Phase II; randomized; openelabel,
`parallelagroup, multicenter study:
`fulvestrant 500 mg; n : 102;
`anastrozole, n : 103M
`
`Fulvestrant 250 mg: 250 mg days 0 and 28, 250 mg/mo thereafter; fulvestrant 250 mg + LD: 500 mg day 0. 250 mg days 14 and 28, 250 mg/mo thereafter; fulvestrant 500 mg: 500 mg days 0,
`14, and 28, 500 mg/mo thereafter.
`Abbreviations: CONFIRM : COmparisoN of Faslodex In Recurrent or Metastatic breast cancer; EFECT : Evaluation of Faslodex versus Exemestane Clinical Trial; FINDER1 : Faslodex InvestigatioN of
`Dose evaluation in Estrogen Receptor—positive advanced breast cancer in Japan; FINDER2 : Fasloolex InvestigatioN of Dose evaluation in Estrogen Receptor—positive advanced breast cancer in Europe;
`FIRST : Fulvestrant fIRst-Iine Study comparing endocrine Treatments; LD : loading dose; PFS : progression-free survival.
`aStudies 0020 and 0021 initially included a fulvestrant 125 mg treatment group that was withdrawn because of lack ofclinioal activity.
`bData irom the FIRST follow-up analysis.
`
`alone as therapy for postmenopausal women at first relapse after
`primary treatment for localized hormone receptor—positive breast
`cancer,33 More than 60% of the participants had received a prior
`endocrine therapy in the adjuvant setting. For
`the primary
`endpoint, median TTP was 108 months in the fiilvestrant
`2 50 mg + LD plus anastrozole combination compared with
`10.2 months in the anastrozole alone treatment group (HR, 0.99;
`95% CI, 0.81-1.20; P : .91).33 The overall incidence ofAEs was
`similar between the 2 treatment groups. Secondary endpoints,
`including objective response rate, clinical benefit rate, and overall
`survival, were also similar between the 2 study arms, indicating no
`benefit
`for
`the anastrozole plus fulvestrant combination over
`anastrozole alone.
`
`The randomized phase 111 Southwest Oncology Group (SWOG)
`50226 trial also compared the combination of anastrozole plus ful—
`vestrant 250 mg + LD with anastrozole alone as first-line therapy for
`postmenopausal women with metastatic breast cancer,54 The pri—
`mary endpoint of PFS was significant in favor of the combination
`group: 15.0 months compared with 13.5 months in the anastrozole
`alone group (HR, 0.80; 95% CI, 0.68—0.94; P : .007), and no
`safety concerns were raised with the fulvestrant plus anastrozole
`combination. 1n a retrospective analysis of those patients naive to
`prior tamoxifen therapy (414/694 patients: 59.7%), the median PFS
`was 17.0 months in the combination group compared with
`12.6 months in the anastrozole alone group (HR, 0.74; 95% CI,
`0.59—0.92; P : .006). In those patients who had received previous
`
`386
`
`Clinical Breast Cancer December 2014
`
`AstraZeneca Exhibit 2071 p. 6
`
`

`

`treatment with tamoxifen (280/694 patients: 40.3%), the median
`PFS was 13. 5 months in the combination group compared with 14.1
`months in the anastrozole alone group (HR, 0.89; 95% CI, 0.69-
`1.15; P : .37).34 In total, 166 of514 patients (32.3%) had received
`no prior adjuvant endocrine therapy in the FACT trial, whereas 414
`of 694 patients (59.7%) were naive to prior tamoxifen in SWOG
`50226. In both trials, less than 2% of patients had received adjuvant
`therapy with an AI. Because the percentage of patients who were
`naive to prior adjuvant endocrine treatment was lower in the FACT
`trial, and any potential differences in clinical effectiveness may be
`more pronounced when comparing endocrine agents in hormone—
`nai‘ve patients, this could provide one potential explanation for the
`differences in efficacy between the FACT and SWOG 50226 trials.
`Furthermore, initial data from the Study of Faslodex, Exemestane
`and Arimidex (SoFEA) trial failed to demonstrate improved efficacy
`for the combination of fulvestrant with an A] over a monotherapy
`treatment in the second-line setting. Similar PFS was reported for
`fulvestrant 250 mg + LD in combination with anastrozole compared
`with fiilvestrant alone in postmenopausal patients with advanced
`breast cancer after progression on nonsteroidal AIs.35
`
`Discussion
`
`Our analysis of fulvestrant in 3 presurgical studies demonstrates
`a strong dose—dependent biological effect
`in the reduction of
`tumor biomarkers. Across each dataset analyzed, increasing fulves—
`trant dose leads to increased reduction in ER, PgR, and KiG7, and
`this dose—dependent reduction in tumor biomarkers corresponds to
`the dose—dependent clinical efficacy seen in postmenopausal women
`with advanced breast cancer in the second—line setting of trials
`0020 and 0021 (fulvestrant 250 mg vs. 125 mg) and CONFIRM
`(fulvestrant 500 mg vs. 250 mg). In the first—line setting, increased
`efficacy of fulvestrant 500 mg (vs. anastrozole in FIRST) versus
`250 mg (vs.
`tamoxifen in Trial 25) has been implied through
`indirect, cross-trial comparisons. Further cross-trial comparison