Breast Cancer Res Treat (2012) 136503-511
`DOI 10.1007/s10549—012—2192—4
`
`
`
`Fulvestrant 500 mg versus anastrozole 1 mg for the first-line
`treatment of advanced breast cancer: follow-up analysis
`from the randomized ‘FIRST’ study
`
`John F. R. Robertson - Justin P. O. Lindemann - Antonio Llombart-Cussac ~
`Janusz Rolski - David Feltl - John Dewar - Laura Emerson - Andrew Dean -
`Matthew J. Ellis
`
`Received: 27 July 2012/ Accepted: 27 July 2012/ Published online: 13 October 2012
`© Springer Science+Business Media, LLC. 2012
`
`Abstract Fulvestrant flRst-line Study comparing endocrine
`Treatments is a phase II, randomized, open-label study com-
`paring fulvestrant 500 mg with anastrozole 1 mg as first-line
`endocrine therapy for postmenopausal women with hormone
`receptor-positive (HR+) advanced breast cancer. At data cut-
`off, only 36 % of patients had progressed and the median time
`to progression (TTP) had not been reached for fulvestrant.
`Here, we report follow-up data for TTP for fulvestrant 500 mg
`
`L. Emerson is a previous employee of Astrazeneca, Charnwood, UK.
`
`)
`J. F. R. Robertson (
`Division of Breast Surgery, Graduate Entry Medicine & Health
`School (GEMS), University of Nottingham, Royal Derby
`Hospital, Uttoxeter Road, Derby DE22 3DT, UK
`e—mail: johnrobertson@nottingham.ac.uk
`
`J. P. O. Lindemann - A. Dean
`Astrazeneca, Alderley Park, Macclesfield, Cheshire, UK
`
`A. Llornba1t—Cussac
`Hospital Amau de Vilanova, Lérida, Spai11
`
`J. Rolski
`Centrum Onkologii, Instytut im M. Sklodowskiej—Curie,
`Krakow, Poland
`
`D. Feltl
`FNsP Ostrava, Radioterapeuticka klinika, Ostrava—Poruba,
`Czech Republic
`
`J. Dewar
`Department of Oncology, Ninewells Hospital and Medical
`School, Dundee, UK
`
`L. Emerson
`Astraleneca, Charnwood, UK
`
`M. J. Ellis
`Washington University School of Medicine, St Louis, MO, USA
`
`versus anastrozole 1 mg. Key inclusion criteria were post-
`menopausal women with estrogen receptor-positive and/or
`progesterone receptor-positive locally advanced or metastatic
`breast cancer and no prior endocrine therapy. Key exclusion
`criteria were presence of life-threatening metastases and prior
`treatment with a non-approved drug. Fulvestrant was admin-
`istered 500 mg/month plus 500 mg on day 14 of month 1;
`anastrozole was administered 1 mg/day. TTP was defined by
`modified Response Evaluation Criteria in Solid Tumors V1.0
`before data cut—off for the primary analysis, and investigator
`opinion after data cut—off. Best overall response to subsequent
`therapy and serious adverse events are also reported. In total,
`205 patients received fulvestrant 500 mg (n = 102) or anas-
`trozole (n : 103). Follow-up analysis was performed when
`79.5 % of patients had discontinued study treatment. Median
`TTP was 23.4 months for fulvestrant versus 13.1 months for
`
`anastrozole; a 34 % reduction in risk of progression (hazard
`ratio 0.66; 95 % confidence interval: 0.47, 0.92; P : 0.01).
`Best overall response to subsequent therapy and clinical benefit
`rate for subsequent endocrine therapy was similar between the
`treatment groups. No new safety concerns for fulvestrant
`500 mg were documented. These longer-term,
`follow-up
`results confirm efficacy benefit for fulvestrant 500 mg versus
`anastrozole as first-line endocrine therapy for HR+ advanced
`breast cancer in terms of TTP, and, importantly, show similar
`best overall response rates to subsequent endocrine therapy.
`
`Keywords Advanced breast cancer - Anastrozole -
`Fulvestrant 500 mg - Hormone receptor-positive - Time to
`progression
`
`Abbreviations
`AE
`Adverse event
`AI
`Aromatase inhibitor
`CBR
`Clinical benefit rate
`
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`504
`
`CI
`
`Confidence interval
`
`CONFIRM COmparisoN of Faslodex In Recurrent or
`Metastatic breast cancer
`Duration of clinical benefit
`
`DoCB
`
`DoR
`ER
`FINDER
`
`FIRST
`
`HR
`ORR
`NEWEST
`
`PFS
`PgR
`PK
`
`RECIST
`SAE
`TTF
`
`TTP
`WHO-PS
`
`Duration of response
`Estrogen receptor
`Faslodex InvestigatioN of Dose evaluation in
`Estrogen Receptor-positive advanced breast
`cancer G3INDER)
`Fulvestrant fIRst-line Study comparing
`endocrine Treatments
`
`Hormone receptor
`Objective response rate
`Neoadjuvant Endocrine therapy for Women
`with Estrogen-Sensitive Tumors
`Progression-free survival
`Progesterone receptor
`Pharmacokinetic
`
`Response Evaluation in Solid Tumors
`Serious adverse event
`Time to treatment failure
`
`Time to progression
`World Health Organization-Performance
`Status
`
`Introduction
`
`Endocrine therapy is a standard first-line treatment option
`for advanced breast cancer in postmenopausal women with
`hormone receptor-positive (HR+) disease. The third-gen-
`eration aromatase inhibitors (AIs) letrozole and anastrozole
`have demonstrated improved time to progression (TTP)
`and tolerability compared with tamoxifen, and are now
`considered the standard treatment in this setting [2, 8, 9].
`Fulvestrant is a pure antiestrogen that binds directly to
`the estrogen receptor (ER) in a mechanism of action dis-
`tinct from other endocrine therapies for breast cancer [21].
`At
`the monthly 250 mg dose, fulvestrant is at least as
`effective as anastrozole for the second—line treatment of
`
`postmenopausal women with advanced breast cancer [5,
`11, 16]. However, at this dose, fulvestrant was not asso-
`ciated with improved efficacy when compared with
`tamoxifen in the first-line setting [4].
`Early clinical data and results of pharmacokinetic (PK)
`modeling suggested that the efficacy of fulvestrant could be
`increased with a higher dosing regimen [15, 17]. This was
`demonstrated in the phase III COmparisoN of Faslodex In
`Recurrent or Metastatic breast cancer (CONFIRM) trial,
`which showed that fulvestrant 500 mg significantly pro-
`longed progression-free survival (PFS), the primary study
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`Breast Cancer Res Treat (2012) 136503-511
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`endpoint, with no detrimental effects on tolerability or
`quality of life. This meant that fulvestrant 500 mg was
`associated with a greater benefit-risk profile compared with
`fulvestrant 250 mg for the treatment of postmenopausal
`women with locally advanced or metastatic breast cancer
`following failure of prior antiestrogen therapy [3].
`Fulvestrant
`fTRst-line Study comparing endocrine
`Treatments (FIRST) is a phase II, randomized, open-label,
`multicenter, parallel—group study designed to compare
`fulvestrant 500 mg with anastrozole 1 mg in the first-line
`setting for the treatment of advanced breast cancer (Clin-
`icalTrials.gov identifier NCT00274469). Findings from this
`study showed that fulvestrant was at least as effective as
`anastrozole in terms of the primary endpoint of clinical
`benefit rate (CBR) and objective response rate (ORR) [19].
`Data cut-off for
`the primary analysis was performed
`6 months after the last patient was randomized. At this
`time, 117 (57.1 %) patients were still receiving study
`treatment and only 35.6 % of patients had progressed
`[30 patients (29.4 %) in the fulvestrant and 43 patients
`(41.7 %) in the anastrozole group]. The median TTP had
`not been reached for
`fulvestrant compared with 12.5
`months for anastrozole [hazard ratio 0.63; 95 % confidence
`interval (CI): 0.39, 1.00; P = 0.0496] [19].
`A more mature follow-up analysis of TTP was therefore
`planned for when approximately 75 % of patients had
`discontinued therapy. Here, we report findings from this
`analysis.
`
`Methods
`
`Study design and patients
`
`The methods have been described elsewhere [19] and are
`described briefly here. Patients were randomized to receive
`fL1lvestrant 500 mg (500 mg/month intramuscularly plus
`500 mg on day 14 of month 1) or anastrozole (1 mg/day
`orally). Treatment continued until disease progression or
`any other discontinuation event.
`postmenopausal
`The
`study population
`comprised
`women with ER-positive (ER+)
`and/or progesterone
`receptor-positive (PgR+) locally advanced or metastatic
`breast cancer who had not received any prior endocrine
`therapy for locally advanced or metastatic disease. Previ-
`ous endocrine therapy for early disease completed more
`than 12 months before randomization was permitted.
`Patients had to have measurable disease, as confirmed by
`Response Evaluation Criteria in Solid Tumors V1.0 (RE-
`CIST) [20], or bone lesions with a lytic component. Key
`exclusion criteria included the presence of life-threatening
`metastases, prior treatment with a non-approved drug,
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`abnormal laboratory test Values, and a history of bleeding
`diatheses.
`
`between scheduled treatment visits. In a post hoc analysis,
`TTF was calculated for fulvestrant as the date of the next
`
`Randomization and masking
`
`Patients were randomized sequentially using randomization
`cards. The clinical study team were unaware of the ran-
`domization scheme until the data had been collected and
`
`locked for primary analysis. To prevent biasing the results
`of the tumor assessments, a blinded independent review
`was performed by a radiologist at Biolmaging Technolo-
`gies (Leiden, The Netherlands). Other post hoc analyses
`were performed by the Biostatistics department
`at
`AstraZeneca.
`
`intended injection (the date of the patient’s last injection
`plus 28 days). This analysis was performed because most
`patients with advanced breast cancer have their treatment
`changed at a scheduled clinic visit.
`Best overall response to first subsequent breast cancer
`therapy was determined by investigator opinion.
`
`Tolerability
`
`World Health Organization-Performance Status (WHO-PS)
`and serious adverse events (SAES) were reported for ful-
`vestrant and anastrozole throughout the follow-up period.
`
`Efficacy analysis
`
`Statistics
`
`The primary study endpoint was CBR; secondary endpoints
`included ORR, TTP, duration of clinical benefit (DOCB),
`and duration of response (DoR). CBR, ORR, DoCB, and
`DoR were not assessed in the follow-up period. Both CBR
`and TTP were relevant endpoints for this study; CBR
`allowed comparison of de novo response and progression
`rates but not assessment of acquired resistance.
`This follow-up analysis was planned for when 75 % of
`patients had discontinued (failed) study treatment, with
`final analysis of data being performed within 12 months of
`the last patient discontinuing their randomized treatment.
`As this was a phase II trial, no formal adjustments were
`made for multiple testing. TTP was defined as the date
`from randomization to progression. For patients who pro-
`gressed before the primary data cut-off, the date of pro-
`gression, as deterrnined by modified RECIST criteria, was
`already available. “Modified” RECIST relates to those
`patients with non-measurable disease at baseline, who had
`bone lesions with a lytic component, where progression of
`lytic bone lesions was regarded as a progression event. For
`patients who progressed after the data cut-off for the pri-
`mary analysis, TTP was determined by investigator
`opinion.
`Time to treatment failure (TTF) was also evaluated;
`defined as the time from randomization to cessation of trial
`
`therapy. For patients who stopped treatment before the
`primary data cut-off, this date was already available. For
`patients who stopped treatment after the primary data cut-
`off, the date of cessation of trial therapy was recorded on
`the case report form as the date that the last dose of drug
`was administered. As fulvestrant 500 mg is administered
`monthly,
`it
`is possible that
`the decision to discontinue
`treatment may have occurred at any point between the last
`injection and the next
`intended injection 28 days later.
`Therefore, TTF was calculated for fulvestrant as the date of
`last
`injection plus 14 days,
`representing the midpoint
`
`The full analysis set included all randomized patients and
`was used to analyze efficacy. The safety analysis set
`included patients who received treatment after the data cut-
`off for the primary analysis.
`For the analysis of TTP and TTF, Kaplan—Meier plots
`were generated. Hazard ratios, 95 % Cls, and P values
`were calculated using a log-rank test, unadjusted for
`baseline covariates.
`
`A secondary analysis of TTP and TTF was also con-
`ducted. This was calculated using a Cox proportional
`hazards regression model and was adjusted for treatment
`and baseline covariates, including age (<65 vs. 365 years),
`hormone receptor status (both ER+ and PgR+ vs. not both
`ER+ and PgR+), visceral involvement (yes vs. no), prior
`chemotherapy (yes vs. no), and the presence or absence of
`measurable disease. A global interaction test using a 1 %
`significance level was performed to determine whether the
`overall treatment benefit was consistent across each of the
`baseline covariates.
`
`Results
`
`Patients
`
`In total, 205 patients received fulvestrant (n = 102) or
`anastrozole (n : 103) (Fig. 1). Baseline demographics and
`disease characteristics were well balanced between the
`
`treatment groups. The primary study endpoint, CBR, was
`72.5 % in the fulvestrant group compared with 67.0 % in
`the anastrozole group (odds ratio 1.30; 95 % Cl: 0.72, 2.38;
`P = 0.386) [19]. The data cut-off for this follow-up anal-
`ysis was March 26, 2010. At this point, 163 (79.5 %)
`patients had discontinued study treatment. Median duration
`of follow-up for TTP was 18.8 months in the fulvestrant
`group and 12.9 months in the anastrozole group.
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`506
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`Breast Cancer Res Treat (2012) 136503-511
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`Enrolled
`(n
`233)
`
`Randomized
`(n = 205)
`
`Not randomized (n = 28)
`Incorrect enrollment (n : 20)
`Death (/1 = 1)
`Adverse event (n = 1)
`Voluntary patient discontinuation (n = 4)
`
`Other (n = 2)
`
`Fulvestrant 500 mg
`(n = 102)
`
`Anastrozole 1 mg
`(n = 103)
`
`Voluntary patient discontinuation
`(n = 1)
`
`Received fulvestrant 500 mg
`(n : 101)
`
`Received anastrozole 1 mg
`(n : 103)
`
`Discontinued study treatment
`Voluntary patient discontinuation (n = 3)
`Death (n = 11)
`Adverse event (n = 0)
`Other (n = 5)
`Lost to tollow—up (n : 6)
`
`Discontinued study treatment
`Voluntary patient discontinuation (n= 6)
`Death (n = 18)
`Adverse event (n = 2)
`Other (n = 5)
`Lost to follow-up (n : 7)
`
`
`
`Completed study
`(77 = 51)
`Ongoing study treatment
`at data cut—ott
`(n = 25)
`
`Completed study
`(I1 = 49)
`Ongoing study treatment
`at data cut—off
`(n = 16)
`
`Fig. 1 CONSORT diagram
`
`Efficacy
`
`At the time of the folloW—up analysis, 142 (69.3 %) patients
`had progressed; 63 (61.8 %)
`in the fulvestrant group
`compared with 79 (76.7 %)
`in the anastrozole group.
`Median TTP was 23.4 months for the fulvestrant group
`Versus 13.1 months for the anastrozole group (hazard ratio
`0.66; 95 % CI: 0.47, 0.92; P = 0.01), corresponding to a
`34 % reduction in risk of progression (Fig. 2).
`The difference in TTP was also statistically significant
`when adjusted for pre-defined covariates (hazard ratio 0.64;
`95 % Cl: 0.46, 0.90; P = 0.01). The global interaction test
`was not significant (P = 0.34). A forest plot representing
`TTP according to the pre-defined covariates is shown in
`Fig. 3, demonstrating that the treatment effect is consistent
`across all subgroups.
`in the
`The number of patients who failed treatment
`fulvestrant group was 76 (74.5 %) compared with 87
`(84.5 %)
`in the anastrozole group. Median TTF was
`17.6 months for the fulvestrant group Versus 12.7 months
`for the anastrozole group (hazard ratio 0.73; 95 % CI: 0.54,
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`1.00; P : 0.05), calculated by adding 14 days to the last
`fulvestrant injection (Fig. 4). The difference in TTF also
`remained consistent when adjusted for pre-defined covari-
`ates (hazard ratio 0.72; 95 % Cl: 0.52, 0.98; P = 0.04).
`The global interaction test was not significant (P : 0.31).
`In the post hoc analysis with 28 days added to the last
`fulvestrant injection, median TTF was 18.1 months in the
`fulvestrant group versus 12.7 months for the anastrozole
`group (hazard ratio 0.71; 95 % CI: 0.52, 0.96; P = 0.03).
`Subsequent breast cancer treatment was recorded for
`64 patients in the fulvestrant group and 69 patients in the
`anastrozole group. In terms of best overall response to any
`subsequent systemic breast cancer therapy, 15 patients
`(23.4 %) in the fulvestrant group and 15 patients (21.7 %)
`in the anastrozole group achieved either a complete or
`partial response to subsequent therapy. CBR to first sub-
`sequent
`systemic therapy (complete response, partial
`response, or stable disease for 224 weeks) was 43.8 %
`(28/64 patients) in the fulvestrant group compared with
`46.4 % (32/69
`patients)
`in
`the
`anastrozole
`group
`(Table 1). Best response to subsequent endocrine therapy
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`Breast Cancer Res Treat (2012) 136503-511
`
`Fig. 2 Time to progression
`(full analysis set)
`
`507
`
`: Fu|vestrant500 mg
`Anastrozole 1 mg
`
`Hazard ratio (95 % confidence interval): 0.66 (0.47, 0.92)
`P = 0.01
`
`
`
` Proportionofpatientsaliveandprogression—1ree
`
`0.6 —
`
`0.5 —
`
`0.4 —
`
`0.3 —
`
`0.2 —
`
`12
`
`18
`
`24
`
`80
`
`36
`
`42
`
`48
`
`Time (months)
`
`Patients at risk
`
`34
`45
`52
`65
`74
`Fu|vestrant500 mg 102
`21
`30
`39
`55
`69
`Anastrozole 1 mg
`103
`After the primary data cut-off, progression was determined by investigator opinion
`
`20
`8
`
`6
`2
`
`0
`0
`
`n = 85, 69 events
`n = 120, 73 events
`
`n = 156, 99 events
`n = 49, 43 events
`
`n = 99, 56 events
`n = 106, 86 events
`
`n = 151, 106 events
`n = 54, 36 events
`
`4-14
`I
`adj
`I
`«I?
`oéij
`
`II
`
`o
`
`0
`
`:
`
`:I
`
`I
`I
`
`II
`
`D
`
`0
`
`Fig. 3 Time to progression by
`I
`pre—defined covariates (full
`analysis set)
`
`Age
`
`<65 years
`355 Yeats
`
`Receptor status
`
`Both ER+ and PgR+
`Not both ER+ and PgR+
`
`Visceral involvement
`
`Prior chemotherapy
`
`No
`Yes
`
`No
`Yes
`
`No me n = 40, 28 events
`Yes
`joqj
`n = 165, 114 events
`
`II
`
`I
`0.1
`
`n = 205, 142 events
`4:4
`I
`I
`'
`I
`I
`I
`2.2
`0.6
`1.0
`0.4
`0.3
`0.2
`Hazard ratio and 95 % confidence interval<4 4
`Favors tulvestrant 500 mg Favors anastrozole 1 mg
`
`Measurable disease
`
`All patients
`
`EH estrogen receptor, Pg}? progesterone receptor
`
`for breast cancer was also similar between the treatment
`
`groups. CBR to subsequent endocrine therapy for breast
`cancer was 41.2 % (14/34 patients)
`in the fulvestrant
`group and 42.0 % (21/50 patients)
`in the anastrozole
`group (Table 1).
`
`Tolerability
`
`Twelve SAES were reported in seven patients in the ful-
`vestrant group and 10 SAES were reported in seven patients
`
`in the anastrozole group during the period after the primary
`data cut-off. Each SAE by preferred term was only reported
`in one patient. One SAE (pulmonary embolism) was con-
`sidered treatment-related by the investigator in the fulve-
`strant group. No treatment-related SAES were reported in
`the anastrozole group.
`There were no clinically important differences in terms
`of WHO-PS. At each evaluation, the majority (>50 % in
`both treatment groups) of patients still receiving treatment
`had a PS of either 0 or 1.
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`508
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`Fig. 4 Time to treatment
`failure (full analysis set)
`
`1_0 —-4,
`
`0.9 —
`
`0.8 —
`
`0.7 —
`
`0.6 —
`
`0.5 —
`
`0.4 —
`
`0.3 —
`
`0.2 —
`
`0.1 —
`
`0.0
`
`
`
`Proportionofpatientsnotfailed
`
`Breast Cancer Res Treat (2012) 136:503—511
`
`Z Fu|vestrant500 mg
`Anastrozole 1 mg
`Hazard ratio (95 % confidence interval): 0.73 (0.54, 1.00)
`P= 0.05
`
`
`
`I
`6
`
`I
`12
`
`I
`18
`
`I
`24
`
`I
`30
`
`Patients at risk
`
`62
`75
`Fu|vestrant500 mg 102
`52
`74
`Anastrozole 1 mg
`103
`14 days added to the last fulvestrant injection
`
`Time (months)
`
`50
`38
`
`38
`28
`
`31
`20
`
`I
`36
`
`19
`6
`
`I
`42
`
`I
`48
`
`6
`1
`
`0
`0
`
`Table 1 Best response to subsequent therapy (full analysis set)
`
`Number (%) of patients
`Fulvestrant Anastrozole
`500 mg
`1 mg
`n : 102
`n : 103
`
`Received subsequent systemic therapy
`Complete response
`Partial response
`Total responders
`Stable disease 324 weeks
`Total with clinical benefit
`Progressive disease
`Not evaluable
`Received subsequent endocrine therapy
`Complete response
`Partial response
`Total responders
`Stable disease 324 weeks
`Total with clinical benefit
`Progressive disease
`Not evaluable
`
`64
`0
`15 (23.4)
`15 (23.4)
`13 (20.3)
`28 (43.8)
`6 (9.4)
`14 (21.9)
`34
`0
`3 (8.8)
`3 (8.8)
`11 (32.4)
`14 (41.2)
`3 (8.8)
`7 (20.6)
`
`69
`2 (2.9)
`13 (18.8)
`15 (21.7)
`17 (24.6)
`32 (46.4)
`12 (17.4)
`6 (8.7)
`50
`0
`7 (14.0)
`7 (14.0)
`14 (28.0)
`21 (42.0)
`8 (16.0)
`5 (10.0)
`
`Discussion
`
`This follow-up analysis of data from the FIRST trial was
`planned for when approximately 75 % of patients had
`
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`discontinued study treatment, as only 35.6 % of patients
`had progressed at the time of the primary data cut-off.
`Fulvestrant 500 mg as first-line endocrine treatment was
`associated with a significantly longer TTP compared with
`anastrozole 1 mg for the treatment of postmenopausal
`Women with advanced breast Cancer; median TTP Was
`23.4 months
`in the fulvestrant group compared with
`13.1 months in the anastrozole group (hazard ratio 0.66;
`95 % Cl: 0.47, 0.92; P : 0.01). This corresponds to a
`reduction in the risk of progression of 34 %. This is con-
`sistent with the analysis of TTP at the primary data cut-off,
`Where the median TTP for
`fulvestrant had not been
`
`reached, compared with 12.5 months for the anastrozole
`group (hazard ratio 0.63; 95 % CI: 0.39, 1.00; P : 0.0496)
`[19].
`Fulvestrant was also associated with an improved TTF
`compared with anastrozole. In a cautious approach, TTF
`for fulvestrant (adjusted and unadjusted) was calculated as
`the date of last injection plus 14 days, representing the
`midpoint between scheduled treatment Visits. The actual
`decision to discontinue treatment would normally be made
`at the patient’s next treatment visit (28 days later). As the
`addition of 14 days would therefore have the potential for
`bias against fulvestrant, TTF was also calculated in a post
`hoc analysis as the date of last injection plus 28 days. With
`28 days added to the last injection for the fulvestrant group,
`median TTF was significantly longer for fulvestrant Versus
`anastrozole: 18.1 months Versus 12.7 months (hazard ratio
`0.71; 95 % CI: 0.52, 0.96; P = 0.03).
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`Breast Cancer Res Treat (2012) 136503-511
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`509
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`Previous studies of fulvestrant as first-line endocrine
`
`therapy for breast cancer include Trial 0025, which com-
`pared fulvestrant 250 mg with tamoxifen. In the overall
`population, non-inferiority could not be demonstrated for
`fulvestrant 250 mg [4]. However, a relatively large pro-
`portion of patients in Trial 0025 had an unknown HR
`status, and a pre-planned subgroup analysis showed that in
`patients with confirmed HR+ disease, TTP for fulvestrant
`250 mg was
`similar
`to that
`for
`tamoxifen (8.2 and
`8.3 months, respectively; hazard ratio 1.10; 95 % CI: 0.89,
`1.36; P : 0.39). Findings from clinical and biological
`studies and PK modeling suggested that
`increasing the
`actual dose of fulvestrant could further increase the clinical
`
`efficacy [14]. Indeed, the benefits of fulvestrant 500 mg
`versus fulvestrant 250 mg have now been demonstrated for
`the treatment of postmenopausal women with locally
`advanced or metastatic breast cancer following failure of
`prior antiestrogen therapy [3]. Based on these data from the
`CONFIRM trial, fulvestrant 500 mg has now received
`approval in the European Union and the United States as
`the preferred dose regimen for this indication.
`The present study showed that TTP was 23.4 months for
`fulvestrant 500 mg compared with 13.1 months for anas-
`trozole 1 mg, suggesting an improvement for fulvestrant
`500 mg in the first-line setting versus the current standard
`of care. The TTP data presented here for anastrozole are
`consistent with those presented previously. In a combined
`analysis of TTP from Trials 0027 and 0030, comparing
`those patients known to be HR+, median TTP was
`10.7 months for anastrozole compared with 6.4 months for
`tamoxifen [1].
`Trials of alternative AIs as first-line endocrine treatment
`
`for advanced breast cancer include a phase III study that
`compared exemestane with tamoxifen. Median PFS was
`9.9 months for exemestane compared with 5.8 months for
`tamoxifen, although the difference was not significant (log-
`rank P : 0.121) [12]. Letrozole has previously demon-
`strated improved TTP compared with tamoxifen (9.4 vs.
`6.0 months, respectively), a difference that was statistically
`significant (P < 0.001) [3, 8]. The TTP for anastrozole in
`the present study (median 13.1 months) is at least com-
`parable to the TTP for the three AIs described above in the
`first-line setting Versus tamoxifen. Therefore, the signifi-
`cantly longer TTP for fulvestrant 500 mg in the present
`study (median 23.4 months) is unlikely to be due to an
`unexpectedly low TTP for the anastrozole group, but rather
`to the increased efficacy of fulvestrant 500 mg.
`With an increasing number of endocrine therapies
`available, and an increase in use of non-steroidal Als in the
`adjuvant setting, careful selection of the most appropriate
`first-line treatments in advanced disease,
`to maximize
`efficacy while avoiding the development of resistance to
`subsequent
`therapies,
`is
`an important consideration.
`
`Findings from our study show that the best response to
`subsequent endocrine therapy was similar between the two
`treatment groups, with a CBR of 41.2 % in the fulvestrant
`group and 42.0 % in the anastrozole group. These findings
`are consistent with data reported following a retrospective
`analysis of Trial 0025, which showed that patients treated
`with fulvestrant in the first-line setting retained sensitivity
`to subsequent endocrine treatment [18].
`Consistent with findings from the primary analysis as well
`as previous reports investigating the use of fulvestrant 500 mg,
`there were no new safety concerns for fulvestrant 500 mg
`arising from this follow-up analysis. In a recent analysis, safety
`data from CONFIRM were combined with safety data from the
`Neoadjuvant Endocrine therapy for Women with Estrogen-
`Sensitive Tumors (NEVVEST) study [7] and the Faslodex
`InvestigatioN of Dose evaluation in Estrogen Receptor-posi-
`tive advanced breast cancer (FINDER) 1 and 2 studies [10, 13].
`This collectively showed that there was no evidence of any
`dose—related increases in AEs and no new safety concerns
`associated with the use of fulvestrant 500 mg [6].
`Potential limitations of the study should also be noted.
`No formal RECIST evaluations were performed after the
`primary data cut-off, and as such, progression subsequent
`to the primary analysis was determined by the investigator.
`In response to this possible limitation it is noted that the
`separation of the TTP curves in the primary analysis was
`maintained in this follow-up analysis, suggesting that
`investigator-assessed progression was not substantially
`different from that determined by RECIST evaluation. As
`previously reported, no formal central review of imaging
`data was performed for the TTP analysis prior to the data
`cut—off for the primary analysis. In an attempt to address
`this potential limitation, and now with longer follow-up,
`TTF was also examined as part of this analysis, and the
`treatment effect for fulvestrant and anastrozole remained
`
`consistent for both TTP and TTF. Finally, it is noted that
`the study, comparing two intramuscular injections versus a
`single tablet, was an open-label design.
`Although these results should be interpreted within the
`limited power of a phase II study, the role of fulvestrant
`500 mg in the treatment of advanced breast cancer is
`beginning to be more fully elucidated. The phase III Trials
`0020 and 0021 showed that
`following one endocrine
`therapy, fulvestrant 250 mg was equivalent to anastrozole
`in terms of TTP [16], while CONFIRM has shown that
`fulvestrant 500 mg is superior to fulvestrant 250 mg in this
`setting. These data are consistent with the data reported
`here for the FIRST study (phase H trial), where fulvestrant
`500 mg has greater efficacy than anastrozole. On the basis
`of the findings presented here, data collection for a post hoc
`overall survival analysis has now been initiated.
`To our knowledge, the FIRST study is the only study to
`demonstrate increased efficacy for an alternative endocrine
`
`@ Springer
`
`AstraZeneca Ex. 2056 p. 7
`
`

`
`510
`
`Breast Cancer Res Treat (2012) 136503-511
`
`agent compared with a third-generation Al. The findings
`from this analysis are consistent with the primary analysis
`and provide a more mature analysis showing that fulve-
`strant 500 mg is associated with a significantly longer TTP
`compared with anastrozole.
`In addition,
`this follow-up
`analysis shows similar best overall response rates to sub-
`sequent endocrine therapy. Taken together,
`these results
`indicate an efficacy benefit for fulvestrant 500 mg com-
`pared with anastrozole as first—line endocrine therapy for
`patients with HR+ advanced breast cancer.
`
`Acknowledgments This study was funded by AstraZeneca. We
`thank Simon Vass PhD, from Complete Medical Communications,
`who provided medical writing support, funded by AstraZeneca.
`
`John F. R. Robertson has received consultancy,
`Conflict of interest
`honoraria, and speaker fees as well as research funding from Astra-
`Zeneca. Antonio Llombart—Cussac has received consultancy fees from
`AstraZeneca. Janusz Rolski has no conflicts of interest to declare,
`David Feltl and John Dewar have received research funding from
`AstraZeneca. Matthew J. Ellis is a Bioclassifier employee and
`shareholder and has received consultancy fees and research funding
`from AstraZeneca, Novartis, and Pfizer. Justin P, O. Lindemann and
`Andrew Dcan arc AstraZcncca cmployccs and shareholders. Laura
`Emerson is a former AstraZeneca employee.
`
`Ethical standards The study was performed in accordance with the
`Declaration of Helsinki and was consistent with International Con-
`ference on Harmonisation of Technical Requirements for Registration
`of Pharmaceuticals for Human Use Good Clinical Practice. The study
`protocol, patient consent
`fonns,
`and information sheets were
`approved by the relevant independent ethics committees and institu-
`tional review boards.
`
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