Fulvestrant plus anastrozole or placebo versus exemestane
`alone after progression on non-steroidal aromataseinhibitors
`in postmenopausal patients with hormone-receptor-positive
`locally advanced or metastatic breast cancer (SoFEA):
`a composite, multicentre, phase 3 randomisedtrial
`
`Stephen RD Johnston, Lucy S Kilburn, PaulEllis, David Dodwell, David Cameron, Larry Hayward, Young-Hyuck Im, Jeremy P Braybrooke,
`A Murray Brunt, Kwok-Leung Cheung, Rema Jyothirmayi, Anne Robinson, Andrew M Wardley, Duncan Wheatley, Anthony Howell, Gill Coombes,
`Nicole Sergenson, Hui-JungSin, Elizabeth Folkerd, Mitch Dowsett, Judith M Bliss, on behalf of the SoFEA investigators*
`
`Summary
`Background The optimum endocrine treatment for postmenopausal women with advanced hormone-receptor-
`positive breast cancer that has progressed on non-steroidal aromatase inhibitors (NSAIs) is unclear. The aim of the
`SoFEA trial was to assess a maximum double endocrine targeting approach with the steroidal anti-oestrogen
`fulvestrant in combination with continued oestrogen deprivation.
`
`Methods In a composite, multicentre, phase 3 randomised controlled trial done in the UK and South Korea,
`postmenopausal womenwith hormone-receptor-positive breast cancer (oestrogen receptor [ER] positive, progesterone
`receptor[PR] positive, or both) were eligible if they had relapsed or progressed with locally advanced or metastatic
`disease on an NSAI (given as adjuvant for at least 12 months or as first-line treatment for at least 6 months).
`Additionally, patients had. to have adequate organ function and a WHO performancestatus of 0—2. Participants were
`randomly assigned (1:1:1) to receive fulvestrant (500 mg intramuscular injection on day 1, followed by 250 mg doses
`on days 15 and 29, and then every 28 days) plus daily oral anastrozole (1 mg); fulvestrant plus anastrozole-matched
`placebo;or daily oral exemestane (25 mg). Randomisation was done with computer-generated permuted blocks, and
`stratification was by centre and previous use of an NSAIas adjuvant treatmentorfor locally advanced or metastatic
`disease. Participants and investigators were aware ofassignmentto fulvestrant or exemestane, but not of assignment
`to anastrozole or placebo. The primary endpoint was progression-free survival (PFS). Analyses were by intention to
`treat. This trial is registered with ClinicalTrials.gov, numbers NCT00253422 (UK) and NCT00944918 (South Korea).
`
`Findings Between March 26, 2004, and Aug 6, 2010, 723 patients underwent randomisation: 243 were assigned to
`receive fulvestrant plus anastrozole, 231 to fulvestrant plus placebo, and 249 to exemestane. Median PFS was
`4-4 months (95% CI 3-4-5-4) in patients assigned to fulvestrant plus anastrozole, 4-8 months (3-6-5-5) in those
`assigned to fulvestrant plus placebo, and 3-4 months (3- 0-4-6) in those assigned to exemestane. No difference was
`recorded between the patients assigned to fulvestrant plus anastrozole and fulvestrant plus placebo (hazard ratio
`1-00, 95% CI 0-83-1-21; log-rank p=0-98), or between those assigned to fulvestrant plus placebo and exemestane
`(0-95, 0-79-1-14; log-rank p=0-56). 87 serious adverse events were reported: 36 in patients assigned to fulvestrant
`plus anastrozole, 22 in those assignedto fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4
`adverse events were rare; the most frequent werearthralgia (three in the group assignedto fulvestrant plus anastrozole;
`seven in that assigned to fulvestrant plus placebo; eight in that assigned to exemestane), lethargy (three; 11; 11), and
`nausea or vomiting(five; two; eight).
`
`Interpretation After loss of response to NSAIs in postmenopausal women with hormone-receptor-positive advanced
`breast cancer, maximum double endocrine treatment with 250 mg fulvestrant combined with oestrogen deprivation
`is no better than either fulvestrant alone or exemestane.
`
`Funding Cancer Research UK and AstraZeneca.
`
`Introduction
`The optimum endocrine treatment for postmenopausal
`women with advanced hormone-receptor-positive breast
`cancer that has progressed during treatment with non-
`steroidal aromatase inhibitors (NSAIs) is unclear.’ The
`steroidal aromatase inactivator exemestane’’ and the
`
`steroidal oestrogen-receptor downregulator fulvestrant*’
`have been recognised standards of care in this setting.
`The phase 3 EFECTtrial’ showed no difference in clinical
`efficacy between these two treatments for patients with
`oestrogen receptor (ER)-positive metastatic breast cancer
`in the first-line and second-line settings.
`
`www.thelancet.com/oncology Vol14 September 2013
`
`Articles
`
`>r®CrossMark
`
`Lancet Oncol 2013; 14: 989-98
`Published Online
`July29, 2013
`http://dx,doi.org/10.1016/
`$1470-2045(13 )70322-X
`This online publication has
`been corrected. The corrected
`versionfirst appeared at
`thelancet.com/oncology on
`August 27, 2013
`See Comment page 917
`Copyright ©Johnston et al. Open
`Accessarticle distributed under
`the terms of CC BY-NC-SA
`
`*Listed in the appendix
`Royal Marsden NHS
`Foundation Trust, London, UK.
`(Prof S R D Johnston,
`E Folkerd PhD,
`Prof M Dowsett PhD);Clinical
`Trials and Statistics Unit (ICR-
`CTSU), The Institute of Cancer
`Research, London, UK
`(LS Kilburn MSc,
`G Coombes RGN,
`Prof) M Bliss MSc); King’s
`Health Partners, London, UK
`(Prof P Ellis MD); Leeds Teaching
`Hospitals NHS Trust, StJames’s
`University Hospital, Leeds, UK
`(Prof D Docdwell MD); University
`of Edinburgh and NHS Lothian,
`Edinburgh, UK
`(Prof D Cameron MD); Western
`General Hospital, Edinburgh,
`UK (L Hayward MD); Samsung
`Medical Center, Seoul, South
`Korea (Y-H lm MD); Bristol
`Haematology and Oncology
`Centre, Bristol, UK
`(J P Braybrooke MD); University
`Hospital of North
`Staffordshire, Stoke-on-Trent,
`UK (A M Brunt MD);
`Nottingham University
`Hospitals, Nottingham, UK
`(K-L Cheung MD); Kent
`Oncology Centre, Maidstone,
`UK (R Jyothirmayi MD);
`Southend Hospital, Southend,
`
`989
`
`AstraZeneca Exhibit 2063p. 1
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`Articles
`
`UK (A Robinson MD); The
`Christie NHS Foundation Trust,
`Manchester, UK
`(AM Wardley MD,
`Prof A Howell MD); Royal
`Cornwall Hospital, Truro, UK
`(DWheatley MD); CancerClinical
`Trials Team, Information
`Services Division, Edinburgh,
`UK (N Sergenson BSc); and
`AstraZeneca Korea, Seoul,
`South Korea (H-} Sin BSc)
`Correspondenceto:
`Prof Stephen R D Johnston,
`Department of Medicine, The
`Royal Marsden NHS Foundation
`Trust, London SW3 6)J, UK
`stephen.johnston@rmh.nhs.
`uk
`
`See Online for appendix
`
`setting of acquired
`in the
`Treatment options
`resistance to NSAls in ER-positive advanced breast
`cancer have changedsince the results of the BOLERO-2
`trial were reported.”* Thistrial showed that progression-
`free survival (PFS) was longer with the combination of
`exemestane and the mTOR antagonist everolimus than
`with exemestane alone.® However, whether double
`endocrine targeting would be more effective than a
`partially non-cross-resistant endocrine agent
`in the
`setting of acquired resistance is unclear. Preclinical
`studies*”
`have
`suggested
`that
`the
`efficacy of
`fulvestrant could be increased in a low oestrogen
`environment. As a competitive antagonist
`for ER,
`oestradiol can compete with fulvestrant for receptor-
`site
`occupancy.
`In MCF-7
`aromatase-transfected
`xenografts,
`the combination of fulvestrant and an
`aromatase inhibitor was more effective than either
`treatment alone.""” Furthermore, in model systems of
`acquired resistance to long-term oestrogen deprivation,
`breast cancer cells seem to be stimulated by low
`residual amounts of oestrogens, which potentially
`could be enhanced on withdrawal of oestrogen
`suppression at the time of progression."*
`Thus,
`a maximum double endocrine targeting
`approachin the setting of acquired resistance to NSAIs
`should be investigated with fulvestrant in combination
`with continued oestrogen deprivation. The Study of
`Faslodex with or without concomitant Arimidex vs
`Exemestane following progression on non-steroidal
`Aromatase
`inhibitors
`(SoFEA)
`was
`designed.
`Exemestane was the appropriate standard of care
`(control) at the time the trial was designed and was
`compared with the then accepted optimum dosing
`schedule for fulvestrant.
`
`
`
`
`
`723 patients randomly assigned
`
` ¥v
`¥v v
`
`
`
`
`
`
`
`249 assigned to exemestane
`243 assigned to fulvestrant
`231 assigned to fulvestrant
`plus anastrozole
`plus placebo
`
`
`Ly} 2did notstart treatment
`
`
`
`
`t—e 2 did not start treatment
`-—P 1didnotstart treatment
`Vv v Vv
`
`
`
`
`
`230 received assigned
`241 received assigned
`247 received assigned
`treatment
`treatment
`treatment
`
`
`
`
`222 discontinued
`207 progressed
`8 had adverse events
`7 decision by patient
`or investigator
`
`
`
`
`
`
`
`237 discontinued
`213 progressed
`6died
`9 had adverse events
`9 decision by patient
`or investigator
`
`10 still on treatment
`
`
`
`
`
`
`
` Vv
`
`
`
`
`
`
`
`238 discontinued
`221 progressed
`3 died
`7 had adverse events.
`7 decision by patient
`or investigator
`
`Vv
`3 still on treatment
`
`
`Figure 1: Trial profile
`
`
`
`
`
`
`
`¥
`8 still on treatment
`
`Methods
`Study design and participants
`SoFEA was a phase 3 multicentre randomised controlled
`trial
`that was done in 82 UK centres. Additionally,
`investigators in South Korea expressed interest in joining
`the trial. To simplify governance arrangements,a parallel
`trial, sponsored by AstraZeneca and following the SoFEA
`protocol and case report forms, was initiated. Patients
`were recruited from four South Korean centres. The
`SoFEA trial as presented here represents a composite of
`the UK and South Koreaninitiatives.
`Postmenopausal women with hormone-receptor-
`positive breast cancer (ER positive or progesterone
`receptor [PR] positive, or both) were eligible if they
`relapsed or progressed with locally advanced or
`metastatic disease on an NSAI. The NSAI hadto have
`been given as adjuvant treatment for at least 12 months,
`or as
`first-line treatment
`for
`locally advanced or
`metastatic disease for at least 6 months. Patients had to
`have adequate haematological, hepatic, and renal
`function, and a WHO performance status of 0-2.
`Patients
`already
`established
`on
`bisphosphonate
`treatment for at least 6 months or those who were due
`to start bisphosphonate treatment for bone metastases
`with other assessable sites of disease were eligible.
`Patients could have previously received tamoxifen and
`chemotherapy in the adjuvant or neoadjuvant setting or
`chemotherapy as first-line treatment
`for metastatic
`breast cancer followed by an NSAI alone for at least
`6 months. Patients were excluded if they had rapidly
`progressing visceral disease, malignancies other than
`breast cancer
`in the previous 5 years
`(except
`for
`adequately treated in-situ carcinoma of the cervix, or
`basal-cell or squamous-cell carcinoma of the skin), or
`thrombocytopenia (because ofthe risk of bleeding with
`intramuscular injection of fulvestrant). Additionally,
`patients who had received systemic corticosteroids for
`more than 15 days in the 4 weeks before randomisation
`were excluded.
`In the UK,this trial was approved by the Medicines and
`Healthcare
`products
`Regulatory Authority
`and
`South West 2 Multi-Research Ethics Committee (MREC
`03/6/77). In South Korea, the study was approved by
`Korea Food
`and Drug Administration and local
`institutional review boards. All patients provided written
`informed consent. The Institute of Cancer Research-
`Clinical Trials and Statistics Unit (ICR-CTSU; London,
`UK) had overall responsibility for trial management; two
`additional collaborating trials units, Cancer Clinical
`Trials Team Information Services Division (Edinburgh,
`UK) and C+R Research (Seoul, South Korea), were
`responsible for regional data management. The tial
`management group was
`responsible for day-to-day
`running of the trial. The trial was overseen by an
`independenttrial steering committee. Emerging safety
`and. efficacy data were confidentially reviewed regularly
`by the independent data monitoring committee.
`
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`at baseline and
`Plasma oestradiol concentrations
`3 months were also measured as an exploratory endpoint
`in a subset of patients who underwent randomisation
`after Nov 19, 2007, and who consented to and contributed
`at least one blood sample. Oestradiol analyses were done
`by Pharmanet(Princeton, NJ, USA) by gaschromatography
`tandem mass spectrometry with negative ion chemical
`ionisation after derivatisation ofthe steroid. The sensitivity
`of the assay was 0-625 pg/mL (2-3 pmol/L).
`
`Randomisation and masking
`to receive
`Patients were randomly assigned (1:1:1)
`fulvestrant plus anastrozole, fulvestrant plus placebo, or
`exemestane. Computer-generated permuted blocks were
`used, and stratification was by centre and previous use of
`an NSAIas adjuvant treatment orfor locally advanced or
`metastatic disease. Independent randomisation was by
`telephone to ICR-CTSU and the Information Services
`Division in the UK and AstraZeneca in South Korea.
`Participants and. investigators were aware of assignment
`to fulvestrant or exemestane, but not of assignment to
`anastrozole or placebo for patients in the groups assigned
`to fulvestrant.
`
`Statistical analysis
`The sample size was based on two primary aims: to detect
`an improvement in median PFS from 5-5 to 7-5 months
`in patients allocated to fulvestrant plus anastrozole
`compared with fulvestrant plus placebo, and from
`4-0 to 5-5 months in patients allocated to fulvestrant
`compared with exemestane. With a minimum follow-up
`of 6 months, 5% significance level (two-sided), and 90%
`power, 750 patients (250 per group) with 440 progression
`
`
`Exemestane
`Fulvestrant plus
`Fulvestrantplus
`
`(n=249)
`anastrozole (n=243) placebo (n=231)
`63-4 (57:0-73:5)
`
`66.0 (59:2-75-0)
`
`63-8 (57:0-72-0)
`
`
`
`Procedures
`Fulvestrant was given with a loading dose schedule of a
`500 mg intramuscular
`injection into the gluteus
`maximus on day 1, followed by 250 mg injections on
`days
`15 and 29. Thereafter, 250 mg intramuscular
`injections were done every 28 days. Injections were given
`slowly, over the course of at least 2 min. Anastrozole
`(1 mg), matched placebo, and exemestane (25 mg) were
`given orally once daily. All treatments were given until
`Age. at randomisation (years)
`disease progression or withdrawal.
`Hormone-receptor status
`Data for treatment compliance were obtained for
`aici aid
`fulvestrant only, for which a delay was allowed for
`epost Heneynae
`recovery from toxic effects. Dose reductions are not
`Eg pesitide, ERunlsawe
`standard for the treatments investigated in this trial.
`ER negative or unknown,PR positive
`Timing of and reasons for treatment discontinuation
`ER ubkeswg PRunknowin
`were
`recorded. Fulvestrant,
`anastrozole,
`and the
`HER2 status
`anastrozole-matched
`placebo were
`supplied
`by
`pepe
`AstraZeneca. Exemestane was dispensed from hospital
`Negative
`pharmaciesor via the patient’s primary-care physician.
`Unknown
`Clinical assessment and toxicity reporting occurred
`Previous tamoxifen in adjuvant setting
`monthly during the first 6 months, and every 3 months
`Timefrom primary diagnosis to first
`thereafter while treatment continued. Tumour assessment
`(pee OSS:
`with Response Evaluation Criteria in Solid Tumors
`(RECIST:; version 1.0) was done every 3 months and at oa before randomisation
`discontinuation or withdrawal from treatment. Adverse
`setae
`events were graded according to National CancerInstitute
`Locally advanced or metastatic breast
`cancer
`Common Toxicity Criteria (version 3.0) and coded with the
`Medical Dictionary for Regulatory Activities (MedDRA;
`NSAIsetting and time on NSAI
`version 14.0), with central clinical review by SRDJ.
`Adjuvant
`Locally advanced or metastatic breast
`The primary endpoint was PFS, which was defined as
`cancer; <1 year
`time from randomisation to progression of existing
`Locally advanced or metastatic breast
`disease, new sites of disease, second primary cancer if
`cancer; 1 to <2 years
`change in systemic treatment was necessary, or death
`Locally advanced or metastatic breast
`from any cause. Secondary endpoints were overall
`SaRRTAEE YEAS
`survival (time from randomisation to death from any
`cause),
`objective
`response
`(proportion
`achieving Se
`145 (58%)
`LAB LO2)
`138:(67%)
`complete or partial response ontrial treatment), clinical
`“ines
`7A (29%)
`30 (22%)
`SBE)
`benefit
`(proportion achieving complete or partial
`SSTEUSUEDT DEGE
`32 (13%)
`37 (169%)
`37 (15%)
`response, or stable disease for at least 6 monthson trial
`Bone
`treatment), duration of response or clinical benefit (PFS
`Data are n (%) or median (IQR), ER=oestrogen receptor. PR=progesterone receptor, NSAl=non-steroidal aromatase
`inhibitor. *Data missing for one patient assigned to fulvestrant plus placebo and oneassigned to exemestane.
`in patients who had an objective response or clinical
`benefit), time to treatment failure (not reported here),
`Table 1: Baseline characteristics
`and tolerability and safety.
`
`
`
`120 (49%)
`38 (16%)
`83 (34%)
`2 (1%)
`o
`
`1)
`122 (50%)
`104 (43%)
`171. (70%)
`5:0 (2.3-10:0)
`
`124 (54%)
`33 (14%)
`71 (31%)
`1 (<1%)
`2 (1%)
`
`132 (53%)
`23 (9%)
`91 (37%)
`2 (1%)
`1 (<1%)
`
`14 (6%)
`141 (61%)
`76 (33%)
`170 (74%)
`5:1 (2:4-9-7)
`
`17 (7%)
`142 (57%)
`90 (36%)
`166 (67%)
`5:2 (2:0-10.2)
`
`20-1 (12.9-32.9)
`21:2 (120-345)
`21:5 (13-4-34-0)
`a earr
`20:1 (12-6-29.2)
`18-6 (11.7-33.1)
`19.3 (12:1-31.0)
`
`42 (17%)
`44 (18%)
`
`87 (36%)
`
`70 (29%)
`
`50 (22%)
`AQ (21%)
`
`61 (26%)
`
`71 (31%)
`
`42 (17%)
`51 (20%)
`
`88 (35%)
`
`68 (27%)
`
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`events in the two fulvestrant groups were needed for the
`principal analysis. Because ofalong period ofrecruitment,
`in 2010,
`the independent data monitoring committee
`agreed that
`the data were sufficiently mature for
`723 enrolled patients to answer the principal questions
`with the same number of events, but in a smaller total
`numberofpatients who had been followed up foralonger
`period than originally anticipated.
`The principal efficacy analyses included all patients who
`underwent randomisation on an intention-to-treat basis.
`Survival endpoints were shown graphically with Kaplan-
`Meier plots, and treatment comparisons made with the
`log-rank test. Hazard ratios (HRs) were obtained from Cox
`
`
`A
`100
`ao
`
`a
`& 70-4
`z ae
`2
`=
`s 404
`a —_
`e
`
`ae)
`10-
`m
`
`B
`ig
`
`ao
`g0-
`= p-
`z
`2 60-4
`g 50
`¢ a
`%
`8 30
`2-4
`
`9
`oe- = =
`ee
`Fulvestrant plus 234
`ieee
`
`
`
`
`10-4 nena
`i
`-
`+
`1
`I
`I
`“Timnehorhtahdorriteatishtenths
`55
`44
`29
`
`149
`
`90
`
`88
`
`64
`
`42
`
`30
`
`NUTSESTER
`Fulvestrant plus 234
`placebo
`Exemestane 249
`a37
`Figure2: Progression-free survival
`(A) Fulvestrant plus anastrozole vs fulvestrant plus placebo. (B) Fulvestrant plus placebo vs exemestane.
`HR=hazard ratio.
`
`Role ofthe funding source
`The trial was cosponsored by The Royal Marsden NHS
`Foundation Trust and The Institute of Cancer Research in
`the UK; AstraZeneca sponsored the trial in South Korea.
`The funders had norole in data collection, data analysis,
`data interpretation, or writing of the report. The study
`design was peer-reviewed by Cancer Research UKandthe
`protocol was
`approved by the trial
`sponsors and
`AstraZeneca. SRDJ, LSK, and JMB had full access toall
`the data in the study, and SRDJ had fmal responsibility for
`gas
`P
`a
`the decision to submit for publication.
`
`.
`Results
`Between March 26, 2004, and Aug 6, 2010, 723 patients
`underwent randomisation (figure 1): 698 from the UK
`
`ay
`
`tT
`
`B
`
`Fr
`
`1
`
`18
`
`21
`
`2
`
`17
`
`992
`
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`
`proportional hazards regression models, with HRsof less
`than 1 favouring fulvestrant plus anastrozole in the
`comparison of fulvestrant plus placebo and fulvestrant
`plus anastrozole, and fulvestrant plus placebo in the
`comparison of fulvestrant plus placebo and exemestane.
`‘The proportionality assumption of the Cox model was
`tested with Schoenfeld residuals, and was shown to hold.
`Subgroup analyses were reported with forest plots for
`age at randomisation, ER and PR status, HER2 status,
`time from diagnosis to first relapse, dominant site of
`relapse, and NSAI setting and time on NSAI combined.
`In view of the absence of standard prognostic factors in
`this setting, and to avoid overparameterisation of a
`multivariable model, baseline
`characteristics were
`assessed. for prognostic ability, irrespective of treatment
`— Fulvestrant plus anastrozole (median 4-4 months, 95% C13-4-5-4)
`effect. Variables shown to be significant were combined
`Smnine iiiawa in a multivariable model with a forward stepwise method.
`‘Treatment was then added to the model to obtain the
`adjusted HR for
`treatrnent
`effect. Proportions of
`responses were compared with Fisher’s exacttests.
`Safety analyses were doneforall patients who received at
`least one dose oftrial treatment (as treated population).
`The worst grade of adverse event during trial treatment
`was reported and compared with Fisher's exact
`tests.
`All prespecified toxic effects and any MedDRA-coded event
`satisfying predefinedcriteria (ie, >10% frequency, p<0-01,
`or >1% difference in frequency between treatment groups)
`are presented. A significance level of <0-01 allowed some
`adjustment for multiple testing of toxicity endpoints.
`Geometric mean oestradiol concentrations were calculated
`by treatment group at each timepoint.
`This analysis includes all data received and processed
`by Jan 3, 2012. Data were collated at [CR-CTSU, whereall
`interim and final analyses were done. Centralstatistical
`monitoring was done by ICR-CTSU and was supple-
`mented by selected on-site source document verification.
`All analyses were donein Stata (version 10.1).
`This trial is registered as an International Standard
`Randomised Controlled Trial, number ISRCTN44195747,
`and with ClinicalTrials.gov, numbers NCT00253422 (UK)
`and NCT00944918 (South Korea).
`
`HR 1-00 (95% Cl 0-83-1.-21); log-rank p=0-98
`3
`é
`§
`-
`se
`"
`
`149
`
`90
`
`55
`
`»
`@
`
`44
`
`45
`“
`
`29
`
`ag
`~
`
`18
`
`nL
`@
`
`2
`
`24
`”
`
`1
`
`— Fiuluestnnttepliplames WreutcraherentWONTB-wiRt
`— Exemestane (median 3-4 months, 95% Cl3-0-4.6)
`
`
`
`

`

`
`
`
`
`
`ER positive, PR positive
`ER positive, PR negative
`ER positive, PR unknown
`HER2 status
`0-95 (0-75-1:22)
`—_}—_
`263
`HER? gate
`31 fp)? 1.44 (0.68-3.05)
`HER2 positive
`180
`—}___—-
`‘03 (0:76-1-40)
`HER2 unknown
`Time from diagnosis tofirst relapse (years)
`79 +» 118 (074-189)
`0:90 (0:56-1-46)
`<1
`72 —
`75
`—,,Nd4o2Jy¥Sg—————-
`1:13 (0:71-1-80)
`134 (0:84-2:15)
`13
`73
`—_>£\!\!__-1a_—_———_
`
`
`3to <5 82—_—_HdRR0-98 (0-62-1-53)88 —_B-H—_ 0:89 (0:58-1:37)
`
`35
`241 — .06 (0:82-1:38)
`244
`—_zZE-
`0:81 (0-62-1:05)
`Dominantsite of relapset
`—Hte-
`281
`Visceral
`—_}______
`118
`Soft tissueior node
`74 —_2___——_—
`Bone
`NSAI setting andtime on NSAI
`Adjuvant
`92 —_lt¥#__
`Locally advanced or metastatic breast cancer
`<l year 100 te_1.27 (0841.92)93 —_ 0.95 (0:63-1:44)
`
`
`
`1 to <2 years
`148
`——_l__.
`1:26 (0:90-1:77)
`149
`—_fH+
`0-75 (0:54-1:06)
`22
`141 —_—
`0:85 (0-60-1-19)
`139. —— 1:06 (0-75-1:50)
`Country
`
`
`UK 459-—i 1:00 (0:83-1:20) 465 a 0:96 (0:80-1:16)
`
`
`
`South Korea
`15
`p 174 (0-46-6-62)
`15
`2
`P 0-54 (0:14-2:05)
`Overall
`ATAE
`1.05 (0:87-1:26)
`480%
`0:92 (0-77-1-11)
`ye
`06
`20
`o1
`20
`1:0
`12
`—>
`+
`Favours fulvestrant plus placebo
`Favours fulvestrant plus placebo
`
`‘10 (0:86-1:39)
`0:98 (0:67-1:43)
`0:99 (0:61-159)
`
`0:97 (0:64-1:47)
`
`288
`124
`69
`
`92
`
`0-93 (0:73-1-18)
`—}—_
`0-79 (0:54-1:16)
`—_]}__—
`—_a___> 137 (0°83-2:25)
`
`———s
`
`0:90 (0:59-1:38)
`
`
`
`Articles
`
`
`
`A
`B
`
`
`n
`Hazard ratio (95% Cl)
`n
`Hazard ratio (95% Cl)
`
`Age at randomisation(years)
`0:90 (0:49-1:67)
`<50
`45 —————-8
`50-64
`211 — 0:92 (0:70-1:21)
`65-75
`129 —_
`01 (0-70-1-44)
`375
`89 ——____
`06 (0:69-1-63)
`ER and PR status*
`
`7 Spr $151 (059-385)
`210
`—_}__
`0:94 (0:72-1:25)
`135 — 0:81 (0-57-4115)
`108
`——_
`0:95 (0:64-1:42)
`
`0-85 (0-66-1.10)
`244 —ii-_
`fil
`—_It0S—]_ 130 (0-80-2.10)
`154
`—______—_
`17 (0-84-1.63)
`
`256
`56
`162
`
`—_Ht—
`——__—
`—]IE—-_—
`
`283
`31 ¢—___
`166
`
`—s
`——H¥#—
`
`0:94 (0:71-1.23)
`0:85 (0:49-1:48)
`0-93 (0-67-1.29)
`
`1.06 (0:83-1:34)
`0:20 (0-08-0-51)
`0-93 (0-68-1-27)
`
`
`
`06
`o1
`<<
`Favoursfulvestrant plus anastrozole
`
`—i-
`1-0
`
`12
`—>
`Favours exemestane
`
`Figure 3: Subgroupanalyses of progression-free survival
`(A) Fulvestrant plus anastrozole vs fulvestrant plus placebo. (B) Fulvestrant plus placebo vs exemestane, ER=oestrogen receptor. PR=progesterone receptor. NSAl=non-steroidal aromatase inhibitor.
`*Data for the few patients with ER-negative or unknown,and PR-positive disease, and those with unknown hormone-receptor-status not shown here, {Data missing for one patient assigned to
`ulvestrant plus placebo andone assigned to exemestane. +Adjusted for time from diagnosis to first relapse, numberof disease sites at baseline, and NSAI setting and time on NSAI.
`
`and 25 from South Korea. Baseline characteristics, such
`as time from diagnosis to first relapse and sites of
`dominant disease, are representative of a population of
`patients with
`hormone-receptor-positive metastatic
`breast cancer(table 1). 589 (81%) had previously received
`an NSAIin the locally advanced or metastatic setting for
`a median of 19-3 months (IQR 12-1-31-2;
`table 1),
`suggesting that this population had a good response to
`previous NSAI
`treatment. Four patients assigned to
`fulvestrant plus
`anastrozole missed a
`fulvestrant
`injection, and 109 patients (50 assigned to fulvestrant
`plus anastrozole; 59 assigned to fulvestrant plus placebo)
`had atleast one scheduled fulvestrant dose delay.
`After a median follow-upin all patients of 37-9 months
`(IQR 23-1-50-8), 689 progression events were reported:
`235 in patients assigned to fulvestrant plus anastrozole,
`
`221 in those assignedto fulvestrant plus placebo, and 233
`in those assigned to exemestane. No difference in PFS
`was recorded between patients assigned to fulvestrant
`plus anastrozole and fulvestrant plus placebo, or between
`those assigned to fulvestrantplus placebo and exemestane
`(figure 2). A multivariable analysis with adjustment for
`time from diagnosis to first relapse, number of disease
`sites present at baseline, and NSAIsetting and time on
`NSAIdid not substantially affect estimates of treatment
`effect (fulvestrant plus anastrozole vs fulvestrant plus
`placebo: HR 1-05, 95% CI 0-87-1: 26, p=0-62; fulvestrartt
`plus placebo vs exemestane: 0-92, 0-77-1-11, p=0-41).
`Subgroup analyses were consistent with the overall effect
`on PFS (figure 3).
`508 patients had died: 168 (69%) assigned to fulvestrant
`plus anastrozole, 167 (72%) to fulvestrant plus placebo,
`
`www.thelancet.com/oncology Vol14 September 2013
`
`993
`
`AstraZeneca Exhibit 2063 p. 5
`
`

`

`Articles
`
`
`
`100
`
`90-4
`
`80-
`
`70
`
`60-4
`
`50
`
`40-4
`
`307
`
`205
`
`
`
`
`
`Overallsurvival(%)
`
`— Fulvestrantplus anastrozole (median 20:2 months, 95% Cl 17:2-22:5)
`—— Fulvestrant plus placebo (median 19-4 months, 95% Cl 16-8-22-8)
`
`
`
` 0
`
`HR'0-95 (95% Cl.0-76-1.17); log rank p=0-61
`T
`T
`T
`T
`T
`3
`b
`9
`a2
`15018 280-338
`199
`6-182
`165s
`33,
`102 8 57
`46
`39
`37
`
`227
`
`225
`
`192
`
`176
`
`«4154
`
`133
`
`109
`
`86
`
`8668
`
`of
`
`44
`
`34
`
`30
`
`— Fulvestrant plus placebo (median 19-4 months, 95% Cl 16-8-22-8)
`— Exemestane (median 21-6 months, 95% Cl 19.4-23-9)
`
`27
`
`30
`
`33
`
`36
`
`than breast cancer (one pneumonia and one unknown)
`occurred on trial treatment, and neither was deemed to
`be related to treatment.
`No difference in overall survival was recorded between
`patients assigned to fulvestrant plus anastrozole and
`fulvestrant plus placebo, or between those assigned to
`fulvestrant plus placebo and exemestane (figure 4).
`Subgroup analyses were consistent with the overall effect
`on overall survival (appendix).
`(7%) of
`18
`In the intention-to-treat population,
`243 patients assigned to fulvestrant plus anastrozole
`had objective
`tumour
`responses
`(one
`complete
`response,
`17 partial
`response), as did 16
`(7%) of
`231 assigned to fulvestrant plus placebo (all partial
`response), and nine (4%) of 249 assigned to exemestane
`(two complete
`response,
`seven partial
`response;
`fulvestrant plus anastrozole vs fulvestrant plus placebo:
`p=0-88;
`fulvestrant plus placebo vs
`exemestane:
`p=0-27). 558 patients (77%) had measurable disease:
`194 (80%) assigned to fulvestrant plus anastrozole,
`178 (77%) to fulvestrant plus placebo, and 186 (75%) to
`exemestane. Of these patients,
`15
`(8%) patients
`assigned to fulvestrant plus anastrozole achieved
`objective responses(all partial response), as did 14 (8%)
`assigned to fulvestrant plus placebo (all partial
`response), and seven (4%) assigned to exemestane (one
`complete response, six partial response;
`fulvestrant
`plus anastrozole vs fulvestrant plus placebo: p=1-00;
`fulvestrant plus placebo vs exemestane: p=0-17).
`Median duration ofobjective response was 12-3 months
`(IQR 5-7—22.-1) for patients assigned to fulvestrant plus
`anastrozole, 16-5 months (7-829 -2) for those assigned
`to fulvestrant plus placebo, and 17-2 months (9-6—26-9)
`for those assigned to exemestane.
`82 patients
`(34%)
`assigned to fulvestrant plus
`HR 1:05 (95% Cl 0:84-1:29); log rank p=0-68
`anastrozole, 73
`(32%) assigned to fulvestrant plus
`T
`T
`T
`]
`T
`T
`T
`T
`3
`24
`21
`18
`6
`9
`12
`45
`placebo, and 67 (27%) assigned to exemestane achieved
`Time from randomisation (months)
`Number atrisk
`clinical benefit (fulvestrant plus anastrozole vs fulvestrant
`
`
`
`192 34=30176 «49154 «6133 «109 86s 57 44
`Fulvestrant plus 231
`225
`plus placebo: p=0-75;
`fulvestrant plus placebo vs
`placebo
`exemestane: p=0-27).
`In patients with measurable
`Exemestane 249
`disease, 63 (33%) assigned to fulvestrant plus anastrozole,
`55 (31%) assigned to fulvestrant plus placebo, and 43
`(23%) assigned to exemestane achieved clinical benefit
`(fulvestrant plus anastrozole vs fulvestrant plus placebo:
`p=0-94; fulvestrant plus placebo vs exemestane: p=0-16).
`Median duration of clinical benefit was 13-0 months
`(8-9-18-9)
`for patients assigned to fulvestrant plus
`anastrozole, 13-0 months (8-3-17-5) for those assigned
`to fulvestrant plus placebo, and 13-0 months (9-3-21-7)
`for those assigned to exemestane.
`87 serious adverse events were reported, of which
`three were
`suspected unexpected serious
`adverse
`reactions (one in the group assigned to fulvestrant plus
`anastrozole and two in the group assigned to fulvestrant
`plus placebo) and 11 were serious adverse reactions
`(six in the group assignedto fulvestrant plus anastrozole,
`three in that assigned to fulvestrant plus placebo, and
`
`10 9
` 9
`
`
`Numberatrisk
`Fulvestrant plus 243
`anastrozole
`Fulvestrant plus 231
`placebo
`
`B
`100
`
`905
`
`80
`
`705
`
`60
`
`50-4
`
`4044
`
`30
`
`20-4
`
`10
`
`0
`
`
`
`
`
`Overallsurvival(%)
`
` HR=hazard ratio,
`
`
`
`
`
`
`
`
`
`
`225
`
`200
`
`#179
`
`«#4158
`
`134
`
`117
`
`96
`
`8
`
`59
`
`49
`
`37
`
`31
`
`Figure 4: Overall survival
`(A) Fulvestrant plus anastrozole vs fulvestrant plus placebo. (B) Fulvestrant plus placebo vs exemestane.
`
`and 173 (69%) to exernestane. Most deaths were due to
`breast cancer. Only 12 deaths were reportedly due to
`other causes: cardiovascular (one patient assigned to
`fulvestrant plus anastrozole,
`two to fulvestrant plus
`placebo), cerebrovascular (one assigned to fulvestrant
`plus placebo, one to exemestane), primary lung cancer
`(one assigned to fulvestrant plus placebo, one to
`exemestane), pneumonia (one assigned to fulvestrant
`plus anastrozole, one to exemestane), neutropenic sepsis
`(one assigned to fulvestrant plus placebo), and unknown
`(one assigned to fulvestrant plus anastrozole, one to
`exemestane). Only two of the deaths due to causes other
`
`994
`
`www.thelancet.com/oncology Vol14 September 2013
`
`AstraZeneca Exhibit 2063 p. 6
`
`

`

`Articles
`
`
`
`Fulvestrant plus placebo
`Fulvestrant plus anastrozole
`(n=241)
`(n=230)
`
`
`Exemestane (n=247)
`
`
`
`
`
`
`
`0-62
`0:32
`073
`0:64
`0-41
`0.22
`0-73
`0:37
`0-60
`0-67
`0.02
`0.54
`0.08
`0.66
`0.01
`0.44
`0:33
`0-12
`0.12
`0.005
`0.80
`0:07
`O77
`0.37
`1.00
`0-12
`1.00
`0-42
`0-72
`1.00
`1.00
`0.86
`0:29
`059
`0.23
`0-25
`1.00.
`0:33
`0:30
`0-05
`1.00
`0.06
`0.22
`0-12
`0-72
`0.009
`0.07
`0-37
`1.00
`
`0-22
`0:89
`051
`OAL
`0:33
`O71
`034
`1-00
`0-65
`O75
`0:50
`0-84
`031
`0:23
`032
`0:20
`0:41
`0:36
`0-68
`0:13
`0:65
`0.09
`O77
`1.00
`O11
`0:36
`0:04
`0-69
`0:20
`0:08
`0:37
`0.57
`0:69
`1.00
`0-17
`0:50
`0:57
`1.00
`1.00
`0-19
`0:37
`077
`0-51
`O41
`0:05
`0:30
`0-16
`0-62
`0.51
`(Continueson next page)
`
`
`
`p value fulvestrant
`p-value fulvestrant plus
`plus placebo vs
`anastrozole vs
`fulvestrant plus placebo
`exemestane
`
`Any grade
`Grades3and4
` Anygrade Grades3and4 Anygrade
`Grades 3and4
`3 (1%)
`0
`1(<1%)
`0
`5 (2%)
`1 (<1%)
`25 (10%)
`0
`31 (13%)
`0
`32 (13%)
`0
`5 (2%)
`0
`3 (1%)
`1. (<1%)
`6 (2%)
`2 (1%)
`97 (40%)
`3 (1%)
`98 (43%)
`7 (3%)
`115 (47%)
`8 (3%)
`18(7%)
`1 {<1%)
`23 (10%)
`0
`18 (7%)
`1 (<1%)
`21 (9%)
`3 (1%)
`13 (6%)
`3 (1%)
`17 (7%)
`3 (1%)
`5 (2%)
`1 (<19%)
`3 (1%)
`0
`73%)
`0
`4 (2%)
`1(<1%)
`1(<1%)
`0
`1(<1%)
`0
`6 (2%)
`1 (<1%)
`8 (3%)
`4 (2%)
`11 (4%)
`0
`64 (27%)
` 2(1%)
`57 (25%)
`0
`58 (23%)
`1 (<1%)
`8 (3%)
`0
`20(9%)
`1 (<1%)
`17 (7%)
`0
`73 (30%)
`1 (<1%)
`63(27%)
`3 (1%)
`70 (28%)
`3 (1%)
`40 (17%)
`1 (<1%)
`53. (23%)
` 2.(1%)
`47(19%)
`0
`12 (5%)
`0
`9 (4%)
`0
`16 (6%)
`0
`0
`0
`6 (3%)
`0
`3(1%)
`0
`2(1%)
`0
`4 (2%)
`0
`1(<1%)
`0
`52 (22%)
`0
`59 (26%)
`1 (<1%)
`72 (29%)
`0
`0
`0
`3 (1%)
`0
`1(<1%)
`0
`Oo
`0
`3 (1%)
`0
`2 (1%)
`0
`17 (7%)
`1 (<