Breast Cancer Res Treat (2010) 123:453—461
`D01 10. 1007/s10549-010- 1022-9
`
`
`
`Results of a phase II study comparing three dosing regimens
`of fulvestrant in postmenopausal women with advanced breast
`cancer (FINDER2)
`
`Kathleen I. Pritchard - Janusz Rolski - Zsuzsanna Papai - Louis Mauriac -
`Fatima Cardoso - Jose Chang - Lawrence Panasci - Carmen Ianuli -
`Zsuzsanna Kahan - Kenjiro Fukase - Justin P. O. Lindemann -
`Merran P. Macpherson - Patrick Neven
`
`Received: 23 June 2010/ Accepted: 25 June 2010/Published online: 15 July 2010
`© Springer Science+Business Media, LLC. 2010
`
`Abstract The Faslodex Investigation of Dose evaluation
`in Estrogen Receptor-positive advanced breast cancer
`(FlNDER)2 study evaluated the efficacy, safety, and phar-
`macokinetics (PK) of three fulvestrant dosing regimens.
`FINDER2 enrolled Western postmenopausal Women
`recurring or progressing after prior endocrine therapy.
`Primary endpoint: objective response rate (ORR); secondary
`endpoints: time to progression (TTP), clinical benefit rate
`(CBR), tolerability, and PK parameters. Patients were ran-
`domized to receive fulvestrant: 250 mg/month (approved
`dose [AD]); 250 mg plus loading dose (loading dose [LD];
`500 mg on day 0, 250 mg on days 14, 28, and monthly
`thereafter); or 500 mg (high dose [HD]; 500 mg/month plus
`500 mg on day 14 of Month 1). Treatment continued until
`disease progression or discontinuation. 144 patients were
`randomized: fulvestrant AD (n = 47); LD (n = 51); HD
`
`(11 = 46). ORRs were: 8.5% (95% confidence interval [CI]:
`2.4, 20.4%), 5.9% (1.2, 16.2%), and 15.2% (6.3, 28.9%) in
`the AD, LD, and HD arms, respectively. CBRS were: 31.9%
`(95% CI: 19.1, 47.1%), 47.1% (32.9, 61.5%), and 47.8%
`(32.9, 63.1%) for the AD, LD, and HD arms, respectively.
`Median TTP (months) was numerically longer for HD (6.0)
`and LD (6.1) versus AD (3.1). Tolerability was similar
`across dosing regimens. Steady-state plasma fulvestrant
`concentrations were predictable and achieved earlier with LD
`and HD. While there appeared to be a trend toward improved
`efficacy with HD and LD versus AD, no significant differ-
`ences could be shown. A parallel study (PINDER1) has
`reported similar findings in Japanese patients.
`
`Keywords Fulvestrant » Advanced breast cancer -
`Faslodex - High dose - Loading dose - Endocrine
`
`)
`K. I. Pritchard (
`Sunnybrook Odette Cancer Centre
`and the University of Toronto, 2075 Bayview Avenue,
`M4N 3M5 Toronto, ON, Canada
`e—mail: kathy.pritchard@sunnybrook. ca
`
`J. Rolski
`Oncological Institute, Krakow, Poland
`
`Z. Papai
`State Health Centre, Budapest, Hungary
`
`L. Mauriac
`Institut Bergonié, Bordeaux, France
`
`F. Cardoso
`Jules Bordet Institute, Brussels, Belgium
`
`J. Chang
`RS McLaughlin Durham Regional Cancer Centre,
`Oshawa, ON, Canada
`
`L. Panasci
`Jewish General Hospital, Montreal, QC, Canada
`
`C. Ianuli
`Ianuli Med Consult, Bucharest, Romania
`
`Z. Kahan
`Department of Oncotherapy, University of Szeged,
`Szeged, Hungary
`
`K. Fukase
`AstraZeneca KK, Osaka, Japan
`
`J. P. O. Lindemann ~ M. P. Macpherson
`AstraZeneca Pharmaceuticals, Macclesfield, UK
`
`P. Neven
`Multidisciplinary Breast Centre, UZ-KU Leuven, Belgium
`
`‘E Springer
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`

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`454
`
`Introduction
`
`Fulvestrant is an estrogen receptor (ER) antagonist without
`known agonist activity that is able to reduce cellular levels
`of estrogen and progesterone receptors. Fulvestrant has a
`distinct mechanism of action, compared with other endo-
`crine (anti-estrogen)
`therapies,
`thereby lacking cross-
`resistance with other anti-cancer agents such as tamoxifen
`[1, 2].
`On the basis of data from two large, worldwide
`Phase III clinical trials [3, 4], fulvestrant is licensed at a
`dose of 250 mg/month (approved dose; AD)
`for
`the
`treatment of postmenopausal women with advanced
`breast cancer following progression or recurrence after
`prior endocrine therapy. Although fulvestrant AD has
`established efficacy in this setting, it has been hypothe-
`sized that alternative dosing regimens may improve
`efficacy even further [5].
`To address this question, the Faslodex Investigation of
`Dose evaluation in Estrogen Receptor-positive (ER+)
`advanced breast cancer (FINDER) 1 and 2 studies have
`evaluated the efficacy,
`tolerability, and pharmacokinetic
`(PK) profiles of three different fulvestrant dose regimens in
`postmenopausal women with advanced breast cancer, as
`follows:
`
`1. AD (250 mg/month)
`2.
`250 mg loading dose (LD) regimen (500 mg on day 0
`and 250 mg on days 14 and 28 of Month 1, and
`250 mg every 28 days thereafter)
`3. High—dose (HD) regimen (500 mg/month plus 500 mg
`on day 14 of Month 1).
`
`Here, we describe the results from FINDER2, which
`has been performed in a predominantly Western (i.e.,
`non-Japanese) patient population.
`
`Methods
`
`Study design and treatment
`
`FlNDER2 (923811,/0068; NCTO0313l70) was a random-
`ized, double-blind, parallel-group, international, Phase II
`study conducted across 34 centers in eight countries:
`Belgium, Canada, Czech Republic, France, Hungary,
`Poland, Romania, and Turkey.
`Patients were randomized 1:1:1 to one of the three ful-
`
`vestrant dosing regimens (AD, LD, or HD). Treatment
`continued until patients experienced disease progression, or
`until any other criterion for discontinuation was met:
`voluntary discontinuation, safety concerns (according to
`the investigators’ judgment), non—compliance, or lost to
`follow-up.
`
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`Breast Cancer Res Treat (2010) 123:453—461
`
`Patients
`
`FINDER2 enrolled postmenopausal women, all with mea-
`surable disease and documented ER+ (2l0% positive
`staining by immunohistochemistry),
`locally advanced/
`metastatic breast cancer. Eligible patients had: relapsed
`during or within 12 months of completion of adjuvant
`endocrine therapy; progressed after endocrine therapy
`started 312 months after
`the completion of adjuvant
`endocrine treatment; or progressed after first-line endocrine
`therapy for patients with de novo advanced breast cancer.
`Patients were excluded if they had:
`life-threatening
`visceral metastases;
`received more than one previous
`regimen of systemic anti-cancer therapy (other than one
`regimen of endocrine treatment for advanced disease);
`extensive radiation therapy or systemic anti-cancer therapy
`within 4 weeks prior to randomization; abnormal labora-
`tory values or a severe concomitant condition.
`All patients provided written informed consent and the
`study was performed in accordance with the Declaration of
`Helsinki and was consistent with International Conference
`on Harmonization Good Clinical Practice.
`
`Efficacy assessments
`
`The primary study endpoint was the objective response rate
`(ORR) of patients treated with fulvestrant AD, LD, or HD,
`evaluated according to Response Evaluation Criteria In
`Solid Tumors (RECIST) criteria [6]. The best overall
`response for each patient was categorized as a response
`(complete response or partial response) or a non-response
`(stable disease, progressive disease, or not evaluable).
`Secondary endpoints
`included time to progression
`(TTP), clinical benefit
`rate (CBR),
`and duration of
`response (DoR). All endpoints were evaluated according to
`RECIST criteria [6].
`
`Pharmacokinetic parameters
`
`Plasma samples for PK analysis were collected from
`patients who consented to PK measurement. Blood samples
`(4 ml) were drawn at baseline and prior to injection on
`days 14, 28, 56, and 84. Two additional samples were
`collected between days 5 and 10 and days 33 and 38. Dr11g
`concentration—time data were analyzed with NONMEM
`V5.0, using a non-linear mixed-effects model approach.
`The primary PK parameters were fulvestrant clearance and
`volume of distribution at steady state, and secondary
`parameters of maximum plasma concentration (Cum), time
`to maximum plasma concentration (tmax), minimum plasma
`concentration (Cmjn), area under plasma concentration time
`curve from zero to the end of the dosing interval (AUC0_,),
`and half life (tn/,) were derived.
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`Breast Cancer Res Treat (2010) 123:453—461
`
`Safety assessments
`
`The safety and tolerability of the three fulvestrant dosing
`regimens were assessed by continuous evaluation of
`adverse events (AEs), clinical laboratory tests, vital signs,
`electrocardiogram (ECG),
`and physical examinations.
`Safety assessments were performed at baseline, throughout
`the study period, and up to 8 weeks after the last injection
`of study medication.
`
`Statistical analysis
`
`Overall, 43 patients per group were required for 90%
`probability that the best dose regimen by response rate be
`correctly selected, assuming that the lowest response rate
`was 19.2% (based on results for AD in previous studies)
`and that the difference in response rate between the best
`and next-best dose regimen was 15%. To allow for
`
`Fig. 1 Patient disposition
`during FINDER2 (CONSORT
`diagram)
`
`Fulvestrarit 250 mg (AD)
`ln = 47)
`22 patients
`consented to PK
`measurement
`
`Fleceived
`lulvestrant 250 mg
`in : 47)
`
`455
`
`drop-out, a total of 135 patients were to be recruited to this
`study (45 patients per group). No formal hypothesis tests
`were planned for the efficacy endpoints.
`
`Results
`
`Patients
`
`Overall, 144 patients were randomized to treatment (intent-
`to-treat population); fulvestrant AD (n = 47), LD (n : 51),
`and HD (n = 46). One patient in the LD group did not
`receive treatment and was excluded from the safety popu-
`lation. Patient disposition throughout the study is shown in
`Fig. 1.
`including treatment history,
`Baseline characteristics,
`were generally well balanced across the treatment groups,
`with no major discrepancies between arms. The majority of
`
`Excluded (n = 17]
`— adverse event (n = 1)
`— disease progression (n
`— incorrect enrollment (n
`— voluntary patient
`discon1inuation(n =1)
`- other (n = 1)
`
`1
`1
`
`FuLveatranL50.0 mg{HD1
`In = 46)
`are pafirents
`consented to PK
`mQ3EUl‘E|‘l'I6l’1l
`
`Received’
`tulveetrarvt 500 mg
`(n = 46)
`
`Ongoing treatment
`at data cut-off
`ln=11)
`
`€l1n§r;3in§ treatment
`, _ ietl
`
`“Failed inclusion criterion
`“Disease progression
`°Disease progression listed under ‘Other’ on the CRF
`“Dosing error Ln =1):brain metastases (n = 1)
`AD, approved dose; HD, high dose, LD. loading dose, PK. pharmacokinetic
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`Breast Cancer Res Treat (2010) 123:453—461
`
`Fulvestrant regimen
`
`AD (n = 47)
`
`LD (n = 51)
`
`HD (n = 46)
`
`63 (42-88)
`45 (95.7)
`
`69 (38-85)
`51 (100)
`
`67 (49-85)
`46 (100)
`
`26 (55.3)
`20 (42.6)
`0
`
`47 (100)
`
`30 (63.8)
`16 (34.0)
`1 (2.1)
`
`2 (4.3)
`37 (78.7)
`8 (17.0)
`
`1 (2.1)
`46 (97.9)
`34 (72.3)
`
`36 (76.6)
`8 (17.0)
`3 (6.4)
`
`7 (14.9)
`15 (31.9)
`16 (34.0)
`9 (19.1)
`
`25 (53.2)
`28 (59.6)
`
`18 (38.3)
`28 (59.6)
`11 (23.4)
`
`24 (51.1)°
`2 (4.3)
`
`5 (10.6)
`
`31 (60.8)
`16 (31.4)
`4 (7.8)
`51 (100)
`
`32 (62.7)
`18 (35.3)
`1 (2.0)
`
`1 (2.0)
`37 (72.5)
`13 (25.5)
`
`3 (5.9)
`48 (94.1)
`41 (80.4)
`
`39 (76.5)
`4 (7.8)
`8 (15.7)
`
`8 (15.7)
`22 (43.1)
`11 (21.6)
`10 (19.6)
`
`29 (56.9)
`25 (49.0)
`
`15 (29.4)
`36 (70.6)
`12 (23.5)
`
`31 (67.4)
`14 (30.4)
`1 (2.2)
`46 (100)
`
`32 (69.6)
`14 (30.4)
`0
`
`3 (6.5)
`32 (69.6
`11 (23.9
`
`2 (4.3)
`44 (95.7
`37 (80.4
`
`33 (71.7
`6 (13.0
`7 (15.2
`
`5 (10.9
`23 (50.0
`10 (21.7
`8 (17.4
`
`25 (54.3
`26 (56.5
`
`17 (37.0
`27 (58.7
`16 (34.8
`
`18 (35.3)d
`3 (5.9)
`
`15 (32.6
`1 (2.2)e
`
`12 (23.5)f
`
`9 (19.6 g
`
`16 (34.0)
`
`18 (35.3)
`
`20 (43.5
`
`1 (2.2)
`
`Median age, years (range)
`Race Caucasian, IL (%)
`
`WHO performance status, n (%)a
`
`0 1 2
`
`ER status, 11 (%)
`PgR status, n (%)
`PgR+
`PgR-
`Unknown
`
`HER2 status, 11 (%)
`Positive
`
`Negative
`Unknown
`
`Disease stage, n (%)
`Locally advanced only
`Metastatic
`
`Visceral involvement, n (%)
`Tumor histology, n (%)
`Infiltrating ductal carcinoma
`Infiltrating lobular carcinoma
`Other/missing
`Tumor grade, n (%)
`
`1 2 3 U
`
`navailable/unknown
`
`Prior therapy, It (%)
`Radiotherapy
`Chemotherapy
`Endocrine therapyb
`Anastrozole
`Tamoxifen
`Exemestane
`
`Relapse categories, it (%)
`During adjuvant endocrine therapy
`Within 12 months after completion
`of adjuvant endocrine therapy
`>12 months after completion of adjuvant
`endocrine therapy
`Progressed on an endocrine therapy given
`as first—line treatment for de novo
`advanced breast cancer
`
`Otherh
`
`456
`
`Table 1 Baseline
`demographics and disease
`characteristics
`
`AD approved dose, ER estrogen
`receptor, HD high dose, HER2
`human epidermal growth factor
`receptor 2, LD loading dose,
`PgR progesterone receptor,
`WHO World Health
`Organization
`a WHO performance status was
`missing for one patient in the
`AD and HD groups
`b Use of more than one
`endocrine agent in the adjuvant
`setting was acceptable.
`Endocrine therapies with a total
`incidence 310% are shown
`
`° Two patients failed inclusion
`criterion as they had < 12-month
`gap between adjuvant tamoxifen
`therapy and starting aromatase
`inhibitor treatment for advanced
`disease
`
`C1 One patient failed inclusion
`criterion: patient was third line
`6 One patient failed inclusion
`criterion: patient was first line
`
`f One patient failed inclusion
`criterion: patient was third line
`g One patient failed inclusion
`criterion: patient relapsed
`>12 months after completion of
`5 years’ adjuvant hormonal
`therapy, but did not receive
`treatment in the advanced
`setting
`1’ Patient failed inclusion
`criteria
`
`patients were Caucasian (98.6%) and median age across the
`groups was 67 (range 38-88) years (Table 1). All patients
`enrolled were ER+; approximately two-thirds of patients
`
`(65.3%) were progesterone receptor-positive as well as
`ER+. Despite all tumors being Confirmed as ER+, some
`appeared to have the clinical behavior of a relatively
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`Breast Cancer Res Treat (2010) 123:453—461
`
`457
`
`tumor, with many patients relapsing
`endocrine-resistant
`either during adjuvant endocrine therapy (39.6%) or while
`receiving first-line endocrine treatment
`for de novo
`advanced breast cancer (37.5%) (Table 1). Only 18.1% of
`all tumors showed a late recurrence (i.e., >12 months after
`completion of adjuvant endocrine treatment).
`
`Efficacy
`
`Comparison of data across the three treatment arms shows
`that fulvestrant AD, LD, and HD had similar efficacy
`(Table 2). Although ORR was numerically lower with the
`fulvestrant AD (8.5%) and LD (5.9%) regimens compared
`with HD (15.2%), the 95% confidence intervals (Cls) for
`all three treatment arms were overlapping. Similarly, for
`the CBRS observed with fulvestrant AD (31.9%), LD
`(47.1%), and HD (47.8%) the 95% CIs for all three treat-
`ment arms also overlapped (Table 2).
`While the estimated median TTP was numerically shorter
`with fulvestrant AD (3.1 months; Fig. 2), compared with the
`LD and HD arms (6.1 and 6.0 months, respectively), the
`incidence of progression events was similar between groups
`(AD: 35; LD: 31, and HD: 34 events, respectively).
`The low number of responders in all treatment arms
`prevented meaningful assessment of DoR.
`
`Pharmacokinetics
`
`In this study, a two—compartment model with first—order
`absorption and first—order elimination was fitted to the
`concentration—time data from the 72 patients who con-
`sented to PK measurements. Plots of the observed versus
`
`population-predicted fulvestrant concentrations demon-
`strated a reasonable overall fit of the model to the PK data
`
`(Fig. 3).
`
`fulvestrant was
`The mean apparent clearance of
`31.0 l/h; inter-individual variability (IIV) was 39%. The
`mean apparent volume of distribution at steady state was
`56300 1 (IIV 40%), which was similar to values determined
`previously with fulvestrant AD [7]. Residual variability
`was estimated at 22%.
`
`In the fulvestrant AD arm, steady-state concentrations
`were approached during the third month of dosing
`(Table 3; Fig. 3). The inclusion of an additional dose of
`fulvestrant at day 14 in the LD and HD regimens led to the
`achievement of steady-state fulvestrant concentrations in
`the first month of dosing. A higher Cmm for the LD regimen
`and a similar Cmjn for the HD regimen demonstrate this in
`the first versus the third month of dosing for both the LD
`and HD regimens (Table 3; Fig. 3).
`At month 3, Cmin and the AUC were similar for the AD
`and LD regimens, whereas these parameters were approx-
`imately doubled with the HD regimen. This indicates that
`the PK of fulvestrant is linear and predictable in this study
`(Table 3).
`
`S afety
`
`All three fulvestrant dose regimens were well tolerated,
`with no differences observed between the safety profiles.
`The incidence of AEs was generally similar across the
`three treatment regimens: 76.6, 72.0, and 69.6% in the
`AD, LD, and HD groups, respectively, and there was no
`evidence of
`a dose
`response for
`any of
`the AE
`categories.
`Few patients experienced serious AEs (SAES) with a
`non-fatal outcome (4, 9, and 4 patients in the AD, LD, and
`HD arms, respectively), with no clustering of event types.
`Of these, only pleural effusion and pulmonary embolism
`
`Table 2 Summary of efficacy results for each treatment arm (intent—to—treat population)
`
`ORR, n (%) [95% CI]
`CR, n (%)
`PR, n (%)
`SD 324 weeks, n (%)
`CBR, n (%) [95% CI]
`PD, n (%)
`TTP"
`
`Events, n (%)
`Median, months
`
`AD (n : 47)
`
`4 (8.5) [24, 204]
`0
`4 (8.5)
`11 (23.4)
`15 (31.9) [19.1, 47.1]
`24 (51.1)
`
`35 (74.5)
`3.1
`
`Fulvestrant regimen
`
`LD (n : 51)
`
`3 (5.9) [1.2, 16.2]
`0
`
`3 (5.9)
`21 (41.2)
`24 (47.1) [32.9, 61.5]
`20 (39.2)
`
`34 (66.7)
`6.1
`
`HD (n : 46)
`
`7 (15.2) [6.3, 28.9]
`0
`
`7 (15.2)
`15 (32.6)
`22 (47.8) [32.9, 63.1]
`19 (41.3)
`
`31 (67.4)
`6.0
`
`AD approved dose, CBR clinical benefit rate, CI confidence interval, CR complete response, HD high dose, LD loading dose, ORR objective
`response rate, PD progressive disease, PR partial response, SD stable disease, TTP time to progression
`3 TTP was estimated using the Kaplan—Meier method
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`
`458
`
`Fig. 2 Kaplan—Meier plot of
`time to progression
`
`1.0
`0.9
`
`0.8
`
`0.7
`
`0.6
`
`0.5
`
`ProportionNotProgressed 0.2
`
`
`
`0.4
`
`0.3
`
`0.1
`
`0.0
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`Breast Cancer Res Treat (2010) 123:453—461
`
`T Fulvestrant AD
`7
`- —- Fulvestrant LD
`Fulvestrant HD
`
`
`
`I
` I
`
`0
`6
`9
`12
`15
`18
`21
`
`24
`
`24
`0
`1
`0
`
`27
`
`27
`O
`0
`0
`
`Number 01 Patients at Risk:
`Months
`Fulvestrant AD
`Fulvestrant LD
`Fulvestrant HD
`
`0
`47
`51
`46
`
`6
`18
`24
`22
`
`9
`9
`17
`13
`
`Time (Months)
`12
`15
`5
`2
`7
`4
`10
`3
`
`18
`2
`2
`1
`
`21
`2
`2
`1
`
`Tick marks indrcate censored observations
`AD. approved dose: HD. high dose: LD. loading dose
`
`were reported in more than one patient (two patients each).
`One SAE (ischemic stroke) was judged by the investi-
`gator to be related to treatment (AD regimen). Overall,
`five patients died during the study;
`two patients due to
`progressive disease and three patients (2.1%) due to an
`AE (pulmonary embolism, squamous cell
`lung cancer,
`and general physical health deterioration). Of these, one
`death (pulmonary embolism) was considered by the
`investigator to be related to treatment (AD regimen).
`The most frequently reported treatment-related AEs
`were injection-site pain, hot flash, and fatigue (Table 4).
`Overall, six patients (4.2%) discontinued from the study
`due to an AE (2, 3, and 1 patients in the AD, LD, and HD
`arms, respectively). Furthermore, there were no clinically
`important findings or abnormalities in hematology, clinical
`chemistry, ECG, vital signs, or physical examinations in
`any of the treatment groups.
`
`Discussion
`
`Data from this Phase II study showed that fulvestrant AD,
`LD, and HD have similar efficacy and tolerability in a
`population of Western postmenopausal women with ER+
`locally advanced/metastatic breast cancer that had relapsed
`or progressed after prior endocrine (anti-estrogen) therapy.
`There appeared to be a trend toward improved efficacy
`with HD and LD compared with AD, but no clear differ-
`ences could be proven, given that the 95% CIs for all three
`treatment arms overlapped.
`
`A number of studies have previously investigated the
`efficacy and tolerability of fulvestrant LD and HD. Ful-
`vestrant LD data have been reported in the Evaluation of
`Faslodex Versus Exemestane Clinical Trial (EFECT) study
`involving postmenopausal women with advanced breast
`cancer who have experienced progression or recurrence
`during treatment with a non-steroidal aromatase inhibitor
`[8].
`In this
`setting,
`fulvestrant LD and exemestane
`appeared to be efficacious and well tolerated.
`The efficacy and safety of a higher-dose fulvestrant
`regimen has been examined in the Fulvestrant First-line
`Study Comparing Endocrine Treatments (FIRST) study,
`which evaluated fulvestrant HD versus anastrozole in the
`
`first-line advanced breast cancer setting. The FIRST study
`demonstrated that fulvestrant HD significantly prolongs
`TTP compared with anastrozole [9]. Furthermore, a recent,
`small Phase II study has reported that fulvestrant HD was
`efficacious and well tolerated in postmenopausal women
`who had not been previously treated with endocrine ther-
`apy [10].
`In the neoadjuvant setting,
`results from the
`Neoadjuvant Endocrine Therapy for Women with Estro-
`gen-Sensitive Tumors (NEVVEST) trial demonstrated that
`fulvestrant HD reduced ER and the proliferation biomarker
`Ki67 to a significantly greater extent than AD, and that
`both doses were well tolerated [11]. The efficacy trends
`observed in the FINDER2 study appear to support the
`findings from NEWEST, but it is difficult to draw firm
`conclusions. However, the good tolerability of both HD
`and LD has been a consistent observation across all these
`
`studies, including FINDER2.
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`Breast Cancer Res Treat (2010) 123:453—461
`
`459
`
`the achievement of steady—state concentrations, in agree-
`ment with PK results from the EFECT trial [13].
`Despite notable PK differences between regimens in
`our study, and while there appeared to be a trend toward
`improved efficacy with HD and LD compared with AD,
`no clear differences in clinical efficacy could be proven,
`as indicated by the relatively low ORRs observed, which
`did not permit any differences between treatments to
`become apparent. These low ORRS were somewhat
`surprising since, according to baseline characteristics, all
`tumors were ER+. In spite of this, some tumors appeared
`to behave as if they were relatively resistant to endocrine
`therapy,
`i.e., baseline data indicated that only 60% of
`patients had not
`recurred during adjuvant endocrine
`therapy and 62% had not progressed while receiving
`endocrine therapy for de novo advanced breast cancer.
`Overall, only 18% of tumors showed a late recurrence
`(i.e., >12 months after completion of adjuvant endocrine
`treatment), which represents the patient subgroup with
`endocrine-sensitive tumors. Furthermore, during the study,
`43.9% of patients showed disease progression. The lack
`of endocrine sensitivity in some patients may explain the
`relatively low response rates
`reported in this
`study.
`Nonetheless, these results are comparable to previous data
`from the EFECT trial,
`in which patients treated with
`fulvestrant LD achieved an ORR of 7.4% and a CBR of
`
`32.2% (6.7 and 31.5% with exemestane, respectively) [8].
`After 6 months, 70% of patients overall had experienced
`disease progression, implying that, similarly to FINDER2,
`the majority of enrolled patients had hormone-insensitive
`disease [8]. Overall, the findings from FINDER2 confirm
`the clinical feasibility, efficacy, and tolerability of the
`fulvestrant HD and LD regimens in this difficult-to-treat
`patient population.
`A parallel study (FINDER1) using the same fulvestrant
`dosing regimens in a Japanese patient population has also
`shown comparable efficacy results. In FINDER1, ORR was
`similar across the three dose regimens (11.1, 17.6, and
`10.6% for fulvestrant AD, LD, and HD, respectively), with
`overlapping CIs. Median TTP was 6.0, 7.5, and 6.0 months
`and CBRS were 42.2, 54.9, and 46.8% for fulvestrant
`AD, LD, and HD, respectively [14]. The two studies
`also appeared to have similar PK and safety outcomes;
`in FINDER1, PK steady state was reached earlier with
`fulvestrant LD and HD and all
`three doses were well
`
`tolerated [14].
`the results from the two FINDER
`Taken together,
`studies suggest that there were no major differences in the
`efficacy, tolerability, and PK of the three fulvestrant dosing
`regimens in either Japanese or non-Japanese patients.
`Therefore, ethnicity is unlikely to have an impact on the
`success of fulvestrant treatment. While fulvestrant HD did
`
`@ Springer
`
`AstraZeneca Ex. 2007 p. 7
`
`: Predicted
`Observed
`
`I‘
`28
`
`‘I
`56
`
`I
`84
`
`I
`112
`
`Time (Days)
`
`I
`28
`
`I
`56
`Time (Days)
`
`I
`84
`
`I
`112
`
`(a) Fulvestrant AD
`3 50
`40
`
`EE
`
`5
`
`30
`§ 20
`E0 10C
`0 I
`0
`
`oO
`
`(b) Fulvestrant LD
`
`E 50B, 40
`30
`.9
`
`EC
`
`g 20
`EO 10
`8O 0 I
`0
`
`(C) Fulvestrant HD
`r\ 50
`EB, 40
`30
`
`5c
`
`.9
`
`g 20
`EO 10
`8O 0 I
`0
`
`I
`28
`
`I
`56
`
`I
`84
`
`I
`112
`
`AD, approved dose; HD, high dose; LD, loading dose
`
`Time (Days)
`
`Fig. 3 Observed and population—predicted pharmacokinetic profile
`for fulvestrant a AD, b LD, and c HD regimens
`
`Recent data from the large Phase III Comparison
`of Faslodex in Recurrent or Metastatic breast cancer
`
`(CONFIRM) study, which compared the clinical benefit of
`fulvestrant HD versus AD in postmenopausal women with
`ER+ advanced breast cancer have shown that TTP was
`
`significantly longer for fulvestrant HD (11 = 362) than AD
`(n = 374)
`(hazard ratio 0.80; 95% CI, 0.68, 0.94;
`P = 0.006), corresponding to a 20% reduction in the risk
`of progression. Fulvestrant HD also showed numerical
`advantages in other secondary efficacy endpoints while
`keeping a similar tolerability profile to fulvestrant AD.
`Overall, these results suggest that the riskzbenefit profile for
`fulvestrant HD is better than that of AD [12].
`In FINDER2,
`the PK profile of fulvestrant AD was
`comparable to that previously reported in Western popu-
`lations [7], with steady—state concentrations approached
`during the third month of dosing. As expected, higher
`steady—state plasma levels of fulvestrant were reached with
`the HD regimen, and inclusion of a day 14 dose accelerated
`
`

`
`460
`
`Breast Cancer Res Treat (2010) 123:453—461
`
`Table 3 Secondary pharmacokinetic parameters for each treatment arm
`
`Number of patients
`Tm, (mean, [SD] days)
`
`Number of patients
`Cmax (gmean, [CV] ng/ml)
`Tmax (median, [min—max] days)
`Cm (gmean, [CV] ng/ml)
`AUC04 (gmean, [CV] ng h/ml)
`
`Number of patients
`Cm, (gmean, [CV] ng/ml)
`Tmax (median, [min—max] days)
`Cmm (gmean, [CV] ng/m1)
`AUCo,, (gmean 11, [CV] ng h/ml)
`
`AD (n = 47)
`
`22
`55.4 (::11.5)
`
`22
`7.30 (46.2)
`4.9 (4.1—5.9)
`2.64 (22.8)
`3170 (37.8)
`
`14
`11.7 (32.7)
`4.5 (3.9—4.8)
`5.04 (25.0)
`5450 (27.9)
`
`Fulvestrant regimen
`
`LD (11 = 51)
`
`24
`54.1 (::9.00)
`Month 1 (visit 4)
`22
`15.5 (21.9)
`3.7 (3.3—4.0)
`10.3 (15.7)
`8450 (22.3)
`Month 3 (visit 7)
`15
`13.9 (22.3)
`4.4 (4.1—4.6)
`6.93 (21.0)
`6880 (20.6)
`
`HD (n = 46)
`
`26
`54.0 (::9.38)
`
`25
`22.3 (38.2)
`4.3 (3.7—4.9)
`15.6 (31.1)
`10100 (35.5)
`
`16
`26.5 (32.2)
`4.5 (4.0—4.7)
`12.5 (22.9)
`12800 (26.4)
`
`AD approved dose, AUC0,,, area under plasma concentration time curve from zero to the end of the dosing interval, Cmax, maximum plasma
`(peak) drug concentration between days 0 and 28, Cmjn, minimum plasma (trough) drug concentration at the end of the dosing interval, CV
`coefficient of variation, HD high dose, LD loading dose, SD standard deviation, T1/2, half life, Tmax, time between dosing and Cmax
`
`Table 4 Most commonly reported treatment—related adverse events
`(33% in any arm) (safety population)
`
`References
`
`Advsrse event’ n (%)
`
`1. Wakeling AE (2000) Similarities and distinctions in the mode of
`action of different classes of antioestrogens. Endocr Relat Cancer
`Fulvestrant regimen
`7:17-28
`AD (n = 47) LD (n = 50) HD (n = 46)
` 2. Howell A (2006) Fulvestrant (‘Faslodex’): current and future role
`1njection_site pain
`5 (10_6)
`5 (100)
`3 (6.5)
`in breast cancer management. Crit Rev Oncol Hematol 57:
`Hot flash
`6 (12.8)
`2 (4.0)
`1 (2.2)
`255-273
`(2002)
`_
`3. Howell A, Robertson JFR, Quaresma Albano J et al
`Faugue
`Fulvestrant, formerly ICI 182, 780, is as effective as anastrozole
`Nausea
`in postmenopausal women with advanced breast cancer pro-
`Asthenia
`023:1fter prior endocrine treatment.
`J Clin Oncol 20:
`BM‘ Pain
`4. Osborne CK, Pippen J, Jones SE et al (2002) Double—blind,
`Al°P°°ia
`randomized trial comparing the efficacy and tolerability of ful-
`Headache
`vestrant versus anastrozole in postmenopausal women with
`
`2 (43)
`3 (6.4)
`2 (43)
`1 (Z1)
`0
`2 (4.3)
`
`4 (80)
`1 (2.0)
`0
`0
`1 (20)
`0
`
`2 (43)
`0
`1 (2.2)
`2 (43)
`2 (43)
`1 (2.2)
`
`Increased blood pressure 2 (43)
`M al
`,
`2 4 3
`)
`y gm
`(
`‘
`AD approved dose, HD high dose, LD loading dose
`
`0
`0
`
`0
`0
`
`not Show Superior efficacy Versus fulvestrant AD in these
`tW0 Small Phase H Studlesv the CONFIRM Study, which
`was a much larger, Phase III trial has clearly demonstrated
`the clinical benefits of fulvestrant HD over AD in the
`management of postmenopausal women with advanced
`breast Cancen
`
`Acknowledgments The authors would like to thank Katrina de
`Saram, PhD, formerly from Complete Medical Communications, who
`provided medical Writing support funded by AstraZeneca. This study
`was funded by AstraZeneca Pharmaceuticals.
`
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