`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 DJohnston, LucyS Kilburn, Paul Ellis, Dauid Dodwell, David Cameron, Larry Hayward, Young—Hyucl<lm,}eremy P Braybrooke,
`A Murray Brunt, Kwok—Leung Cheung, Remajyothirmayi, Anne Robinson, Andrew M Wardley, Duncan Wheatley, Anthony Howell, Gill Coombes,
`Nicole Sergenson, Hui—}ung Sin, Elizabeth Folkerd, Mitch Dowsett,judith M Bliss, on behalf of the SoFEA investigators*
`
`Summary
`Background The optimum endocrine treatment for postmenopausal women with advanced horrnone-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 (NSAls) 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 EFECT trial5 showed no dilterence 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
`
`Articles
`
`93(3)CrossMark
`
`Lancet Oncol 2013; 14: 98998
`Published Online
`July 29, 2013
`http://dX.doi.org/10.1016/
`S1470-2045(13)7D312-X
`This online publication has
`been corrected. The corrected
`version first appeared at
`thelancetcom/0 ncology on
`August 27, 2013
`See Comment page 917
`Copyright ©Johnston et al. Open
`Access article distributed under
`the terms of CC BY-NC-SA
`‘Listed in the appendix
`Royal Marsden NHS
`Foundation Trust, London, UK
`(Pro 5 R Djohnston,
`E Fo kerd PhD,
`Prof M Dowsett PhD); Clinical
`Tria s and Statistics Unit (|CR-
`CTSU), The Institute ofcancer
`Research, London, UK
`(LS ilburn MSc,
`G Coombes RGN,
`Prof] M Bliss MSc); King’;
`Hea th Partners, London, UK
`(Pro P Ellis MD); LeedsTeaching
`Hospitals NHSTrust, StJames’s
`University Hospital, Leeds, UK
`(Pro D Dodwell MD); University
`of Edinburgh and NHS Lothian,
`Edinburgh, UK
`(Pro DCameron MD); Western
`General Hospital, Edinburgh,
`UK (L Hayward MD); Samsung
`Mec ical Center, Seoul, South
`Korea (Y-H lm MD); Bristol
`Haematology andoncology
`Centre, Bristol, UK
`(J P Braybrooke MD); University
`Hospital of North
`Staffordshire, Stoke-on-Trent,
`UK (A M Brunt MD);
`Nottingham University
`Hospitals, Nottingham, U K
`(K-LCheung MD); Kent
`Oncology Centre, Maidstone,
`UK (Rjyothirmayi MD);
`Southend Hosp ital, Southend.
`
`989
`
`AstraZeneca Ex. 2063 p. 1
`Mylan Pharms. Inc. v. AstraZeneca AB IPR2016-01324
`
`
`
`Articles
`
`UK (A Robinson MD);The
`Christie NHS Foundation Trust,
`Manchester, UK
`(A M Wardley MD,
`ProfA Howell MD); Royal
`Cornwall Hospital, Truro, UK
`(Dwneatley MD); Cancer Clinical
`Tria|sTeam, Information
`Services Division, Edinburgh,
`UK (N Sergenson BSC); and
`AstraZeneca Korea, Seoul,
`South Korea (H—J Sin BSc)
`Correspondence to:
`ProfStephen R Djohnston,
`Department of Medicine,The
`Royal Marsden NHS Foundation
`Trust, London S\l\B 6JJ, UK
`stephen.johnston@rmh.nhs.
`uk
`
`See Online for appendix
`
`setting of acquired
`in the
`Treatinent options
`resistance to NSAIs in ER-positive advanced breast
`cancer have changed since the results of the 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? However, whether double
`endocrine targeting would be more efi"ective 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 MCE-7
`aromatase-transfected
`xenografts,
`the combination of fulvestrant and an
`aromatase inhibitor was more eifective 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 NSAIs
`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
`(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
`243 assigned to fulvestrant
`plus anastrozole
`
`V
`231 assigned to fulvestrant
`plus placebo
`
`V
`249 assigned to exemestane
`
`—> 2 did not start treatment
`
`—b 1 did not start treatment
`
`—b 2 did not start treatment
`
`V
`241 received assigned
`treatment
`
`V
`230 received assigned
`treatment
`
`V
`247 received assigned
`treatment
`
`238 discontinued
`221 progressed
`3 died
`7 had adverse events
`7 decision by patient
`or investigator
`
`I
`
`222 discontinued
`207 progressed
`8 had adverse events
`7 decision by patient
`or investigator
`
`I
`
`237 discontinued
`213 progressed
`6 died
`9 had adverse events
`9 decision by patient
`or investigator
`
`I
`
`V
`3 sti ion 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 sirnplify 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 eflicacy 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. Independent randomisation was by
`telephone to lCR—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. Anast:rozole
`(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 efl"ects. 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 lnstitute
`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 PPS, 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.
`
`vwvw.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 55 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)
`Hormone-receptor status
`ER positive, PR positive
`ER positive, PR negative
`ER positive, PR unknown
`ER negative or unknown, PR positive
`ER unknown, PR unknown
`H ER2 status
`
`Positive
`Negative
`Unknown
`Previoustamoxifen in adjuvant setting
`Time from primary diagnosistofirst
`relapse (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)
`63-8 (57-o—72.o)
`63 -4 (57-c»73-5)
`
`Exemestane
`(n=249)
`66-0(59i2—75-0)
`
`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-O)
`
`14 (6%)
`141 (61%)
`76 (33%)
`170 (74%)
`5-1 (24-97)
`
`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)
`2o-1(12-6-29-2)
`
`24-9 (17-4-41-9)
`18-6 (117-331)
`
`242 (185-419)
`19-3 (12-1-310)
`
`42 (17%)
`44 (18%)
`
`87 (36%)
`
`70 (29%)
`
`138 (57%)
`68 (28%)
`37 (15%)
`
`50 (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 placebo and one assignedto exemestane.
`Tablelz Baseline characteristics
`
`991
`
`Astrazeneca Ex. 2063 p. 3
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`
`
`Articles
`
`100 —
`
`90'
`80-
`
`70-
`
`60-
`
`50-
`
`40-
`
`
`
`
`
`Progression-freesurvival(%) 30-
`
`20-
`
`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 sulficiently mature for
`723 enrolled patients to answer the principal questions
`with the same number of events, but in a smaller total
`I11JII1l)E1' ofpatients who had been followed up for a longer
`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
`
`T Fulvestrantplus anastrozole (median 4-4 months, 95% CI 3-4-5-4)
`T Fulvestrantplus placebo (median 48 months, 95% CI 3-6-5-5)
`
`
`
`HR 1-00 (95% CI 0-83-1-21); log-rankp=0-98
`
`3'
`148
`
`149
`
`é
`89
`
`90
`
`é
`67
`
`55
`
`1'2
`51
`
`44
`
`1'5
`34
`
`29
`
`1'2
`23
`
`18
`
`2‘1
`17
`
`12
`
`2'4
`13
`
`11
`
`T Fulvestrantplus placebo (median 4-8 months, 95% Cl 3-6-5-5)
`T Exemestane (median 3-4 months, 95%C| 3 04-6)
`
`
`
`10-
`
`O
`
`0
`
`Number at risk
`Fulvestrant plus 243
`anastrozole
`Fulvestrant plus
`placebo
`
`231
`
`70-
`
`50-
`
`40-
`
`
`
`
`
`Progression-freesurvival(%) 30-
`
`20-
`
`10-
`
`HR 0-95 (95% CI o-79-1-14): IDg-rankp=O-56
`I
`I
`I
`I
`I
`15
`12
`3
`6
`9
`Time from randomisation (months)
`SS
`44
`2 9
`
`231
`
`149
`
`90
`
`249
`
`137
`
`88
`
`64
`
`42
`
`30
`
`I
`18
`
`18
`
`21
`
`I
`21
`
`12
`
`17
`
`I
`24
`
`11
`
`13
`
`Number at risk
`Fulvestrant plus
`placebo
`Exemestane
`
`Figure 2: Progression-free survival
`(A) Fulvestrant plus anastrozole us fulvestrant plus placebo, (B) Fulvestrant plus placebo vs exemestane.
`-lR=hazard ratio.
`
`991
`
`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, a.r1d 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
`efl"ect. 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 fiequency 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 Ian 3, 2012. Data were collated at ICR-CTSU, where all
`interim and final analyses were done. Central statistical
`monitoring was done by ICR-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 ISRCTN4419574-7,
`and with ClinicalTrials.gov, numbers NCT00253422 (UK)
`and NCT00944918 (South Korea).
`
`Role of the 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
`
`www.theIancet.com/oncology Vol 14 September 2013
`
`AstraZeneca Ex. 2063 p. 4
`
`
`
`Articles
`
`A
`
`n
`Age at randomisation (years)
`0-90 (0-49-1-67)
`<50
`45 T
`0-92 (070-121)
`50-64
`211 T-T
`65-75
`129 §IT 101 (070-144)
`275
`89 TIT 106 (069-163)
`ER and PR status"
`
`Hazard ratio (95% CI)
`
`B
`
`n
`
`Hazard ratio (95% Cl)
`
`27 > 1-51 [0-59-3-85)
`210
`T-T
`0-94 (072-125)
`135
`TIT
`0-81 (09-115)
`108
`T}
`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 } 1 30 (O-80-2-10)
`154 TIT 1-17 (O-84-1-63)
`
`TIT
`256
`56 T
`162
`T-T
`
`0-95 (075-122)
`263 —IT
`HER2 negative
`31 T» 144 (068-305)
`HER2 posltlve
`180 T-T
`103 (076-140)
`HER1 unknown
`Time from diagnosisto first relapse (years)
`0-90 (0-56-1-46)
`<1
`72 T-—
`1—3
`73 T; 1 34 (084-215)
`3to <5
`88 TIT
`0-89(0-58-1-37)
`25
`241
`TIT
`106 (082-138)
`Dominant site of relaipsei
`110 (086-139)
`TIT
`281
`Visceral
`118 T 0-98 (0-67-1-43)
`Soft tissue or node
`74 TIT 0-99 (0-61-1-59)
`Bone
`NSAI setting andtime on NSAI
`Adjuvant
`92 TIT 097 (064-147)
`Locally advanced or metastatic breast cancer
`0-95 (O-63-1-44)
`<1 year
`93 T}
`1 to <2 years
`148 TIT 1-26 (090-177)
`22
`141 TIT
`0-85 (060-119)
`Country
`
`0.94 (0714.23)
`O-85 (O-49-1-48)
`0-93 (O-67-1-29)
`
`1-06 (0-83-1-34)
`0-20 (0-08-0-51)
`0-93 (0-68-1-27)
`
`283
`31 (T
`166
`
`_ I
`T-T
`
`79 TuT 1-18 (0-74-1-89)
`75 TIT 113 (071-180)
`82 TIT 0-98 (062-153)
`244
`—I——
`0-81 (0-62-1-05)
`
`0-93 (0-73-1-18)
`T'T
`2 88
`0-79 (0-54-1-16)
`_.j_
`121
`69 FT; 137 (0-83-2-25)
`
`92
`
`T-—
`
`090 (0 59-1-38)
`
`100 T 1-27 (084-191)
`149
`—IT—
`0-75 (054-106)
`139
`T-T 1-06 (0-75-1-50)
`
`UK
`South Korea
`
`Overall
`
`1-00 (0-83-1-20)
`—-T
`459
`15 TT 174 (O-46-6-62)
`
`465
`15
`
`—I—
`
`-
`
`47411: + 105 (087-126)
`Ol5
`1-0
`1l2
`2lO
`0'1
`4?
`*5
`Favours fulvestrant plus anastrozole
`Favours fulvestrant plus placebo
`
`4801:
`Dl6
`0|-1
`{j
`Favours fulvestrant plus placebo
`
`—I—
`10
`
`1l2
`*5
`Favours exemestane
`
`0-96 (0-80-1-16)
`> 0-54 (0-14.2-05)
`
`092 (077-111)
`2lO
`
`Figure3: Subgroup analyses of progression-free survival
`(A) Fulvestrarit plus anastrozole us fulvestrarit plus placebo. (B) Fulvestrant plus placebo vs exemestarie. ER=oestrogen receptor. PR=prog esterone receptor. NSA|=non-steroidal aromatase inhibitor.
`*Data for the few patientswith ER-negative or unknown, and PR-positive disease, and those with unknown hormone-receptor-status not shown here. 'iData missing for one patient assigned to
`ulvestrant plus placebo and one assig ned to exemestarie. 3FAdjusted for time from diagnosisto first relapse, number of disease sites at baseline, and N SAI setting and time on N SAI.
`
`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 193 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 PFS
`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 afiect estimates of treatrnent
`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 efl"ect
`on PFS (figure 3).
`508 patients had died: 168 (69%) assigned to fulvestrant
`plus anastrozole, 167 (72%) to fulvestrant plus placebo,
`
`vwvw.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 efi"ect
`on overall survival (appendix).
`(7%) of
`18
`In the intention-to-treat population,
`243 patients assigned to fulvestrant plus anastrozole
`had objecljve
`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 (7~8—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 (fulve strant 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
`
`(89-189) for patients assigned to fulvestrant plus
`anastrozole, 13-0 months (83-175) for those assigned
`to fulvestrant plus placebo, and 13-0 months (9 - 3-21-7)
`for those assigned to exernestane.
`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.the|ancet.com/oncology Vol 14 September 2013
`
`AstraZeneca Ex. 2063 p. 6
`
`Articles
`
`T Fulvestrant plus anastrozole (median 20-2 months, 95% CI17-2-22-5)
`T Fulvestrant plus placebo (median 19-4 months, 95% C|16-8-22-8)
`
`
`
`50-
`
`40-
`
`30-
`20-
`
`10-
`
`
`
`
`
`Overallsurvival(Va)
`
`HR 0-95 (95% Cl 0-76-1-17); log rank p=D-61
`
`0
`
`0
`
`Number at risk
`Fulvestrantplus 243
`anastrozole
`Fulvestrantplus 231
`placebo
`
`1%
`199
`
`192
`
`_c',
`182
`
`176
`
`1'2
`165
`
`154
`
`1'5
`133
`
`133
`
`1%
`112
`
`109
`
`2'1
`89
`
`36
`
`2'4
`77
`
`68
`
`2'7
`57
`
`57
`
`3'0
`46
`
`44
`
`3'3
`39
`
`34
`
`3'5
`37
`
`30
`
`I3
`
`227
`
`225
`
`B
`100
`
`90‘
`80-
`
`70-
`60-
`
`S0-
`
`40*
`
`30-
`20-
`
`10-
`
`T Fulvestrantplus placebo (median 19-4 months, 95% C|16-8-11-8)
`T Exemesiane (median 21-6 months, 95%C|19-4-23-9)
`
`
`
`
`
`
`
`Overallsurvival(“/o)
`
`HR 1-05 (95% CI 0-84-1-29); log rankp=0-68
`
`2'4
`2'1
`1'3
`1'5
`1'2
`Time from randomisation (months)
`154
`133
`109
`36
`68
`
`153
`
`134
`
`117
`
`95
`
`79
`
`2'7
`
`57
`
`59
`
`3'0
`
`44
`
`49
`
`3'3
`
`34
`
`37
`
`3'5
`
`30
`
`31
`
`_c',
`
`176
`
`179
`
`6'
`
`192
`
`200
`
`3 2
`
`25
`
`225
`
`Number at risk
`Fulvestrant plus
`placebo
`Exemeslane
`
`231
`
`249
`
`Figure4: Overall survival
`(A) Fulvestrant plus anastrozole us 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=Z41)
`
`Fulvestra nt plus placebo
`(n=230)
`
`Exemestane (n=2 47)
`
`p value fu lvestrant plus
`anastrozole vs
`fulvestrant plus placebo
`
`p value fulvestra nt
`plus placebo vs
`exemestane
`
`Upper abdominal pain
`Alopecia*
`Anaemia
`Artl1ralgia'”
`Back Jain
`Bonepain
`Breast pain
`Cellu itis
`Chest pain
`Constipation*
`COUg‘I
`Decreased appetite*
`Diarr1oea*
`Dizziness
`Dry 5 in
`Dysgeusia
`Dyspepsia“
`Dysp wagia
`Dysp wonia
`Dyspnoea
`'atigue
`-ieadache*
`-lot flUSl1*
`-lyperhidrosis
`-lypertension
`-lypotension
`nfection
`nsomnia*
`oint swelling
`_etl1argy"
`Localised infection
`_ower—respiratory—tract infection
`_ymphoedema
`Altered mood*
`Mucosal inflammatiorf“
`Muscularweakness
`Musculoskeletal chest pain
`Nlusculoskeletal pain
`Myalgia
`Nausea or vomiting*
`Neck pain
`Peripheral neuropathy
`Peripheraloedema
`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%)
`o
`2 (1%)
`52 (22%)
`O
`0
`17 (7%)
`7 (3%)
`49 (20%)
`88 (37%)
`4 (2%)
`4(2%)
`0
`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%)
`0
`3 (1%)
`4 (2%)
`15 (6%)
`4(2%)
`4 (2%)
`
`Grades 3 and 4
`0
`o
`0
`3 (1%)
`1 (<1%)
`3 (1%)
`1 (<1%)
`1 (<1%)
`1 (<1%)
`2 (1%)
`0
`1 (<1%)
`1(<1%)
`0
`o
`0
`0
`0
`O
`1(<1%)
`1 (<1%)
`1 (<1%)
`2 (1%)
`O
`2 (1%)
`O
`0
`1 (<1%)
`0
`3 (1%)
`0
`2 (1%)
`O
`o
`O
`O
`O
`0
`o
`