`
`(H cori
`A Good Drug Made Better: The Fulvestrant
`Dose-Response Story
`John F.R. Robertson,’ Justin Lindemann,” Sally Garnett,* Elizabeth Anderson,”
`Robert I. Nicholson,* Irene Kuter,” Julia M.W. Gee*
`
`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 cancerafterfailure
`of prior antiestrogen therapy.Initially approved at a monthly dose of 250 mg, the recommended fulvestrant dose was
`revised to 500 mg (600 mg/mo plus 500 mg on day 14 of month 1) after demonstration of improved progression-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 (8 previously
`reported studies: Study 18, Neoadjuvant Endocrine Therapy for Women with Estrogen-Sensitive Tumors, and Trial 57)
`and from a review ofclinical 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-dependentclinical efficacy observed in the treatment of advanced
`breast cancerafterfailure of prior antiestrogen therapy. Although it remains to be determined in a phaseIll trial; cross-
`trial comparisons suggest a dose-dependentrelationship for fulvestrant as first-line treatment for advanced breast
`cancer. Overall, biological and clinical data demonstrate a strong dose-dependentrelationship 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 ElsevierInc. 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 teceptort-positive [ER+] and/or progester-
`one receptor-positive [PgR+]), both in the adjuvant setting’ and for
`the treatment of advanced disease.
`Aromatase inhibitors (Als), which block production ofestrogen
`through their
`interaction with the estrogen-producing enzyme
`
`‘Graduate Entry Medicine and Health School (GEMS), University of Nottingham,
`Derby, UK
`?AstraZeneca, Alderley Park, Macclesfield, UK
`*Formerly AstraZeneca, Alderley Park, Macclesfield, UK
`“Breast Cancer Molecular Pharmacology Group, School of Pharmacy and
`Pharmaceutical Sciences, Cardiff University, Cardiff, UK
`>Massachusetts 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 & Graduate Entry Medicine, School of Medicine, Faculty of Medicine &
`Health Sciences, University of Nottingham, Royal Derby Hospital Centre, Derby
`DE22 3DT, UK
`Fax: +44 (0)1332 724880; e-mail contact: john.robertson@nottingham.ac.uk
`
`aromatase, have demonstrated increased efficacy compared with the
`ER antagonist
`tamoxifen in postmenopausal women as first-line
`endocrine treatment for ER+ advanced breast cancer”® and as
`adjuvant
`therapy for postmenopausal women with early breast
`cancer,” As such, Als 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
`Fulvestrant, a 17B-estradiol analog,
`competes with endogenous estrogen for binding to the ER.’°
`However, unlike
`tamoxifen, which exhibits partial
`estrogen
`agonist activity, fulvestrant has no tecognized 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,” Furthermore, the paucity of data led
`
`1526-8209/S- see frontmatter © 2014 Elsevier Inc. All rights reserved.
`http://dx.doi.org/10.1016/j.clbc.2014.06.005
`
`Clinical Breast Cancer December 2014
`
`381
`
`AstraZeneca Exhibit 2071 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`
`
`
`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
`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.'* Similarly in
`the clinical setting, many postmenopausal women with advanced
`breast cancer
`that
`responded to first-line fulvestrant
`remained
`responsive
`to further
`endocrine
`treatment.'*'* Furthermore,
`tumors that have responded to prior treatment with an anties-
`trogen’?"° or an Al'”'® 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.” Reduction in Ki67 expression, a nuclear antigen and
`markerofcell proliferation, is reported to correlate with treatment
`response to endocrine therapy in ER+ breast cancer,’ and Ki67 in
`short-term neoadjuvant studies has been shownto predict outcome
`in long-term adjuvanttrials.”
`Clinical
`efficacy of fulvestrant was demonstrated in post-
`menopausal women with advanced breast cancer that had pro-
`16,23,24
`2
`and was
`gressed or recurred on prior antiestrogen therapy
`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 [IM] injection plus 500 mg on day 14 of month 1)
`versus the 250 mgdose. This led to approval of the 500 mg dose for
`the treatment of postmenopausal women with ER+ advanced breast
`cancer after failure of prior antiestrogen therapy,”
`This review investigates the dose-dependenteffects 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.
`
`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.”° 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
`compated 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
`
`range of 50 to 500 mg administered using the commercially avail-
`able long-acting formulation. Data from Study 18,7" Neoadjuvant
`Endocrine Therapy for Women with Estrogen-Sensitive Tumors
`(NEWEST),”’ and Trial 577° were combinedin 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 untteated primary breast cancer.” 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 (ClinicalTrials.gov 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 sutgery
`in postmenopausal women with ER+ locally advanced breast
`cancer,”’ Tumor biomarker levels at week 4 have been used in the
`present analysis for the closest consistency with data ftom Study 18
`and Trial 57.
`
`Trial 57
`Trial 57 (ClinicalTrials.gov identifier NCT00259090) was a
`randomized, multicenter, double-blind, phase II trial comparing
`fulvestrant 500 mg (single IM 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,** 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.
`
`Tumor Biomarker Expression and
`Statistical Analyses
`ER, PgR, and KiG7 expression were determined in each study by
`immunochemistry on sections of formalin-fixed, parafhin-embedded
`tissue. Study 18 used the following antibodies: ER, H222 (Abbott
`Laboratories, Abbott Park, IL); PgR, KD68 (Abbott); Ki67, MIB-1
`(Coulter Electronics, Luton, UK). In NEWEST,
`the antibodies
`used were the following: ER, 1D5 (Dako Ltd, Carpinteria, CA);
`PgR, 636 (Dako Ltd); Ki67, MIB-1 (Coulter Electronics), The
`antibodies used in Trial 57 were as follows: ER, 6F11 (Novocastra,
`Newcastle, UK); PgR, 636 (Dako Ltd); KiG7, Clone MIB-1 (Dako
`Ltd). Antigen retrieval methods and secondary detection methods
`varied between the studies and have been described,?°?”7" ER, PeR,
`and Ki67 expression levels at pre- and post-treatment (14-21 days
`
`382
`
`Clinical Breast Cancer December 2014
`
`AstraZeneca Exhibit 2071 p. 2
`
`
`
`Table 1 Change From Baseline in ER H-Score
`
`John F.R. Robertson et al
`
`Trial 57 Initial Phase|Trial 57 Main Phase
`Study 18
`(—69.5 to 28.9)
`—37.3
`(—
`(—
`(—82.5 to —15.9}
`—61.7
`—67.6 (-83.7 to —35.5)
`—75.2 (-87.0 to —52.4)
`—84.0 (—91.7 to —69.1) —10.7 (—30.3 to 14.4}
`—52.9 (—63.0 to —40.1}
`
`—44.6 (-53.9 to —33.4)
`
`—21.0 (-56.2 to 42.4)
`
`Placebo
`Tamoxifen
`Fulvestrant 50 mg
`Fulvestrant 125 mg
`Fulvestrant 250 mg
`Fulvestrant 500 mg
`Fulvestrant 250 mg plus anastrozole
`—48,9 (—58.1 to 37.6)
`Fulvestrant 500 mg plus anastrozole
`Anastrozole
`5.8 (41.0 10 89.7)|14.7 (29.7 to 3.5)
`
`Back-Transformed Least Squares Mean Change From Baseline (%) (95% Cl) Treatment
`
`—43.2 (68.4 to 2.1)
`
`Abbreviations: Cl = 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 underlight microscopy. ER
`and PgR expression were determined as the H-score, calculated
`
`as (0.5 xX %+)+0 x %4+)4+(2x %44)4+ 3 « %+4+44),
`
`where % =, % +, % ++, and % +++ representthe overall per-
`cetitage 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 ofthe total numberofcells counted.
`Tumor biomarker expression data were analyzed by study using
`an analysis of covariance (ANCOVA) model(log-transformedratio
`ofpost- to pretreatment) with the log-transformed baseline value
`and treatment included as factors, The least squares mean and
`confidence interval
`(CI) values were back-transfurmed to the
`original scale. To assess the impact of fulvestrant dose while
`allowing for between-study variability, a second ANCOVA model
`was produced including log-transformed baseline, dose (as a
`continuous variable), and study as factors. The firss ANCOVA
`included all
`treatment groups within each trial;
`the second
`ANCOVA 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, NEWEST,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 NEWEST,
`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-dependenteffect 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
`
`carpe vy 2 Su
`from
`80>) Trial 57(i)
`baseline 60-4 Trial57
`(%)
`40
`20
`
`L
`
`e@
`a
`
`e
`-20
`40
`e
`20
`-100
`
`3
`a
`[
`
`é
`T
`T
`T
`T
`T
`T
`T
`T
`1
`PT S50
`F125
`F250
`F500
`F250 F500
`A
`+A
`+A
`
`t
`
`Study 18 (n)
`NEWEST {n)
`Trial 57(i) (n)
`Trial 57 (n)
`
`40
`
`32
`
`38
`
`35
`
`40
`92
`6
`
`99
`35
`
`6
`
`31
`
`6
`37
`
`Least squares mean and 95% confidence interval; output from an analysis ofcovariance model
`of ER changefram baseline (naturallog transformed) with treatmentas a factor.
`Trial 57(0: data from initialpatients inTrial 57, treated with F250,priorto protocol amendment.
`A, anastrozole; ER, estrogen receptor; F50/125/250/500,fulvestrant 50/125/250/500 mg;P, placebo;
`T, tamoxifen.
`
`
`
`Abbreviation: NEWEST = Neoadjuvant Endocrine Therapy for Women With Estrogen-Sensitive
`Tumors.
`
`Clinical Breast Cancer December 2014
`
`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 (%) (95% Cl)
` Treatment
`Trial 57 Initial Phase|Trial 57 Main Phase
`Study 18
`Placebo
`40.3 (—25.8 to 165.4)
`Tamoxifen
`160.1 (27.7 to 429.8)
`Fulvestrant 50 mg
`—62,7 (-80.6 to —28.6)
`Fulvestrant 125 mg
`~78.8 (-88.4 to —61.3)
`
`Fulvestrant 250 mg
`43,7)
`47.5 (82.8 to 60.3)
`86.4 (92.8 to
`74.2)
`67.3 (-81.0 to
`Fulvestrant 500 mg
`Fulvestrant 250 mg plus anastrozole
`Fulvestrant 500 mg plus anastrozole
`Anastrozole
`
`—91.4 (95.0 to —85.0) —63.2 (-77.2 to —40.6)
`
`—49.2 (-82.9 to 50.9)
`
`65.9 (88.8 to 4.0)
`
`58.3 (-75.5 to —29.0)
`—59.2 (-75,0 to —33.6)
`
`Abbreviations: Cl = confidence interval, NEWEST = Neoadjuvait 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 KiG67labeling 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 Therapy for
`Advanced Breast Cancer
`The clinical efficacy of fulvestrant at a dose of 250 mg/mo was
`established in the registration trials 0020 and 0021, which
`compared fulvestrant 250 mg with anastrozole for the treatment of
`postmenopausal women with advanced breast cancer
`that had
`progressed ot recurred on prior antiestrogen therapy.°?* In a
`combined analysis of data from both studies (fulvestrant, n = 428;
`anastrozole, n = 423), fulvestrant 250 mg was shownto be atleast
`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%
`Cl, 0.82-1.10; P = .48).'° This led to the approval of fulvestrant
`250 mgfor 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 alteady 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 I COmparisoN of Faslodex 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-
`vestrant 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 monthsin the fulvestrant 250 mg group
`(HR, 0.80; 95% CI, 0.68-0.94; P = .006), demonstrating a clear
`dose-dependent
`relationship
`for
`fulvestrant
`in
`this
`setting
`(Table 4).?? 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
`
`gtoups 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
`
`follow-up 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 sutvival between
`the treatment groups (HR, 0.81; 95% CI, 0.69-0.96; nominal
`P= .016).””
`
`Fulvestrant Dose-Response in First-Line Therapy for
`Advanced Breast Cancer
`Cross-trial comparisons also suggest a dose-responserelationship
`for fulvestrant as first-line therapy for advanced breast cancer, 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-
`.
`:
`:
`.
`2
`viously untreated with endocrine therapy for advanced disease.”
`
`Figure 2 Change From Baseline in PgR Expression
`
`T
`Fd
`
`Change
`from
`baseline
`(%)
`
`450
`200
`150
`100
`50
`
`Teese
`z
`5
`_ a
`
`g
`-50:
`-100
`
`|
`t
`
`a Ja 6
`
`T
`T
`T
`T
`T
`7
`T
`T
`1
`P
`T
`F50
`F125
`F250
`F500
`F250 F500
`A
`+A
`+A
`
`Study 18 (n)
`NEWEST (n)
`Trial 57()} (n)
`Trial 57 (n)
`
`40
`
`32
`
`38
`
`35
`
`40
`92
`6
`
`99
`35
`
`6
`
`31
`
`6
`37
`
`Least squares mean and 95% confidence Interval; outputfrom an analysis ofcovarlance model
`of PgR change from baseline (naturallog transformed) with treatmentas a factor.
`Trial 57(): data frominitial patients inTrial 57, treated with F250,prior to protocol amendment.
`A, anastrozole; F50/125/250/500,fulvestrant 50/125/250/500 mg; P. placebo; PgR, progesterone receptor;
`T, tamoxifen.
`
`
`
`Abbreviation: NEWEST = Neoadjuvant Endocrine Therapy for Women With Estrogen-Sensitive
`Tumors.
`
`384
`
`Clinical Breast Cancer December 2014
`
`AstraZeneca Exhibit 2071 p. 4
`
`
`
`PELMMAMacemerece IeM ILM CLoramleeleneIMLELedg
`
`John F.R. Robertson et al
`
`Back-Transformed Least Squares Mean Change From Baseline (%) (95% Cl)
` Treatment
`Trial 57 Initial Phase|Trial 57 Main Phase
`Study 18
`Placebo
`3.7
`(—18.0 to 31.1)
`(—
`(—
`Tamoxifen
`35.8
`(—51.3 to —15.5)
`Fulvestrant 50 mg
`—23.3 (—40.6 to —0.9)
`—46.1
`(—58.6 to —29.7}
`Fulvestrant 125 mg
`(—
`
`58.1 to
`Fulvestrant 250 mg
`46.5 ( 28.2)|—79.0 (-90.4 to —53.7)31.6)
`
`
`45.5 (—58.5 to
`Fulvestrant 500 mg
`Fulvestrant 250 mg plus anastrozole
`Fulvestrant 500 mg plus anastrozole
`Anastrozole
`
`—81.2 (—85.8 to —75.0) —74.4 (-81.5 to 64.5)
`
`—91.1 (96.0 to —80.2)
`—83.4 (—88.5 to 76.0)
`
`85.0 (-89.1 to
`-79.4)
`84.4 (—92.9 to —65.6)
`
`Abbreviations: Cl = confidence interval; NEWEST = Neoadjuvait Endocrine Therapy for Women with Estrogen-Sensitive Tumors.
`
`tumor responserate at week 4 was 17.4% for the fulvestrant 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
`tesponse was 22.9% in the fulvestrant 500 mg group compared.
`with 20.6% in the fulvestrant 250 mg group (OR, 1.30; 95% CI,
`0.64-2.64; P = .47).””
`
`Fulvestrant in Combination Therapy
`Together with its distinct mechanism of action and reduced risk
`of cross-resistance with other endocrine treatments, the observa-
`tion of incomplete ER reduction with fulvestrant 250 mg,
`in
`the short,-” medium, and long term (Agrawal, in press), led to
`combination therapies being developed, aiming to further reduce
`ERactivity 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 (fulvestrant 250 mg + LD: 500 mg day 0, 250
`mg days 14 and 28, 250 mg/mothereafter) versus anastrozole
`
`Figure 3 Change From Baseline in Ki67 Labeling Index
`
`. pay
`a Trial 576i)
`& Trial 57
`
`a
`
`-|
`
`:
`
`D
`k
`A
`i
`T
`T
`T
`T
`T
`T
`T
`T
`1
`P
`ni
`F50
`F125
`F250
`F500
`F250 F500
`A
`+A +A
`
`40
`ag
`0
`
`° 6
`
`0
`
`-80
`-100
`
`Change
`from
`baseline
`(%)
`
`Study 18 (n)
`NEWEST(n)
`Trial 57(i) (n}
`Trial 57 (n)
`
`40
`
`32
`
`38
`
`35
`
`40
`92
`6
`
`99
`35
`
`6
`
`3
`
`6
`37
`
`Least squares mean and 95% confidence Interval; output from an analysisofcovariance model
`of Ki67 labelling index change from baseline (naturallog transformed) with treatment asa factor,
`Trial 57(i): data from initial patients inTrial 57, treated with F250,priorto protocol amendment.
`A, anastrozole; F50/125/250/500,fulvestrant 50/125/250/500 mg; P, placebo;T, tamoxifen.
`
`
`
`Abbreviation: NEWEST = Neoadjuvant Endocrine Therapy for Women With Estrogen-Sensitive
`Tumors.
`
`Clinical Breast Cancer December 2014
`
`385
`
`AstraZeneca Exhibit 2071 p. 5
`
`shown to demonstrate
`previously
`anastrozole was
`Because
`improvements in efficacy ovet tamoxifen,’ 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 3 to 6 months to steady state for the fulves-
`trant 250 mg regimen could have led to the underperformance of
`this treatment group.
`In the phase II Fulvestrant f[Rst-line Study comparing endocrine
`Treatments (FIRST) study, fulvestrant 500 mg was compared with
`anasttozole 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 shownto be atleast as effective as anastrozole in terms
`of the primary endpointofclinical benefit rate (fulvestrant, 72.5%;
`anasttozole, 67.0%), and the secondary endpoint of TIP was
`significantly longer for fulvestrant 500 mg compared with anas-
`ttozole.°' Safety data indicated that fulvestrant 500 mghas 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
`(AR, 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 AI in the first-line setting for advanced breast
`cancer and indirectly suggests a dose-response relationship for ful-
`vestrant 500 mg over fulvestrant 250 mgas first-line therapy for
`advanced breast cancer. Given that fulvestrant 250 mg demon-
`strated noninferiority to anastrozole (in the second-line setting of
`the registrationtrials 0020 and 0021'°?**),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.
`
`Fulvestrant Dose Response in the Neoadjuvant Setting
`NEWEST was the first study to compare the biological and
`clinical activity of the fulvestrant 500 mg dose regimen versus ful-
`vestrant 250 mg. Although the primary endpoint of NEWEST
`was biological (change in KiG7 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
`
`
`
`Fulvestrant Dose-Response Story
`
`Table 4
`
`PFS in Fulvestrant Monotherapy Trials for Advanced Breast Cancer
`
`Fulvestrant Tamoxifen|Anastrozole|Exemestane
`
`Fulvestrant
`Study Design
`250 mg
`250 mg + LD
`25 mg/d
`500 mg
`
`PFS (mo) Fulvestrant
`
`Second-line
`studies
`
`Study 20°
`
`Study 21°
`
`EFECT
`
`FINDER
`
`FINDER2
`
`CONFIRM
`
`First-line
`studies
`Trial 25
`
`FIRST?
`
`
`
`3.7
`
`
`
`
`
`
`
`PhaseIll, randomized, open-label,
`parallel-group, multicenter study:
`fulvestrant 250 mg, n = 222;
`anastrozole, n = 229°
`PhaseIll, randomized, double-blind,
`parallel-group, double-dummy,
`multicenter study: fulvestrant 250 mg,
`n = 206: anastrozole, n = 194°"
`PhaseIll, randomized, double-blind,
`double-dummy, multicenter study:
`fulvestrant 250 mg + LD,
`n = 351;
`exemestane, n = 342°
`Phase ll, randomized, double-blind,
`parallel-group, multicenter study:
`tulvestrant 500 mg, n = 47;
`fulvestrant 250 mg + LD, n = 51;
`fulvestrant 250 mg, n = 45°°
`Phase Il, randomized, double-blind,
`parallel-group, multicenter study:
`fulvestrant 500 mg, n = 46;
`tulvestrant 250 mg + LD, n = 51;
`fulvestrant 250 mg, n = 47°°
`PhaseIll, randomized, double-blind,
`parallel-group, multicenter study:
`fulvestrant 500 mg, n = 362;
`fulvestrant 250 mg, n = 374°
`
`PhaseIll, randomized, double-blind,
`parallel-group, double-dummy,
`multicenter study: fulvestrant 250 mg,
`n = 313: tamoxifen, n = 274°°
`PhaseIl, randomized, open-label,
`parallel-group, multicenter study:
`tulvestrant 500 mg, n = 102;
`anastrozole, n = 103"
`
`Fulvestrant 250 mg: 250 mg days 0 and 28, 250 mg/mothereafter; fulvestrant 250 mg +- LD: 500 mg day 0, 250 mg cays 14 and 28, 250 mg/mo thereafter; fulvestrant 500 mg: 500 mg days 0,
`14, and 28, 500 mg/mothereafter.
`Abbreviations: CONFIRM = COmparisoN of Faslodex In Recurrent or Metastatic breast cancer; EFECT = Evaluation of Faslodex versus Exemestane Clinical Trial; FINDER’ = Faslodex InvestigatioN of
`Dese evaluation in Estrogen Receptor-positive advanced breast cancer in Japan; FINDER2 = Faslocex InvestigatioN of Dose evaluation in Estrogen Receptor-positive advanced breast cancerin Europe;
`FIRST = Fulvestrant fiRst-line Stucly comparing endocrine Treatments; LD = loading dese; PFS = progression-free survival.
`*Studies 0020 and 0021 initially included a fulvestrant 125 mg treatment group that was withdrawn because of lackofclinical activity,
`®Data from the FIRST follow-up analysis.
`
`alone as therapy for postmenopausal womenat first relapse after
`primary treatment for localized hormone receptor-positive breast
`cancer,’ More than 60% ofthe participants had received a prior
`endocrine therapy in the adjuvant setting. For
`the primary
`endpoint, median TTP was 10.8 months in the fulvestrant
`250 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).*° The overall incidence of AEs 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 II Southwest Oncology Group (SWOG)
`$0226 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.** 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. In a retrospective analysis of those patients naive to
`prior tamoxifen therapy (414/694patients: 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
`PES was 13.5 monthsin the combination group compared with 14.1
`months in the anastrozole alone group (HR, 0.89; 95% CI, 0.69-
`1.15; P= .37).*! In total, 166 of 514 patients (32.3%) hadreceived
`no prior adjuvant endocrine therapy in the FACT trial, whereas 414
`of 694 patients (59.7%) were naive to prior tamoxifen in SWOG
`$0226, In both trials, less than 2% ofpatients 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
`mote pronounced when comparing endocrine agents in hormone-
`naive patients, this could provide one potential explanation for the
`differences in efficacy between the FACT and SWOG S0226trials,
`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 AI over a monotherapy
`treatment in the second-line setting, Similar PFS was reported for
`fulvestrant 250 mg + LD in combination with anastrozole compared
`with fulvestrant alone in postmenopausal patients with advanced
`breast cancer after progression on nonsteroidal Als.”
`
`Discussion
`Ouranalysis of fulvestrant in 3 presurgical studies demonstrates
`a strong dose-dependent biological effect
`in the teduction of
`tumor biomarkers, Across each dataset analyzed, increasing fulyes-
`trant dose leads to increased reduction in ER, PgR, and Ki67, 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 comparisons
`show that in the registration trials 0020 and 0021 (in the second-
`line setting), fulvestrant 250 mg was noninferior to anastrozole,
`but in the phase II FIRST trial (fulvestrant 500 mgvs. anastr