Articles
`
`Fulvestrant 500 mg versus anastrozole 1 mg for hormone
`receptor-positive advanced breast cancer (FALCON):
`
`@KCQ
`
`an international, randomised, double-blind, phase 3 trial
`
`john F R Robertson *, lgor M Bondarenko, Ekaterina Trishkina, Mikhail Dvorkin, Lawrence Panasci, Alexey Manikhas, Yaroslav Shparyk,
`Servando Cardona-Huerta, Kwok-Leung Cheung, Manueljesus Philco-Salas, Manuel Ruiz-Borrego, Zhimin Shao, Shinzaburo Noguchi,
`jacqui Rowbottom, Mary Stuart, Lynda M Grinsted, Mehdi Fazal, Matthew} Ellis*
`
`Summary
`Background Aromatase inhibitors are a standard of Care for hormone receptor-positive locally advanced or metastatic
`breast cancer. We investigated whether the selective oestrogen receptor degrader fulvestrant could improve
`progression-free survival compared with anastrozole in postmenopausal patients who had not received previous
`endocrine therapy.
`
`Methods In this phase 3, randomised, double-blind trial, we recruited eligible patients with histologically confirmed
`oestrogen receptor-positive or progesterone receptor-positive, or both, locally advanced or metastatic breast cancer
`from 113 academic hospitals and community centres in 20 countries. Eligible patients were endocrine therapy-naive,
`with WHO performance status 0—2, and at least one measurable or non-measurable lesion. Patients were randomly
`assigned (1:1) to fulvestrant (500 mg intramuscular injection; on days 0, 14, 28, then every 28 days thereafter) or
`anastrozole (1 mg orally daily) using a computer-generated randomisation scheme. The primary endpoint was
`progression-free survival, determined by Response Evaluation Criteria in Solid Tumors version 1-1, intervention by
`surgery or radiotherapy because of disease deterioration, or death from any cause, assessed in the intention-to-treat
`population. Safety outcomes were assessed in all patients who received at least one dose of randomised treatment
`(including placebo). This trial is registered with ClinicalTrials.gov, number NCT01602380.
`
`Findings Between Oct 17, 2012, and Iuly 11, 2014, 524 patients were enrolled to this study. Of these, 462 patients were
`randomised (230 to receive fulvestrant and 232 to receive anastrozole). Progression-free survival was significantly
`longer in the fulvestrant group than in the anastrozole group (hazard ratio [HR] 0-797, 95% CI 0-637—0-999,
`p=0 - 0486). Median progression-free survival was 16- 6 months (95% CI 13- 83—20- 99) in the fulvestrant group versus
`13- 8 months (11-99—16-59) in the anastrozole group. The most common adverse events were arthralgia (38 [17%] in
`the fulvestrant group vs 24 [10%] in the anastrozole group) and hot flushes (26 [11%] in the fulvestrant group vs
`24 [10%] in the anastrozole group). 16 (7%) of 228 patients in in the fulvestrant group and 11 (5%) of 232 patients in
`the anastrozole group discontinued because of adverse events.
`
`Interpretation Fulvestrant has superior efficacy and is a preferred treatment option for patients with hormone
`receptor-positive locally advanced or metastatic breast cancer who have not received previous endocrine therapy
`compared with a third-generation aromatase inhibitor, a standard of care for first-line treatment of these patients.
`
`Funding AstraZeneca.
`
`Introduction
`post-
`for
`recommendations
`First-line
`treatment
`menopausal women with hormone receptor-positive
`(oestrogen receptor or progesterone receptor, or both)
`locally advanced or metastatic breast cancer includes
`endocrine therapy with a third-generation aromatase
`inhibitor
`(anastrozole,
`letrozole, or exemestane) or
`tamoxifen?3 In hormone receptor-positive disease, third-
`generation aromatase inhibitors have increased efficacy
`compared with tamoxifen in terms of
`time
`to
`progression.Hg
`Fulvestrant, a selective oestrogen receptor degrader
`that blocks oestrogen receptor function by inducing
`oestrogen receptor
`degradation,9
`is
`approved
`for
`postmenopausal women with hormone receptor-positive
`
`advanced breast cancer and disease progression after
`anti-oestrogen therapy.”11 The 500 mg dose of fulvestrant
`was approved based on data from the phase 3,
`double-blind Comparison of Faslodex in Recurrent or
`Metastatic Breast Cancer
`(CONFIRMW study that
`compared fulvestrant 500 mg with fulvestrant 250 mg in
`patients with hormone receptor-positive advanced breast
`cancer who had progression after endocrine therapy. In
`CONFIRM, progression-free survival (hazard ratio [HR]
`080, 95% CI 0-68—0~94; p=0~006)12 and overall survival
`(HR 081, 069—096; p=0~02)13 were increased with
`fulvestrant 500 mg versus fulvestrant 250 mg.
`Improved
`eficacy of
`first-line
`treatment with
`fulvestrant compared with anastrozole was shown in the
`phase
`2,
`open-label Fulvestrant First-Line Study
`
`Published Online
`November 28,2016
`http://dx.doi.org/10.1016/
`50140—6736(16)32389—3
`See Online/Comment
`http://dx.doiorg/10.1016]
`sor4o-6736(16)32418—7
`*Contributed equally tothis
`article
`Division of Medical Sciences
`and Graduate Entry Medicine,
`School of Medicine, University
`of Nottingham, Royal Derby
`Hospital Centre, Derby, UK
`(ProfJFR Robertson MD,
`K—L Cheung MD); Oncology
`Department, Dnipropetrovsk
`State Medical Academy,
`Dnipropetrovsk, Ukraine
`(Prof IM Bondarenko PhD);
`Leningrad Regional Oncology
`Dispensary, St Pete rsburg,
`Russia (ETrishkina PhD); Clinical
`Oncology Dispensary, Omsk,
`Russia (M Dvorkin MD);
`Department ofOncology,
`Jewish General Hospital,
`Montreal, Canada
`(Prof L Panasci MD); City Clinical
`Oncology Dispensary,
`St Petersburg, Russia
`(A Manikhas MD); Lviv State
`Oncology Regional Treatment
`and Diagnostic Centre, Lviv,
`Ukraine (Y Shparyk PhD); Breast
`Cancer Center, Tecnoiégico de
`Monterrey, Monterrey, Mexico
`(S Cardona-Huerta PhD); Unidad
`de Investigacién, Institute
`Oncologico de Lima, Lima, Peru
`(MJ Philco-Salas MD); Hospital
`Universitario Virgen del Rocio,
`Seville, Spain
`(M Ruiz-Borrego MD); Fudan
`University Shanghai Cancer
`Center, Shanghai, China
`(Prof Z Shao MD); Department
`of Breast and Endocrine
`Surgery, Osaka University
`Graduate School of Medicine,
`Osaka,Japan
`(Prof S Noguchi PhD);
`AstraZeneca, Alderley Park,
`Macclesfield, UK
`(J Rowbottom MSc,
`M Stuart MD); AstraZeneca,
`
`www.the|ancet.com Published online November 28, 2016 http://dx.doi.org/10.1016/50140-6736(16)32389-3
`
`AstraZeneca Exhibit 2154 p. 1
`InnoPharma Licensing LLC V. AstraZeneca AB IPR2017-00904
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`
`Cambridge, UK
`(Lynda M Grinsted MSc);
`AstraZe neca, Gaithersburg,
`MD, USA (M Fazal MD); and
`Lester and Sue Smith Breast
`Center, BaylorCollege of
`Medicine, Houston,Texas, USA
`(Prof M] Ellis PhD)
`Correspondence to:
`ProfJohn F R Robertson, Division
`of Medical Sciences and Graduate
`Entry Medicine,
`School of Medicine, Faculty of
`Medicine and Health Sciences,
`University of Nottingham, Royal
`Derby Hospital Centre, Derby
`DE22 EDT, UK
`john.robertson@nottingham.
`ac.uk
`
`See Online for appendix
`
`Research in context
`
`Evidence before this study
`We did a general search on PubMed and ClinicalTrials.gov using
`the search terms ”fulvestrant 500 mg" and "clinical trial" to
`identify clinical studies of fulvestrant 500 mg, a selective
`oestrogen receptor deg rader, versus any third—generation
`aromatase inhibitor. No date or language limitations were
`applied. A previous open—label, phase 2 study (FIRST) in
`postmenopausal women with hormone receptor—positive
`locally advanced or metastatic breast cancer, most ofwhom
`were endocrine—naive, showed that first—line fulvestrant was at
`least as effective as anastrozole in terms of clinical benefit rate
`
`and was superior in terms oftime to progression and overall
`survival.We identified no phase 3, double—blind trials
`comparing fulvestrant with anastrozole in hormone receptor—
`positive postmenopausal women with advanced breast cancer
`who have not received previous endocrine treatment.
`
`Added value of the study
`To our knowledge, the FALCON study is the first randomised,
`double—blind, multicentre trial to assess the efficacy and
`
`safety of fulvestrant compared with anastrozole in hormone
`receptor—positive postmenopausal women with advanced
`breast cancerwho have not received previous endocrine
`treatment—a clinically meaningful patient population.
`Results from our study therefore add to the extensive data for
`the efficacy and safety of fulvestrant in patients with
`advanced breast cancer and consolidate evidence for superior
`efficacy for fulvestrant compared with anastrozole shown in
`FIRST.
`
`Implications of all the available evidence
`The results ofthe FALCON study support the notion that a
`selective oestrogen receptor degrader is a more efficacious
`treatment than a third—generation aromatase inhibitor, which
`is the standard—of—care in first—line endocrine therapy for
`patients with hormone receptor—positive advanced breast
`cancer. These findings consolidate the known clinical
`effeCHVeness of fulvestra nt and support the use of fulvestrant
`monotherapy in endocrine—naive patients with hormone
`receptor-positive advanced breast cancer.
`
`in
`(FIRST)“
`Treatments
`Endocrine
`Comparing
`postmenopausal women with hormone receptor-positive
`locally advanced or metastatic breast cancer. Fulvestrant
`was shown to be at least as effective as anastrozole in
`
`terms of clinical benefit rate (74 [73%] of 102 with
`fulvestrant vs 69 [67%] of 103 with anastrozole; odds ratio
`[OR] 1-30, 95% CI 072—2-38, p=0~386).” In subsequent
`follow-up analyses, fulvestrant was associated with a
`longer progression-free survival/tune to progression
`than anastrozole (HR 0-66, 95% CI 0-47—0-92, p=0~01)15
`and improved overall survival compared with anastrozole
`(HR 0-70, 050—0-98, p=0.04).16
`In the Fulvestrant and Anastrozole Compared in
`Hormonal Therapy Naive Advanced Breast Cancer
`(FALCON) trial, we aimed to assess the progression-free
`survival advantage for fulvestrant versus anastrozole
`observed in the FIRST study. The population for
`FALCON were postmenopausal women with hormone
`receptor-positive locally advanced or metastatic breast
`cancer who had not received previous endocrine therapy
`to avoid reducing efficacy of the control group through
`exposure to adj uvant endocrine therapy.
`
`in Asia, Europe, North America,
`countries
`20
`South America, and South Africa.
`Eligible patients were postmenopausal women who
`had a WHO performance status of 0—2, and one or more
`measurable or non-measurable lesion. Key exclusion
`criteria were previous hormonal treafinent for breast
`cancer; presence of life-threatening, metastatic visceral
`disease; previous systemic therapy for breast cancer,
`except one line of cytotoxic chemotherapy; radiotherapy
`ifcompleted within 28 days before randomisation (unless
`for bone pain control); human epidermal growth factor
`receptor
`over-expression
`or
`gene
`amplification;
`concomitant anticancer treatment (except bisphospho-
`nates or denosumab); or systemic oestrogen-containing
`hormone-replacement
`therapy use within 6 months
`before randomisation (appendix).
`The study was done in accordance with the Declaration
`of Helsinki
`and
`International Conference
`on
`
`Harmonisation and Good Clinical Practice guidelines.
`An ethics committee or
`institutional
`review board
`
`approved the final protocol at each study site. All patients
`provided written, informed consent.
`
`Methods
`
`Study design and participants
`In this phase 3,
`randomised, double-blind, double-
`dummy international trial, we compared the efficacy and
`tolerability
`of
`fulvestrant with
`anastrozole
`in
`postmenopausal women with histologically confirmed
`hormone receptor-positive (oestrogen receptor-positive
`or progesterone
`receptor-positive, or both)
`locally
`advanced
`or metastatic
`breast
`cancer
`from
`
`113 academic hospitals and community centres in
`
`Randomisation and masking
`Patients were randomly assigned (1:1) sequentially to
`receive either fulvestrant 500 mg or anastrozole 1 mg
`using a computer-generated randomisation scheme and
`an integrated voice or web response system. Patients
`were stratified at randomisation according to locally
`advanced or metastatic breast cancer; previous or no
`previous
`treatment with chemotherapy for
`locally
`advanced or metastatic breast cancer; and measurable or
`non-measurable disease. Study drugs were labelled using
`
`www.thelancet.com Published online November 28, 2016 http://dx.doi.org/10.1016/50140-6736(16)32389-3
`
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`
`a unique identifier linked to the randomisation scheme.
`Neither participants nor investigators (including those
`assessing
`outcomes) were
`aware
`of
`treatment
`assignment. The active study drug and placebo for
`fulvestrant (prefilled syringes) and anastrozole (tablets)
`were identically packaged to maintain blinding.
`
`adverse events, discontinuations because of adverse
`events, deaths because of adverse events, and predefined
`adverse events of special interest (joint disorders and back
`pain). Laboratory variables, electrocardiogram recordings,
`physical examination, and vital signs were monitored at
`prespecified timepoints throughout the study.
`
`Procedures
`
`Study treatment was initiated at randomisation (day 0).
`Eulvestrant 500 mg (plus daily anastrozole placebo) was
`administered on days 0, 14 (plus or minus 3 days),
`28 (plus or minus 3 days), and every 28 (plus or minus
`3 days) days thereafter as two 5 mL intramuscular
`injections at each visit. No fulvestrant dose reductions
`were permitted. Anastrozole (plus fulvestrant placebo on
`days 0,
`14, 28, and every 28 days thereafter) was
`administered once daily as a single tablet. Treatment
`continued until objective disease progression or other
`criteria for discontinuation were met in terms of adverse
`
`events, protocol non-adherence, or patient’s decision to
`withdraw.
`
`Study visits occurred at screening (within 28 days
`before randomisation), randomisation (day 0), day 14,
`every 4 weeks from week 4to week 24, and every 12 weeks
`thereafter until
`disease
`progression.
`Safety
`and
`tolerability were assessed at each study visit, and for up
`to 8 weeks after the last fulvestrant or placebo injection.
`Health-related quality of
`life
`questionnaires17 were
`administered at baseline and every 3 months thereafter.
`After disease progression or treatment discontinuation,
`health-related questionnaires will be administered every
`6 months until a final overall survival analysis.
`
`Outcomes
`
`The primary endpoint of the study was progression-free
`survival of patients treated with fulvestrant versus
`anastrozole. A progression event was determined based
`on tumour assessments done locally by each investigator
`and was defined by Response Evaluation Criteria in Solid
`Tumors version 1-1, or surgery or radiotherapy for
`worsening of disease, or death from any cause.
`Secondary endpoints included objective response rate
`(best overall response of either complete response or
`partial response in patients with measurable disease at
`baseline), duration of response, and expected duration of
`response, clinical benefit rate (best overall response of
`complete response, partial response, or stable disease
`224 weeks), duration of clinical benefit, expected duration
`of clinical benefit, and overall survival
`(time from
`randomisation until death by any cause).
`Health-related quality of life was assessed using the
`Trial Outcome Index derived from the Functional
`
`Assessment of Cancer Therapy for Breast Cancer
`(FACT-B) questionnaire,17 and FACT-B total score.
`Safety and tolerability assessments included adverse
`events
`(graded according to Common Terminology
`Criteria for Adverse Event [CTCAE], version 4-0), serious
`
`Statistical analysis
`For the primary outcome, progression-free survival was
`assessed at a single timepoint when approximately
`306 progression events had occurred. Randomisation of
`approximately 450 patients was planned to achieve
`306 progression events. The HR of 0-69 was considered
`to be a reasonable estimate of the true HR in the
`
`FALCON population based on results from a phase 2
`study.”15 If 0-69 was the true progression-free survival
`HR for the comparison of fulvestrant with anastrozole,
`then 306 events was calculated to provide 90% power for
`statistical significance at
`the 5% two-sided level. A
`progression-free survival HR of 0-80 would deliver a
`statistically significant difference
`for
`the primary
`outcome. The primary analysis for this study was done in
`the intent-to-treat population comprising all randomly
`assigned patients. All safety outcomes were assessed in
`all patients who received at least one dose of randomised
`treatment (including placebo) according to the actual
`treatment initially received.
`Comparison of progression-free survival for fulvestrant
`versus anastrozole was done using a stratified log-rank
`test at
`the two-sided 5% significance level
`in the
`intention-to-treat population. Strata
`included were
`previous chemotherapy for locally advanced or metastatic
`disease and measurable disease; locally advanced versus
`metastatic disease was not included because only a small
`number of patients had locally advanced disease. Results
`are presented as an estimate of the HR, associated
`95% CI, and p value. An interim analysis of overall
`survival was done at the time of progression-free survival
`analysis, and overall survival was analysed in the same
`way as progression-free survival. Overall survival and
`objective response rate were tested with a multiple
`testing procedure with an a-exhaustive recycling strategy
`to control type I error at the overall 0L level.” Clinical
`benefit rate was analysed with a logistic regression model
`including the
`same
`stratification factors
`as
`for
`progression-free survival and examination of the OR of
`the two treatment groups. Objective response rate was
`analysed in the same way as clinical benefit rate; however,
`measurable disease was not
`included in the model.
`
`Kaplan-Meier plots were produced for duration of clinical
`benefit and duration of response. Expected duration of
`clinical benefit and expected duration of response are
`designed to provide an unbiased treatment comparison
`of duration of clinical benefit and duration of response
`by including all randomly assigned patients (rather than
`only responding patients) and were calculated using the
`method described by Ellis and colleagues.19 Expected
`
`www.the|ancet.com Published online November 28, 2016 http:lldxrdoi.org/10.1016/50140-6736(16)32389-3
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`
`
`524 enrolled
`
`62 not randomised
`44 eligibility criteria not fulfilled
`—> 13 patientdecision
`V
`2 lost to follow-up
`462 randomised
`3 other
`
`
`V
`V
`
`232 assigned to anastrozole 1 mg
`230 assigned to fu vestrant 500 mg*
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`49 ongoing study treatment at data cutoff
`
`
`
`
`
`5.6.
`
`
`Role ofthe funding source
`The funder of the study was involved in study design,
`reviewing and interpreting the data, and writing the
`manuscript. The funder of the study reviewed the
`manuscript before submission to ensure medical and
`scientific accuracy and for protection of intellectual
`property. All authors were involved in data analysis and
`interpretation, manuscript writing, and approved the
`final manuscript. All authors had full access to all the
`data in the study and had final responsibility for the
`decision to submit for publication.
`
`Results
`Between Oct 17, 2012, and July 11, 2014, 524 patients were
`enrolled to this study. Of these, 462 patients were
`randomly assigned and make up the intention-to-treat
`population (230 to the fulvestrant group and 232 to the
`anastrozole group; figure 1). Data cutoffwas April 11, 2016,
`when the target number of progression-free survial
`events (306) was expected to have been met. Two patients
`in the fulvestrant group did not receive study treatment
`after randomisation (patient decision);
`therefore,
`the
`safety population had 228 patients in the fulvestrant
`group and 232 patients in the anastrozole group.
`14 protocol deviations related to eligibility criteria were
`observed in both the fulvestrant and anastrozole groups.
`Three patients were reported to have received previous
`endocrine therapy. These protocol deviations were
`considered unlikely to affect the interpretation of study
`data. Baseline demographic and disease characteristics
`were generally well balanced between groups (table 1).
`There were 309 progression events at data cutoff. Of
`these, 143 (62%) of 230 occurred in the fulvestrant group
`and 166 (72%) of 232 occurred in the anastrozole group.
`Fulvestrant was associated with a statistically significant
`improvement
`in progression-free survival compared
`with anastrozole (HR 0-797, 95% CI 0-637—0-999,
`p=0~0486; figure 2). Median progression-free survival
`was 166 months (95% CI 1383—2099) with fulvestrant
`and 13 -8 months
`(11-99—16 - 59) with anastrozole
`(difference in medians: 2 - 8 months).
`the objective
`In patients with measurable disease,
`response rate was 46% (89/193) with fulvestrant and 45%
`(88/196) with anastrozole (OR 1~07, 95% Cl 072—161,
`p=0~7290). Duration of response in patients with
`measurable disease at baseline is shown in the appendix.
`Median duration ofresponse was longer in the fulvestrant
`group (20-0 months [95% CI 15-90—27-63]) than in the
`anastrozole group (13 -2 months [95% CI 10-64—16~72]).
`Expected duration of response was 11-4 months in the
`fulvestrant group and 7-5 months in the anastrozole
`group (expected duration of response ratio 152, 95% Cl
`1.03—2 . 26, p=0~0367).
`Clinical benefit rate was 78% (180/230) with fulvestrant
`and 74% (172/232) with anastrozole (OR 125, 95% Cl
`082—193, p=0~3045;
`table 2). Duration of clinical
`benefit in patients with clinical benefit is shown in the
`
`---~
`
`—p
`
`---~
`
`—p
`
`183 discontinued study treatment
`167 discontinued study treatment
`158 hadworsening of condition’r
`134 hadworsening of condition’r
`11 had adverse events
`16 had adverse events
`10 patient decision
`10 patient decision
`1 non-adherence to protocol
`3 non-adherence to protocol
`0 lost to follow-up
`1 lost to follow-up
`3 other
`3 other
`
` V V
`
`
`61 ongoing study treatment at data cutoff
`
`
` V V
`230 included in intention-to-treat analysis
`232 included in intention-to-treat analysis
`137 ongoing in study at data cutoff
`131 ongoing in study at data cutoff
`93 patients terminated study
`101 patients terminated study
`68 died#
`63 diedi
`2 eligibility criteria not fulfilled
`3 eligibility criteria not fulfilled
`22 patient decision
`29 patient decision
`6 lost to follow-up
`1 lost to follow-up
`
`Figure 1:Tria| profile
`"wo patients in the fulvestrant 500 mg group did not receive treatment (patient decision). ”(Includes pa ients
`with disease progression. iDeaths exclude patients whoterminated the study for other reasons (four patients in
`the fulvestrant group and seven patients in the anastrozole group) but were subsequently found to have died.
`
`duration of response and expected duration of clinical
`benefit allow a statistical comparison to be made on the
`duration of response and clinical benefit between the two
`treatment groups. An analysis of time to deterioration of
`Trial Outcome Index and FACT-B total score was done as
`
`described for progression-free survival.
`A subgroup analysis was done on progression-free
`survival data in the intention-to-treat population for the
`following baseline covariates: oestrogen receptor-positive
`and progesterone receptor-positive (yes or no), metastatic
`disease (yes or no), concomitant use of bisphosphonates
`(yes or no), measurable disease (yes or no), previous
`chemotherapy for locally advanced or metastatic breast
`cancer (yes or no), geographic region, previous systemic
`oestrogen containing hormone replacement
`therapy
`(yes or no), and visceral disease (yes or no). HRs and
`95% CI were calculated, and a Kaplan-Meier was generated
`for each subgroup. A global interaction test was done with
`a Cox-proportional hazard model to assess whether the
`treatment effect was consistent across the covariates. A
`
`post-hoc interaction test to assess for consistency of the
`treatment effects across the visceral and non-visceral
`
`events were
`done. Adverse
`also
`subgroups was
`summarised descriptively using the Medical Dictionary
`for Regulatory Activities preferred terms. SAS versions 9.2
`and 9.4 were used for statistical analyses. This trial is
`registered with ClinicalTrialsgov, number NCT01602380.
`
`www.the|ancet.com Published online November 28, 2016 http://dx.doi.org/10.1016/50140-6736(16)32389-3
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`
`Age (years)
`Patients aged 265 years
`Race
`
`64-0 (38—87)
`108 (47%)
`
`62-0 (36—90)
`91 (39%)
`
`White
`Asian
`Black or other
`Time from diagnosis of breast
`cancerto randomisation
`
`:2 months
`>2 monthsto 51 year
`>1 year
`Receptor status
`Oestrogen receptor positive,
`progesterone receptor positive
`Oestrogen receptor positive,
`arogesterone receptor negative
`Oestrogen receptor positive,
`arogesterone receptor
`unknown
`
`Oestrogen receptor negative,
`arogesterone receptor positive
`Oestrogen receptor negative,
`arogesterone receptor negative
`Human epidermal growth factor
`receptor status
`Rositive
`Negative
`W-lO performance status*
`0
`1
`2
`Disease stage
`Locally advanced
`Metastatic
`Site of disease
`
`
`
`175 (76%)
`36 (16%)
`19 (8%)
`
`102 (44%)
`58 (25%)
`70 (30%)
`
`174 (75%)
`34 (15%)
`24 (10%)
`
`99 (43%)
`66 (28%)
`67 (29%)
`
`175 (76%)
`
`179 (77%)
`
`44 (19%)
`
`43 (19%)
`
`10 (4%)
`
`1 (<1%)
`
`0
`
`7 (3%)
`
`3 (1%)
`
`O
`
`0
`230 (100%)
`
`1 (<1%)
`231 (100%)
`
`117 (51%)
`106 (46%)
`7 (3%)
`
`28 (12%)
`202 (88%)
`
`115 (50%)
`105 (45%)
`12 (5%)
`
`3 2 (14%)
`200 (86%)
`
`Visceral disease‘f
`Bone or m usculoskeletal only
`Breast only
`Skin or soft tissue only
`Other non-visceral
`Measurable disease
`
`119 (51%)
`135 (59%)
`24 (10%)
`24 (10%)
`2 (1%)
`3 (1%)
`6 (3%)
`8 (3%)
`81 (35%)
`6O (26%)
`196 (84%)
`193 (84%)
`(Table 1 continues in next column)
`
`
`Fulvestrant
`Anastrozole
`Anastrozole
`Fulvestrant
`
`
`
`
`500 mg (n=230) 1 mg (n=232) 500 mg (n=230) 1 mg (n=232)
`(Table continued from previous column)
`Previoustreatmenti
`
`
`
`
`
`
`Chemotherapy
`Locally advanced or
`metastatic breast cancerS
`Adjuvant
`Neoadjuvant
`Radiotherapy
`Immunotherapy
`Hormonal therapy
`
`36 (16%)
`
`35 (15%)
`11 (5%)
`53 (23%)
`O
`2 (1%)
`
`43 (19%)
`
`27 (12%)
`16 (7%)
`50 (22%)
`0
`1 (<1%)
`
`Data are median (range) and n ("0). *ForWHO performance status, 0 represents
`normal activity, 1 represents restricted activity, and 2 represents being in bed 50%
`of the time or less. fl ncludes patients with site of baseline disease as any of the
`following: adrenal, bladder, CNS, oesophagus, liver, lung, peritoneum, pleura,
`renal, small bowel, stomach,pancreas, thyroid, colon, rectal, ovary, biliary‘tract,
`ascites, pericardial effusion, spleen, or pleural effusion. fPrevlous enrolment
`categories are not mutually exclusive. Slncludes first-line,second-line, third-line,
`metastatic, and palliative chemotherapies (two patients were reported as
`deviations for having received second-line chemotherapy and one patient was
`reported in errorto have received three previous lines of chemotherapy).
`
`Table 1: Patient baseline demographics and disease characteristics ofthe
`intention-to-treat population
`
`Treatment effects on progression-flee survival were
`largely
`consistent
`across
`the
`prespecified patient
`subgroups
`(global
`interaction test
`p=0~1061), with
`the
`following
`exceptions:
`patients with
`previous
`chemotherapy for locally advanced or metastatic disease,
`patients with non-measurable disease, patients who were
`not oestrogen receptor-positive and progesterone receptor-
`positive at baseline, and patients with visceral disease
`(figure 3). For patients with non-visceral disease, the HR
`was 0 ~59 (95% CI 0 ~42—0 ~84), with a median progression-
`free survival of 22 ~ 3 months (95% CI 16 ~ 62—32 ~79) in the
`fulvestrant group versus 13-8 months (1104—16-59) in
`the anastrozole group (figure 3). In the visceral disease
`subgroup, the HR was 0-99 (074—133), with median
`progression-free survival of 13 8 months (1104—16-53) in
`the fulvestrant group versus 15-9 months (11~ 27—16 ~89) in
`the anastrozole group. A post-hoc interaction test to assess
`for consistency of the treatment effects across the visceral
`and non-visceral subgroups gave a p value of0 ~ 0092.
`At data cutoff, median duration of actual exposure to
`fulvestrant was 147 months (range 09—377) and to
`anastrozole was 13 ~ 9 months (range 0 ~ 2—36 ~ 0). 166 (73%)
`of 228 patients in fulvestrant group and 173 (75%) of
`232 patients in the anastrozole group reported adverse
`events (table 3). Serious adverse events were reported by
`30 (13%) of 228 patients receiving fulvestrant versus
`31 (13%) of 232 patients receiving anastrozole (appendix).
`Overall, 16 (7%) of 228 patients in the fulvestrant group
`and 11 (5%) of 232 patients in the anastrozole group
`discontinued because of adverse events
`(appendix).
`Grade 3 or worse adverse events were reported by
`51
`(22%) of 228 patients receiving fulvestrant and
`
`appendix. The median duration of clinical benefit was
`22 ~1 months (95% CI 18 ~46—24-87) with fulvestrant and
`191 months
`(1653—2047) with anastrozole. The
`expected duration of clinical benefit was 21 ~ 9 months in
`the fulvestrant group and 17 ~ 5 months in the anastrozole
`group (expected duration of clinical benefit ratio 126,
`95% CI
`0~99—1~59,
`p=0~0561). Median
`overall
`survival could not be calculated because of insufldcient
`
`follow-up time (31% maturity). At data cutoff, 67 (29%)
`of 230 patients in the fulvestrant group and 75 (32%) of
`232 patients in the anastrozole group had died (HR 0 ~88,
`95% Cl 063—122, p=0~4277).
`
`www.thelancet.com Published online November 28, 2016 http:lldxrdoi.org/10.1016/50140-6736(16)32389-3
`
`AstraZeneca Exhibit 2154 p. 5
`
`

`

`Articles
`
`
`
`
`
`
`
`Progression-freesurvival(Va)
`
`
`
`
`
`
`
`
`— Fulvestrant 500 mg (n=230)
`— Anastrozole 1 mg (n=232)
`
`100
`
`9.0-
`80—
`
`7o—
`60—
`
`50—
`
`4o—
`
`30—
`20—
`10—
`HR’O-797 (95% CI 0-637—0-999); p=o-o486
`
`
`
`were reported. Overall, no clinically significant changes
`in laboratory variables, electrocardiogram recordings,
`physical examination, or vital signs were observed in
`either group.
`Mean FACT-B and Trial Outcome Index scores were
`
`maintained and similar in both treatment groups. Time
`to deterioration did not differ significantly between
`treatment groups for both Trial Outcome Index score
`(HR 0-90, 95% CI 0-70—1~15, p=0~4008) and FACT-B
`total score (HR 084, 95% (:1 066—107, p=0~ 1594).
`
`Discussion
`
`The primary endpoint of this phase 3 study was met,
`with patients receiving fulvestrant having a significantly
`longer progression-free survival than patients receiving
`anastrozole, supporting the hypothesis that fulvestrant
`is a more efficacious treatment than anastrozole in
`
`postmenopausal women with hormone receptor-positive
`locally advanced or metastatic breast cancer who have not
`received previous treatment with endocrine therapy. This
`represents a meaningful and relevant finding for which
`clinical data are limited.20
`
`Strengths of this study are the inclusion of a diverse
`patient population, the double-dummy study design, and
`the use of a standard-of-care comparison group. Unlike
`many other studies where patients were allowed to
`receive previous adj uvant endocrine therapy, patients in
`the
`FALCON study were
`completely
`endocrine
`therapy-naive and hormone replacement therapy had to
`be completed more than 6 months before randomisation
`given the known effect of hormone replacement therapy
`withdrawal. Therefore,
`this study provides a direct
`comparison of the therapeutic eificacy between the
`selective oestrogen receptor degrader fulvestrant and a
`third-generation
`aromatase
`inhibitor without
`the
`confounding effects of previous adjuvant endocrine
`therapy exposure of any type. The HR for progression-
`free survival seen in this study (0797) is similar to the
`improvement
`shown by third-generation aromatase
`inhibitors compared with tamoxifen.H In addition to the
`primary endpoint results, predefined subgroup analyses
`were done. The test for heterogeneity was not statistically
`significant across all the subgroups, although potential
`enhanced treatment effects with fulvestrant versus
`
`including
`anastrozole were seen in some subgroups,
`patients with non-visceral disease compared with visceral
`disease. However, this observation requires further study.
`Data from FALCON add to the extensive data for the
`
`efldcacy of fulvestrant in patients with advanced breast
`cancer and consolidate the evidence for superior efficacy
`for fulvestrant over a third-generation aromatase inhibitor,
`initially raised by the results of the phase 2 FIRST study,
`where most patients were also endocrine-naive.1L“3
`The superiority of fulvestrant over anastrozole in an
`endocrine therapy-naive patient population warrants
`future clinical assessment of fulvestrant
`in other
`
`endocrine therapy-naive patient populations, such as the
`
`www.the|ancet.com Published online November 28, 2016 http://dx.doi.org/10.1016/50140-6736(16)32389-3
`
`AstraZeneca Exhibit 2154 p. 6
`
`6
`
`9
`
`Number at risk
`Fulvestr