`
`Fulvestrant plus anastrozole or placebo versus exemestane
`alone after progression on non-steroidal aromatase inhibitors
`in postmenopausal patients with hormone-receptor-positive
`locally advanced or metastatic breast cancer (SoFEA):
`
`a composite, multicentre, phase 3 randomised trial
`
`Stephen R D Johnston, LucyS Kilburn, Paul Ellis, David Dodwell, David Cameron, Larry Hayward, Young—Hyucl<Im,}eremy P Braybrooke,
`A Murray Brunt, Kwol<—Leung Cheung, Remajyothirmayi, Anne Robinson, Andrew M Wardley, Duncan Wheatley, Anthony Howell, Gill Coombes,
`Nicole Sergenson, Hui—}ung Sin, Elizabeth Folkerd, Mitch Dowsett,}udith 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 women with 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 performance status 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 NSAI as adjuvant treatment or for locally advanced or metastatic
`disease. Participants and investigators were aware of assignment to 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 assigned to fulvestrant plus placebo, and 29 in those assigned to exemestane. Grade 3-4
`adverse events were rare; the most frequent were arthralgia (three in the group assigned to 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 fulvestrarit”
`have been recognised standards of care in this setting.
`The phase 3 EFECT trials showed no difference in clinical
`eflicacy 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 September2013
`
`Lancet Oncol 2013; 14: 989-98
`Published Online
`July 29, 2013
`http://dX.doi.org/10.1016/
`S1470-2045(13)70322-X
`This online publication has
`been corrected.The corrected
`version first appeared at
`the|ancet.com/o ncology on
`August 27, 2013
`See Comment page 917
`Copyright©Johnston et al. Open
`Access article distributed under
`the terms ofCC BY-NC-SA
`
`*Listed in the appendix
`Royal Marsden NHS
`FoundationTrust, London, UK
`(Prof S R Djohnston,
`E Folkerd PhD,
`Prof M Dowsett PhD); Clinical
`Trials and Statistics Unit (|CR-
`CTSU), The Institute ofCancer
`Research, London, UK
`(L S Kilburn MSc,
`G Coombes RGN,
`Prof] M Bliss MSc); King's
`Health Partners, London, UK
`(Prof P Ellis MD); LeedsTeaching
`Hospitals NHSTrust, StJames’s
`University Hospital, Leeds, UK
`(Prof D Dodwell 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 Im MD); Bristol
`Haematology andOnco|ogy
`Centre, Bristol, UK
`(J P Braybrooke MD); University
`Hospital of North
`Staffordshire, Stoke-o n-Trent,
`UK(A M Brunt MD);
`Nottingham University
`Hospitals, Nottingham, UK
`(K-LCheung MD); Kent
`0nco|ogyCentre,Maidstone,
`UK (Rjyothirmayi MD);
`Southend Hospital, Southend,
`
`989
`
`AstraZeneca EX. 2063 p. 1
`Mylan Pharms. Inc. V. AstraZeneca AB IPR2016-01325
`
`
`
`Articles
`
`UK(A Robinson MD);The
`Christie NHS FoundationTrust,
`Manchester, UK
`(A M Wardley MD,
`ProfA Howell MD); Royal
`Cornwall Hospital, Truro, UK
`(DWheat|ey MD); Cancer Clinical
`Trials Team, Information
`Services Division, Edinburgh,
`UK (N Sergenson BSc); and
`AstraZeneca Korea, Seoul,
`South Korea (H-J Sin BSc)
`Correspondence to:
`Prof Stephen R Djohnston,
`Department of Medicine,The
`Royal Marsden NHS Foundation
`Trust, London SW3 6]], 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 changed since the results ofthe BOLERO-2
`trial were reported.” This trial showed that progression-
`free survival (PES) was longer with the combination of
`exemestane and the mTOR antagonist everolimus than
`with exemestane alone.8 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
`efl"icacy 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.
`ln MCE-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
`approach in the setting of acquired resistance to NSAls
`should be investigated with fulvestrant in combination
`with continued oestrogen deprivation. The Study of
`Easlodex with or without concomitant Arimidex vs
`
`Exemestane following progression on non-steroidal
`Aromatase
`inhibitors
`(SoEEA)
`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 assignec
`
`V
`243 assigned to fulvestrant
`plus anastrozole
`
`V
`231 assigned to fulvestrant
`plus placebo
`
`V
`249 assigned to exemestane
`
`—D 2 did not start treatment
`
`—b 1 did not start treatment
`
`—b 2 did not start treatment
`
`V
`
`241 received assi ned9
`treatment
`
`V
`
`230 received assi ned9
`treatment
`
`V
`
`247 received assi ned9
`treatment
`
`238 discontinued
`221 progressec
`
`222 discontinued
`207 progressec
`
`237 discontinued
`213 progressec
`
`I
`
`3 died
`7 had adverse events
`7decision by patient
`or investigator
`
`I
`
`8 had adverse events
`7 decision by patient
`orinvestigator
`
`I
`
`6 died
`9 had adverse events
`9decision by patient
`or investigator
`
`V
`3 sti I on treatment
`
`V
`8 sti Ion treatment
`
`V
`10 still on treatment
`
`Figure 1:Trial profile
`
`990
`
`Methods
`Study design and participants
`SoEEA 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 SoEEA
`protocol and case report forms, was initiated. Patients
`were recruited from four South Korean centres. The
`
`SoEEA trial as presented here represents a composite of
`the UK and South Korean initiatives.
`
`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 had to 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 adj uvant 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 of the 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 trial
`management group was
`responsible for day-to-day
`running of the trial. The trial was overseen by an
`independent trial steering committee. Emerging safety
`and efl"icacy data were confidentially reviewed regularly
`by the independent data monitoring committee.
`
`www.thelancet.com/oncology Vol 14 September 2013
`
`AstraZeneca Ex. 2063 p. 2
`
`
`
`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 NSAI as adjuvant treatment or for locally advanced or
`metastatic disease. lndependent 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.
`
`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. lnjections 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
`disease progression or withdrawal.
`Data for treatment compliance were obtained for
`fulvestrant only,
`for which a delay was allowed for
`recovery from toxic effects. Dose reductions are not
`standard for the treatments investigated in this trial.
`Timing of and reasons for treatment discontinuation
`were
`recorded. Fulvestrant,
`anastrozole,
`and the
`anastrozole-matched
`placebo were
`supplied
`by
`AstraZeneca. Exemestane was dispensed from hospital
`pharmacies or via the patient’s primary-care physician.
`Clinical assessment and toxicity reporting occurred
`monthly during the first 6 months, and every 3 months
`thereafter while treatrnent continued. Tumour assessment
`
`with Response Evaluation Criteria in Solid Tumors
`(RECIST; version 1.0) was done every 3 months and at
`discontinuation or withdrawal from treatment. Adverse
`
`events were graded according to National Cancer Institute
`Common Toxicity Criteria (version 3 .0) and coded with the
`Medical Dictionary for Regulatory Activities (MedDRA;
`version 14.0), with central clinical review by SRD].
`The primary endpoint was PFS, which was defined as
`time from randomisation to progression of existing
`disease, new sites of disease, second primary cancer if
`change in systemic treatment was necessary, or death
`from any cause. Secondary endpoints were overall
`survival (time from randomisation to death from any
`cause),
`objective
`response
`(proportion
`achieving
`complete or partial response on trial treatment), clinical
`benefit
`(proportion achieving complete or partial
`response, or stable disease for at least 6 months on trial
`treatment), duration of response or clinical benefit (PFS
`in patients who had an objective response or clinical
`benefit), time to treatment failure (not reported here),
`and tolerability and safety.
`
`www.thelancet.com/oncology Vol14 September2013
`
`Articles
`
`Plasma oestradiol concentrations
`
`at baseline and
`
`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, N], USA) by gas chromatography
`tandem mass spectrometry with negative ion chemical
`ionisation after derivatisation ofthe steroid. The sensitivity
`ofthe assay was 0625 pg/mL (2-3 pmol/L).
`
`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
`
`Age at randomisation (years)
`Horm one-receptor status
`ER positive, PR positive
`ER positive, PR negative
`ER positive, PR unknown
`ER negative or unknown, PR positive
`ER unknown, PR unknown
`HER2 status
`
`3ositive
`Negative
`Jnknown
`Previoustamoxifen in adjuvant setting
`Time from primary diagnosistofirst
`re apse (years)
`Time on NSAI before randomisation
`(months)
`Adj uvant
`Locally advanced or metastatic breast
`cancer
`
`NSAI setting and time on NSAI
`Adj uvant
`Locally advanced or metastatic breast
`cancer; <1 year
`Locally advanced or metastatic breast
`cancer; 1 to <2 years
`Locally advanced or metastatic breast
`cancer; 22 years
`Site of relapse*
`Visceral
`Soft tissue or node
`Bone
`
`Fulvestrant plus
`Fulvestrant plus
`anastrozole (n=243) placebo (n=231)
`
`Exemestane
`(n=249)
`
`63-8 (57-0-72-0)
`
`63-4 (57-0-73-5)
`
`66-0 (59-2-75-o)
`
`120 (49%)
`38 (16%)
`83 (34%)
`2 (1%)
`0
`
`124 (54%)
`33 (14%)
`71 (31%)
`1 (<1%)
`2 (1%)
`
`132 (53%)
`23 (9%)
`91 (37%)
`2 (1%)
`1 (<1%)
`
`17 (7%)
`122 (50%)
`104 (43%)
`171 (70%)
`5-0 (2-3-10-0)
`
`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)
`
`215 (134-340)
`
`212 (120-345)
`
`2o-1(12-9-32-9)
`
`35-0 (240-447)
`20-1(12-6-29-2)
`
`24-9 (17-4-41-9)
`18-6 (117-331)
`
`242 (185-419)
`19-3 (12-1-31-0)
`
`42 (17%)
`44 (18%)
`
`87 (36%)
`
`70 (29%)
`
`138 (57%)
`68 (28%)
`37 (15%)
`
`5o (22%)
`49 (21%)
`
`61 (26%)
`
`71 (31%)
`
`143 (62%)
`50 (22%)
`37 (16%)
`
`42 (17%)
`51 (20%)
`
`88 (35%)
`
`68 (27%)
`
`145 (58%)
`71 (29%)
`32 (13%)
`
`Data are n (%) or median (IQR). ER=oestrogen receptor. PR=progesterone receptor. NSA|=non-steroidal aromatase
`inhibitor. *Data missing for one patient assigned to fulvestrant plus placeboand one assigned to exemestane.
`
`Table 1: Baseline characteristics
`
`991
`
`AstraZeneca Ex. 2063 p. 3
`
`
`
`proportional hazards regression models, with HRs of 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
`effect. Variables shown to be significant were combined
`in a multivariable model with a forward stepwise method.
`Treatment was then added to the model to obtain the
`
`effect. Proportions of
`treatment
`adjusted HR for
`responses were compared with Fisher’s exact tests.
`Safety analyses were done for all patients who received at
`least one dose of trial 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 predefined criteria (ie, 210% frequency, p<0-01,
`or >1% difference in frequency between treatrnent 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 ]an 3, 2012. Data were collated at lCR-CTSU, where all
`interim and final analyses were done. Central statistical
`monitoring was done by lCR-CTSU and was supple-
`mented by selected on-site source document verification.
`All analyses were done in Stata (version 10.1).
`This trial is registered as an International Standard
`Randomised Controlled Trial, number lSRCTN44195747,
`and with ClinicalTrials.gov, numbers NCT00253422 (UK)
`and NCT00944918 (South Korea).
`
`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 no role in data collection, data analysis,
`data interpretation, or writing of the report. The study
`design was peer-reviewed by Cancer Research UK and the
`protocol was
`approved by the trial
`sponsors and
`AstraZeneca. SRD], LSK, and ]MB had full access to all
`the data in the study, and SRD] had final responsibility for
`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
`
`wvvw.thelancet.com/oncology Vol 14 September 2013
`
`AstraZeneca Ex. 2063 p. 4
`
`Articles
`
`A
`100 —
`
`90-
`
`80-
`
`E 70-
`E 60-
`
`E"
`
`3 §
`
`50-
`
`SE
`
`Cl)
`4O_
`51
`9 30-
`D.
`
`20-
`
`10-
`
`O
`
`O
`
`Number at risk
`Fulvestrant plus 243
`anastrozole
`Fulvestrant plus
`placebo
`
`231
`
`B
`100 —
`90-
`
`80-
`
`E 70-
`E 60-
`
`E"
`
`3 E
`
`é
`.% 4O_
`D.
`" 30-
`20-
`
`50-
`
`10-
`
`O
`
`2 E
`
`— Fulvestrant plus placebo (median 4-8 months, 95% CI 3-6-5-5)
`— Exemestane (median 3-4 months, 95% CI 3-0-4-6)
`
`HR 0-95 (95% CI O-79-1-14); log-rank p=O-56
`
`events in the two fulvestrant groups were needed for the
`principal analysis. Because ofa long period ofrecruitment,
`in 2010,
`the independent data monitoring committee
`agreed that
`the data were sufliciently mature for
`723 enrolled patients to answer the principal questions
`with the same number of events, but in a smaller total
`number ofpatients who had been followed up for a longer
`period than originally anticipated.
`The principal eflicacy 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
`
`— Fulvestrant plus anastrozole (median 4-4 months, 95% CI 3-4-5-4)
`— Fulvestrant plus placebo (median 4-8 months, 95% CI 3-6-5-5)
`
`
`
`HR 1-oo (95%C| 0-83-1-21); log-rankp=O-98
`
`3
`
`148
`
`149
`
`é
`
`89
`
`90
`
`9
`
`67
`
`55
`
`1l2
`
`51
`
`44
`
`1%
`
`34
`
`29
`
`1l8
`
`23
`
`18
`
`*
`
`2l4
`
`13
`
`11
`
`2l1
`
`17
`
`12
`
`O
`
`Number at risk
`Fulvestrant plus
`placebo
`Exemestane 249
`
`231
`
`3
`
`149
`
`137
`
`é
`
`90
`
`88
`
`1%
`1l2
`9
`Time from randomisation (months)
`
`55
`
`64
`
`44
`
`42
`
`29
`
`30
`
`1l8
`
`18
`
`21
`
`2l1
`
`12
`
`17
`
`2l4
`
`11
`
`13
`
`Figure2: Progression-free survival
`(A) Fulvestrant plus anastrozole vs fulvestrant plus placebo. (B) Fulvestrant plus placebo vs exemestane.
`-lR=hazard ratio.
`
`992
`
`
`
`Articles
`
`A
`
`n
`Age at randomisation (years)
`o-9o (049-167)
`<50
`45 T-—
`0-92 (0-70-1-21)
`50-64
`211 —-—T
`-01 (0-70-1-44)
`65-75
`129
`jfle
`275
`89 Tie -06 (0-69-1-63)
`ER and PR status*
`
`Hazard ratio (95% CI)
`
`B
`
`n
`
`Hazard ratio (95% Cl)
`
`27 99-9» 1-51(o-59-3-85)
`210
`—-T
`0-94 (0-72-1-25)
`135
`—I——
`0-81 (0-57-1-15)
`108
`—[
`0-95 (0-64-1-42)
`
`ER positive, PR positive
`ER positive, PR negative
`ER positive, PR unknown
`HER2 status
`
`0-85 (0-66-1-10)
`_I__
`244
`71 > -30 (O-80-2-10)
`154 9-9 -17 (084-163)
`
`:'T
`256
`TI—
`56
`162 —-9
`
`0-94 (0-71-1-23)
`O-85 (O-49-1-48)
`O-93 (O-67-1-29)
`
`1-06 (0-83-1-34)
`0-20 (0-08-0-51)
`0-93 (0-68-1-27)
`
`0-95 (075-122)
`263 —-Z
`HER2 negative
`31 44-9» -44(0-68-3-05)
`HER2 positive
`180 mm
`-03 (0-76-1-40)
`HER2 unknown
`Time from diagnosisto first relapse (years)
`0-90 (0-56- -46)
`<1
`72 9}
`1—3
`73 > -34 (0-84-2-15)
`3to <5
`88 —I—e
`0-89 (0-58- -37)
`
`283
`31 49
`166
`
`T.
`:-.T
`
`79 m 1-18 (0-74-1-89)
`75 Tue 1-13 (0-71-1-80)
`82 TIT 0-98 (0-62-1-53)
`
`25
`Dominant site of relapsei’
`
`241 Tie
`
`-06 (0-82- -38)
`
`244
`
`—I——
`
`0-81 (0-62-1-05)
`
`-10 (0-86- -39)
`——-j
`281
`Visceral
`O-98 (O-67- -43)
`118 TIT
`Softtissue or node
`74 9-9 0-99 (0-61- -59)
`Bone
`NSAI setting andtime on NSAI
`Adjuvant
`92 9-3 0-97 (0-64- -47)
`Locally advanced or metastatic breast cancer
`0-95 (0-63- -44)
`<1 year
`93 —I-
`1 to <2 years
`148 :9 1-26 (0-90- -77)
`22
`141 —'—T
`0-85 (0-60- -19)
`Country
`
`0-93 (0-73-1-18)
`—IT
`288
`O-79 (O-54-1-16)
`j':T
`121
`69 } 137 (083-225)
`
`92
`
`jI—
`
`0-90 (0-59-1-38)
`
`100 T 1-27 (0-84-1-91)
`149
`Z-——
`0-75 (0-54-1-06)
`139
`Tim 1-06 (0-75-1-50)
`
`UK
`South Korea
`
`Overall
`
`459
`15
`
`—I—
`
`1-00 (0-83- -20)
`1-74 (0-46-6-62)
`
`465
`15
`
`—I—
`
`I
`
`474:1: + 105 (087-126)
`0l6
`1-0
`1l2
`2-0
`lj
`Favours fulvestrant plus anastrozole
`
`—>
`Favours fulvestrant plus placebo
`
`0|-1
`
`480:1:
`0|-1
`
`0l6
`4?
`Favours fulvestrant plus placebo
`
`—I—
`1-0
`
`1l2
`—>
`Favours exemestane
`
`0-96 (080-116)
`> 0-54 (0-14-2-05)
`
`092 (077-111)
`2l0
`
`Figure3: Subgroup analyses of progression-free survival
`(A) Fulvestrant plus anastrozole vs fulvestrant plus placebo. (B) Fulvestrant plus placebo vs exemestane. ER=oestrogen receptor. PR=progesterone receptor. NSA|=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 and one assigned to exemestane. iAdjusted for time from diagnosisto first relapse, number of 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 NSAI in 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 at least one scheduled fulvestrant dose delay.
`After a median follow-up in 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 assigned to fulvestrant plus placebo, and 233
`in those assigned to exemestane. No difference in PPS
`Was recorded between patients assigned to fulvestrant
`plus anastrozole and fulvestrant plus placebo, or between
`those assigned to fulvestrant plus 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 NSAI setting and time on
`NSAI did not substantially affect estimates of treatment
`effect (fulvestrant plus anastrozole vs fulvestrant plus
`placebo: HR 1-05, 95% Cl 0-87—1-26, p=0-62; fulvestrant
`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 September2013
`
`993
`
`AstraZeneca EX. 2063 p. 5
`
`
`
`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 of objective response was 12-3 months
`(IQR 5 ~7—22 ~ 1) for patients assigned to fulvestrant plus
`anastrozole, 16- 5 months (78-29 - 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
`anastrozole, 73
`(32%) assigned to fulvestrant plus
`placebo, and 67 (27%) assigned to exemestane achieved
`clinical benefit (fulvestrant plus anastrozole vs fulvestrant
`plus placebo: p=0-75;
`fulvestrant plus placebo vs
`exemestane: p=0~27).
`In patients with measurable
`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
`
`for patients assigned to fulvestrant plus
`(8~9—18-9)
`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 assigned to fulvestrant plus anastrozole,
`three in that assigned to fulvestrant plus placebo, and
`
`www.thelancet.com/oncology Vol 14 September 2013
`
`AstraZeneca Ex. 2063 p. 6
`
`Articles
`
`— Fulvestrant plus anastrozole (median 20-2 months, 95% CI17-2-22-5)
`— Fulvestrant plus placebo (median 19-4 months, 95% CI16-8-22-8)
`
`
`
`50-
`
`40-
`
`30-
`
`20-
`
`10-
`
`
`
`
`
`Overallsurvival(%)
`
`HR 0-95 (95% CI O-76-1-17); log rank p=O-61
`
`5
`199
`
`192
`
`9')
`182
`
`176
`
`1'2
`165
`
`154
`
`1'5
`133
`
`133
`
`1'8
`112
`
`109
`
`2'1
`89
`
`86
`
`2'4
`77
`
`68
`
`2'7
`57
`
`57
`
`3'0
`46
`
`44
`
`3'3
`39
`
`34
`
`3'6
`37
`
`30
`
`I3
`
`227
`
`225
`
`0
`
`O
`
`Numberatrisk
`Fulvestrantplus 243
`anastrozole
`Fulvestrantplus
`placebo
`
`231
`
`B
`100
`
`90-
`
`80-
`
`70-
`
`60-
`
`50-
`
`40-
`
`30-
`
`20-
`
`10-
`
`— Fulvestrant plus placebo (median 19-4 months, 95% CI16-8-22-8)
`— Exemestane (median 21-6 months, 95%C|19-4-23-9)
`
`
`
`
`
`
`
`Overallsurvival(%)
`
`HR 1-05 (95% Cl 084-129); log rank p=O-68
`
`2'4
`2'1
`1b
`1'5
`1'2
`Time from randomisation (months)
`154
`133
`109
`86
`68
`
`158
`
`134
`
`117
`
`96
`
`79
`
`2'7
`
`57
`
`59
`
`3'0
`
`44
`
`49
`
`3'3
`
`34
`
`37
`
`3'6
`
`30
`
`31
`
`9')
`
`176
`
`179
`
`é
`
`192
`
`200
`
`3 2
`
`25
`
`225
`
`Number at risk
`Fulvestrant plus
`placebo
`Exemestane
`
`231
`
`249
`
`Figure4: Overall survival
`(A) Fulvestrant plus anastrozole vs fulvestrant plus placebo. (B) Fulvestrant plus placebo vs exemestane.
`-lR=hazard ratio.
`
`and 173 (69%) to exemestane. 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
`
`
`
`Articles
`
`Fulvestrant plus anastrozole
`(n=241)
`
`Fulvestrant plus placebo
`(n=230)
`
`Exemestane (n=247)
`
`p value fulvestrant plus
`anastrozole vs
`fulvestrant plus placebo
`
`p value fulvestrant
`plus placebo vs
`exemestane
`
`Upper abdominal pain
`Alopecia*
`Anaemia
`Arthralgia*
`Back Jain
`Bone pain
`Breast pain
`Cellu itis
`Ches pain
`Cons ipation*
`Cough
`Decreased appetite*
`)iarr1oea*
`Dizziness
`Dry 5 in
`Dysgeusia
`)yspepsia*
`Dysp 1agia
`Dysp 1onia
`Dyspnoea
`:atigue
`-leadache*
`-lOtl'lUSh*
`-lyperhidrosis
`-lypertension
`-lypotension
`nfection
`nsomnia*
`oint swelling
`_ethargy*
`_ocalised infection
`_ower-respiratory-tract infection
`_ymphoedema
`Altered mood*
`Mucosal inflammation*
`Muscularweakness
`Musculoskeletal chest pain
`Musculoskeletal pain
`Myalgia
`Nausea orvomiting*
`Neck pain
`Peripheral neuropathy
`Peripheral oedema
`Oral candidosis
`Oropharyngeal pain
`Pain
`Pain in extremity
`Paraesthesia
`Pruritus
`
`Any grade
`3 (1%)
`25 (10%)
`5 (2%)
`97 (40%)
`18 (7%)
`21 (9%)
`5 (2%)
`4 (2%)
`6 (2%)
`64 (27%)
`8 (3%)
`73 (30%)
`40 (17%)
`12 (5%)
`0
`2 (1%)
`52 (22%)
`O
`O
`17 (7%)
`7 (3%)
`49 (20%)
`88 (37%)
`4 (2%)
`4 (2%)
`O
`1 (<1%)
`75 (31%)
`3 (1%)
`151 (63%)
`1 (<1%)
`17 (7%)
`6 (2%)
`53 (22%)
`15 (6%)
`3 (1%)
`8 (3%)
`11 (5%)
`1o (4%)
`83 (34%)
`2 (1%)
`1 (<1%)
`8 (3%)
`O
`3 (1%)
`4 (2%)
`15 (6%)
`4 (2%)
`4 (2%)
`
`Grades 3 and 4
`O
`o
`0
`3 (1%)
`1 (<1%)
`3 (1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`2 (1%)
`0
`1 (<1%)
`1 (<1%)
`O
`0
`O
`0
`O
`O
`1 (<1%)
`1 (<1%)
`1 (<1%)
`2 (1%)
`O
`2