`
`CLINICAL REVIEW
`
`Clinical Review Section
`
`Table 43: Reviewer’s Results of Sensitivity Analysis of Difference " in
`Response Rates
`
`Population
`
`lTT
`
`Estimated % Difference in Response Rates
`{fulvestrant ~ anastrozole)
`-0.02
`
`95.4% C1
`
`(—8.02, 7.98)
`
`
`
`0.29PP (-8.58, 9.17)
`
`
`
`' A difference in response rates greater than 0 indicates that fulvestrant 250 mg is associated with higher response
`rate compared with anastrozole 1mg.
`
`Reviewer comment: FDA concurred with the Applicant’s conclusions that with a non-
`inferiority margin of 10% fulvestrant 250 mg was non-inferior to anastrozole with respect to best
`objective response rate.
`
`(d)
`
`Subgroup Analyses (exploratory)
`
`Response rates for subpopulations based on age and race are summarized in the following table:
`
`Table 44: Best Objective Response Rate by Age and Race (Trial # 21)
`
`Population
`
`Subgroup
`
`
`Number (%) of responders
`
`
`Fulvestrant 250 mg
`AnaSWOZOIC 1 mg
`
`lTT
`
`PP
`
`Age
`
`Race
`
`Age
`
`Race
`
`< 65
`2 65
`
`24/108 (= 22.2%)
`11 /98 (= 11.2%)
`
`20 /l 14 (= 17.5%)
`13 /80 (= 16.3%)
`
`White
`Non-white
`
`431 /177 (= 17.5%)
`3 /20 (= 15.0%)
`
`< 65
`2 65
`
`18 /89 (= 20.2%)
`11 /82 (= 13.4%)
`
`27/157 (= 17.2%)
`6/24 (= 25.0%)
`
`16 /89 (= 18.0%)
`10 /67 (= 14.9%)
`
`21 /128 (=16.4%)
`25 /146 (=17.1%)
`White
`5 /28 (= 17.9%)
`4/25 (= 16.0%)
`Non—white
`
`
`Response rates for subpopulations based on hormonal receptor status are summarized in the
`following table:
`
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`
`Table 45: Best Objective Response Rate by Hormonal Receptor Status (Trial
`# 21)
`
`
`Population
`
`(ER, PR) status
`
`Number (%) of responders
`
`
`Combined
`Anastrozole 1 mg
`Fulvestram 250
`mg
`N = 194
`N = 400
`
`N = 206
`ITT
`
`(+, +)
`(+, -)
`(+, 7)
`
`(-,+)
`(-, -)
`(-, ?)
`
`(7, +)
`
`(1),?)
`
`27/128 (= 21.0%)
`2/37 (= 5.4%)
`1/5 (= 20.0%)
`
`20/106 (= 18.9%)
`6/40 (= 15.0%)
`1/10 (= 10.0%)
`
`47/234 (= 20.1%)
`8/77 (= 10.4%)
`2/15 (= 13.3%)
`
`1/9 (= 11.1%)
`1/14 (= 7.1%)
`0/0
`
`3/12 (= 25.0%)
`2/9 (= 22.2%)
`0/1
`
`4/21 (= 19.0%)
`3/23 (= 13.0%)
`0/1
`
`0/0
`
`0/1
`
`0/1
`
`3/l3(=23.l%)
`
`l/15(= 6.7%)
`
`4/28 (=l4.3%)
`
`Reviewer comment: Although definitive conclusions can not be reached from non pre specified
`post hoc analyses, response rates may be decreased in the elderly population. A few patients in
`this trial who are negative for estrogen and/or progesterone receptors appeared to respond to
`hormonal therapy.
`
`(3)
`
`Time to Progression
`
`(3)
`
`Descriptive Results
`
`Time to progression was defined as the time from randomization to the time of objective disease
`progression. Most of the patients had disease progression by the data cutoff date. The
`Applicant’s description of time to disease progression data is summarized in the table below,
`followed by the Kaplan-Meier plots.
`
`Table 46: Applicant’s Descriptive Summary of Time to Disease Progression
`
`Population
`
`Fulvestrant 250 mg
`
`Anastrozole 1 mg
`
`ITT
`
`Median
`(in days)
`
`165
`
`# of patients
`censored (%)
`
`34 (16.5%)
`
`Median
`(in days)
`
`103
`
`# of patients
`censored (%)
`
`27 (13.9%)
`
`
`
`141 23(13.5%) 90PP 19(12.1%)
`
`
`
`
`
`
`
`In the intent to treat population, median time to progression was 165 days for fulvestrant and 103
`days for anastrozole. Per protocol data similarly show a longer median time to progression in the
`fulvestrant arm, suggesting a longer time to progression for Fulvestrant over anastrozole. The
`Kaplan—Meier plots for the different arms, however, are similar and the point differences
`observed at the medians are not sustained:
`
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`
`Figure 5: Kaplan-Meier Plot of Time to Progression (ITT Population)
`
`Time to Ploglession
`
`
`
`FULVESTRANT 25
`* + * ANASTFDZOLE 'MG
`
`
`
`Figure 6: Kaplan-Meier Plot of Time to Progression (PP Population)
`
`Tim D Progressbn (PP Population)
`
`10
`
`
`
`FULVESTFVKNT 25
`* * * ANASTFDZOLE MG
`
`
`
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`
`(b)
`
`Statistical Analysis of TTP
`
`The analyses of time to disease progression are summarized in table 42 below:
`
`Table 47: Results of Analysis of Time to Disease Progression
`
`Analysis
`
`Population
`
`FDA Estimated hazard ratio
`Applicant’s Estimated hazard
`(95.4% CI)
`ratio ' (95.14% C1)
`‘W—TW
`lTT
`Adjusted
`0.92 (0.74, 1.14)
`0.92 (0.74, 1.14)
`
`p = .4295
`p = .4295
`
`Unadjusted ‘
`
`0.88 (0.71, 1.10)
`p = .2594
`
`0.88(0.71, 1.10)
`p = .2594
`
`PP
`
`Adjusted
`0.95 (0.74, 1.21)
`0.95 (0.74, 1.21)
`
`p = .6662
`p = .6662
`
`0.91 (0.72, 1.15)
`N/A
`Unadjusted
`p = .4134
`
`‘ A hazard ratio ofless than 1 indicates that fulvestrant 250 mg is associated with a longer time to disease
`progression compared with anastrozole 1mg.
`Primary analysis. Cox proportional-hazards model with baseline covariates: age, performance status, measurable
`compared with non-measurable disease, receptor status, previous response to hormone therapy, previous use of
`cytotoxic chemotherapy, and use of bisphosphonate therapy for bone disease.
`c Cox proportional-hazards model without baseline covariates.
`
`Whether analyses were performed on the ITT or PP population, adjusted or unadjusted analysis,
`the p-values were relatively large, indicating that there was no statistically significant difference
`in TTP between the two treatment arms. Superiority in time to progression was therefore not
`demonstrated. The FDA statistical reviewer defined the per protocol (PP) population slightly
`differently from the applicant and constructed a 95.4% (instead of 95.14%) confidence interval,
`adjusting for the interim analysis. None of the confidence intervals of the hazard ratios exceeded
`1.25,
`thus ruling out a 25% shorter time to progression for fulvestrant compared with
`anastrozole.
`
`(c)
`
`Covariate analysis
`
`Patients who had measurable disease only and patients with a performance status of 1 or 2
`seemed to be associated with a higher instantaneous risk of disease progression compared with
`all other patients. Patients whose receptor status was unknown seemed to be associated with a
`lower risk compared with all other patients although only a very small proportion of patients was
`in this stratum and the finding was only seen in the ITT population. Results of covariates used in
`the adjusted analysis are summarized in the following table:
`
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`
`Table 48: Results of Covariates Analysis of Time to Disease Progression
`
`Variable
`
`PP population
`lTT population
`Hazard ratio
`P-value
`Hazard ratio
`P-value
`(95.4% CI)
`(95.14% C1)
`
`Measurable disease
`1.62
`0.0005
`1.59
`0.0019
`
`only
`Who PS 1
`
`Who PS 2
`
`Previous response to
`hormones
`
`Receptor
`neg
`
`Receptor status
`Unknown
`
`(123,214)
`1.30
`
`(1.02, 1.65)
`1.59
`
`(106,2.39)
`
`1.02
`(0.68, 1.54)
`
`1.06
`(0.67, 1.70)
`
`0.48
`(0.29, 0.81)
`
`0.0317
`
`0.0233
`
`0.9288
`
`0.7937
`
`0.0053
`
`(l.l8,2.l4)
`1.21
`
`(0.93, 1.58)
`1.77
`
`(1.13,2.78)
`
`0.79
`(0.47, 1.33)
`
`1.16
`(0.72, 1.85)
`
`0.61
`(0.36, 1.04)
`
`0.1559
`
`0.0118
`
`0.3714
`
`0.5350
`
`0.0658
`
`Hazard Ratio > 1 = higher risk ofprogression.
`
`(d)
`
`Conclusions regarding TTP
`
`Superiority in time to progression was not demonstrated. Although the FDA statistical reviewer
`used a slightly different confidence level and the PP population was slightly different from the
`Applicant’s, the FDA was able to concur with the Applicant’s finding that, with a non-inferiority
`margin of 25%, fulvestrant 250-mg was non-inferior to anastrozole with respect to time to
`progression. As in trial #20, patients with worse performance status appeared to have a higher
`risk for progression, and patients whose hormone receptor status was unknown appeared to have
`a lower risk of progression. Bisphosphonate therapy, age over 65, and previous chemotherapy
`were not risk factors for progression. Unlike trial #20, receptor negativity and a previous
`response to hormones were not associated with increased or decreased risk of progression,
`respectively. The increased risk for progression in patients with measurable disease only was not
`seen in trial #20. The numbers are small, and the differences between studies may be due to
`artifact of small numbers.
`
`(4)
`
`Survival analysis
`
`The survival data in the original NDA submission was cut off on June 30, 2000. Since the
`original survival data were not mature (65.5% of the 400 patients were censored), the Division
`requested the applicant for an updated survival data. The updated survival data were received on
`August 28, 2001; the data were cut off on April 30, 200]. The FDA statistical reviewer’s
`survival data analysis results are summarized in the following tables:
`
`Page 80
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`Clinical Review Section
`
`Table 49: Descriptive Survival Results (ITT population)
`Data cut-off date
`Fulvestrant
`Anastrozole
`
`(N = 194)
`(N = 206)
`Median
`# of deaths
`Median
`# of deaths
`
`
`June 30, 2000
`
`848
`
`73 (35.4%)
`
`878
`
`65 (33.5%)
`
`
`
`837 109 (52.9%) 90]April 30, 2001 92 (47.4%)
`
`
`
`
`
`
`
`Figure 7: Reviewer’s Kaplan-Meier Probability of Updated Survival Time
`(ITT Population) Study #21
`
`Time to Death (ITT Population, Updated)
`
`1.0
`
`
`
`
`FULVESTRANT 25
`+ + + ANASTROZOLE 1MG
`
`
` 0.8
`
`0.6
`
`Rate
`
`0.4
`
`0.2
`
`0.0
`
`o
`
`200400600800100012001400
`
`Days
`
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`
`Clinical Review Section
`
`Table 50: FDA Statistical Reviewer’s Analysis of Survival
`
`Population
`Data cut- Comparison
`Hazard ratio '
`95% two-sided
`P-value
`
`off date
`C]
`fulvestrant: anastrozole
`
`ITT
`
`April 30,
`200‘
`
`Adjusted analysis 5
`Unadjusted analysis ‘
`
`1.12
`1.10
`
`(0.85, 1.49)
`(0.83, 1.45)
`
`0.422
`0.509
`
`0.366
`(0.84, 1.59)
`1.16
`“Edit—1351335663".
`April 30,
`PP
`
`
`
`
`200‘ 0.405 Unadjusted analysis 1.14 (0.84, 1.56)
`
`' A hazard ratio of less than ] indicates that fulvestrant 250 mg is associated with a longer time to death compared
`with anastrozole 1 mg.
`b Cox proportional-hazards model with baseline covariates: age, performance status, measurable compared with
`non-measurable disease, receptor status, previous response to hormone therapy, previous use of cytotoxic
`chemotherapy, and use of bisphosphonate therapy for bone disease.
`c Cox proportional-hazards model without baseline covariates.
`
`Reviewer comment: As in study #20, all hazard ratios were approximately 1, and the Kaplan
`Meier curves are similar, suggesting no difference in survival between the two treatment groups.
`However, the study was not designed to show non-inferiority or superiority with respect to
`survival; therefore, there was limited power to detect treatment difference in survival.
`
`(5)
`
`Time to Treatment Failure
`
`The Applicant’s analysis results of time to treatment failure are summarized as below.
`
`Table 51: Applicant’s Results of Descriptive Summary of Time to Treatment
`Failure
`
`Population
`
`Fulvestrant 250 mg (N = 206)
`
`Anastrozole 1 mg (N = 194)
`
`ITF
`
`Median
`(in days)
`
`I41
`
`# of patients
`censored (%)
`
`28(13.6%)
`
`Median
`(in days)
`
`101.5
`
`# of patients
`censored (%)
`
`24(12.4°/o)
`
`The Applicant’s results did not suggest any treatment difference with respect to time to treatment
`failure. FDA does generally not regard this endpoint as clinically relevant.
`
`(6) Duration of Objective Response
`
`Duration of objective response was assessed in responders only (patients who has an objective
`response of CR or PR) in two ways:
`
`1.
`
`2.
`
`from the date of randomization to the date of first determined progression or death from any
`cause, and
`from the date of first documentation of response to the date of first determined progression or
`death from any cause.
`
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`
`Clinical Review section
`
`Per Applicant’s report, 36/206 (=17.5%) patients randomized to the fulvestrant 250-mg group
`and 34/194 (=17.5%) patients randomized to the anastrozole group had an objective response.
`The Applicant’s results are summarized as below.
`
`Table 52: Results of Duration ' of Best Objective Response (ITT Population)
`Treatment
`
`Fulvestrant 250 mg
`
`Anastrozole 1 mg
`
`' ii of Responders
`
`Median response duration (days)
`from Date of Randomization
`
`Median response duration (days)
`from Date of Response
`FDA 95% C1 for median
`
`’ from date of response started.
`
`36
`
`587.5
`
`335
`
`34
`
`319.6
`
`171
`
`(192, 623)
`
`(132, 271)
`
`Reviewer comment: The duration of response defined from the date of randomization may not
`be clinically meaningful since duration of response for patients who started response late tends to
`be overestimated. The duration of response between the two groups should not be compared
`because the two respective responder subgroups were treatment-outcome dependent. The
`duration of response should be reported only for the specific treatment under consideration along
`with the response rate.
`
`(7) Duration of Clinical Benefit
`
`Clinical benefit was defined by the applicant as patients who had CR, PR, or SD224 weeks.
`Duration of clinical benefit was defined by the applicant as the time from the date of
`randomization to date of clinical benefit. Per Applicant’s report, 87/206 (=42.2%) patients
`randomized to the fulvestrant 250-mg group and 70/194 (=36.1%) patients randomized to the
`anastrozole group had a clinical benefit. When performed on the ITT population the median
`duration of clinical benefit was 391 days for patients with clinical benefit who were randomized
`to the fulvestrant 250-mg group and 329 days for patients with clinical benefit who were
`randomized to the anastrozole group.
`
`(8) Quality of Life analysis
`
`In trial #21, most patients participated in QOL assessments. A total of 317 (83.6%) of 379
`patients completed all questionnaires for data collected in the periods up to the date of the
`patient’s last visit within the previous 12 months or the visit at which the patient was determined
`to have disease progression. The majority [42 (67.7%) of 62] of patients who did not complete
`the required number of questionnaires missed only 1 visit. The pattern of TOI for patients who
`completed the last questionnaire was similar to that of patients who did not complete the last
`questionnaire.
`
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`
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`
`(3)
`
`Treatment Outcome Index (TOI)
`
`There was no significant difference in T01 between the 2 groups (p = .8) . Additionally, there
`was no evidence at the 5% level of a treatment-by-time interaction. This suggested that there
`was no evidence of change in T01 over time for either treatment group.
`
`(b)
`
`Time to Deterioration in Quality of Life
`
`Most patients in the North American trial (#21) participated in the QOL surveys. Patients
`excluded from the QOL analysis were those either did not have a baseline TOL value or whose
`baseline questionnaire was completed more than 7 days after treatment. Approximately 95% of
`all patients were included in the analysis of time to deterioration. Insufficient quality-of-life data
`were collected afier disease progression to allow the data after progression to be used in the
`statistical analysis. Only 113 (35.1%) of 322 patients with disease progression completed all the
`questionnaires up to the data cutoff date. The FDA statistical reviewer obtained the distribution
`of patients included in the analysis of time to deterioration, and obtained the 95% confidence
`interval for the median time to deterioration, included in Table 48:
`
`Table 53: Descriptive Summary of Time to Deterioration (lTT population)
`
`
`Fulvestrant 250 mg
`Anastrozole 1 mg
`
`# ofpatients censored
`Median, days
`# ofpatients
`Median, days
`(FDA 95% C1.)
`censored (%)
`(FDA 95%
`(%)
`
`Cl.)
`260 (165,276)
`106 (54.4%)
`209 (165, 276)
`85 (46.2%)
`
`
`# ofpts. (%)
`included in the
`
`195 /206 (94.7%)
`
`184 /l 94 (94.8%)
`
`TTD analysis
`it patients (%) with
`deterioration in
`QOL
`
`99/184 (53.8 %)
`
`89/195 (45.6%)
`
`Differences between treatment groups in median time to deterioration were 51 days in favor of
`fulvestrant; this was not statistically significant (p=0. 1971). Time to deterioration in QOL was
`comparable between treatment groups.
`
`(c)
`
`Symptomatic Response
`
`(i)
`
`Analgesic use
`
`The proportions of patients in the fulvestrant group who used no analgesics from month I
`onward were similar to or slightly greater than that for patients in the anastrozole group.
`
`(ii)
`
`Global Pain Score
`
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`
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`
`Global pain scores (patients’ assessments) were generally similar between treatment groups for
`Visits 1 to 12 (compared with baseline scores). Slightly more patients in the fulvestrant group
`reported global pain scores of no pain compared with patients in the anastrozole group.
`Differences were not statistically significant.
`
`Reviewer comment: QOL responses were comparable between treatment arms. Despite a
`higher initial rate of collection of QOL data in trial #21 compared with trial #20, meaningful
`conclusions on time to deterioration could not be made on account of censoring due to the low
`rate of collection of data following progression.
`
`x.
`
`Preliminary Results of trial #0025 in first line indication
`
`(1)
`
`Introduction
`
`Trial 0025 was a double-blind, randomized, parallel-group, multicenter, comparative trial
`conducted in postmenopausal women with advanced breast cancer designed to compare the
`efficacy and safety of fulvestrant with tamoxifen in the initial
`treatment of advanced breast
`cancer. Patients had received no prior therapy or had completed adjuvant tamoxifen at least 12
`months prior to entry. Preliminary results of this trial were supplied by the applicant but the data
`was not reviewed in detail. This trial was intended to support registration of fulvestrant in the
`hormonal treatment of advanced metastatic breast cancer in the first-line indication.
`
`The population of breast cancer patients studied in this trial was distinct and different
`from that included in trials 0020 and 002] which were reviewed in the previous sections. These
`trials included patients who had progressed or relapsed after prior endocrine therapy as adjuvant
`therapy or treatment of advanced disease. In trial 0025, patients who had received previous
`endocrine treatment for breast cancer were excluded, although patients who had received
`tamoxifen as adjuvant treatment were eligible provided treatment had been stopped at least 12
`months before randomization. Patients who had received surgical oophorectomy or ovarian
`radiation were also eligible. The primary statistical analyses of the objective efficacy end points
`in the trial (ie, time to progression, objective response rate, and time to treatment failure) were
`conducted using an randomized patients on an intention-to-treat basis. Secondary (supportive)
`statistical analyses of these end points were conducted using a per—protocol population.
`
`(2) Reported Results
`
`A total of 587 patients from 170 centers, including 60 patients from 17 Japanese centers, were
`randomized to trial treatment with either fulvestrant 250 mg (313 patients) or tamoxifen 20 mg
`(274 patients). Patients were followed for a median of 441 days. 234/313 (75%) of patients
`treated with fulvestrant were strogen receptor positive, 202/274 (74%) of patients treated with
`tamoxifen were estrogen receptor positive.
`
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`
`Table 54: Study 0025 Median Time to Progression
`
`(All uts)
`
`206 da 5
`
`Tamoxifen 20
`252 da 5
`
`95% C].
`Hazard Ratio (F:T
`—ll§- ,
`-
`.98 l 44
`
`.0876
`
`m—ositive
`
`
`or unknown
`
`
`
`
`
`
`
`
`
`
`
`TTP was not statistically significantly different at the 5% level between fulvestrant and o
`tamoxifen (p=0.0876). The hazard ratio indicates that the average risk of progression, over a
`given period of time, for patients randomized to fulvestrant 250mg was approximately 18%
`higher than for those randomized to tamoxifen 20 mg. The 95% confidence interval indicates
`that the risk for patients randomized to fulvestrant could be between 2% lower and 44% higher
`than for those randomized to tamoxifen. The upper limit of the 95% confidence interval (1.44)
`does not satisfy the predefined criterion 1.25 for concluding noninferiority of fileestrant
`compared with tamoxifen.
`
`Table 55: Response rates in study #25
`
`
`
`
`
`
`
`
`
`
`Efficacy
`Parameter
`
`Complete
`Res onse
`
`Clinical Benefit
`
`
`
`Tamoxifen 20
`Fulvestrant 250
`m_ N = 313
`m_ (N = 274
`
`Odds
`Ratio
`
`
`
`30 (9.6%)
`
`19 (6.9%)
`
`69 (22 %)
`
`74 (27%
`
`_-—
`.87
`61,124
`93 (33.9%)
`99 (31.6%)
`
`54.3% _m. .48, .95
`
`95% Cl.
`
`P value
`
`
`
`
`.026
`
`The proportion of patients who were classed as responders (CR plus PR) was similar in
`the 2 treatment groups, although the proportion of patients considered to have clinical benefit
`was lower in the fulvestrant group compared with the tamoxifen group. Randomization to
`fillvestrant 250 mg was not statistically significantly different at the 5% level from
`randomization to tamoxifen 20 mg in terms of objective response rate (p=0.4508). The odds ratio
`indicates that the odds of having a response for patients randomized to fulvestrant 250 mg was
`13% lower than for those randomized to tamoxifen 20 mg, given that both groups had the same
`baseline covariates. The 95% confidence interval indicates that the odds of a response for
`patients randomized to fulvestrant could be between 39% lower and 24% higher than for those
`randomized to tamoxifen.
`
`(3) Conclusions
`
`Trial 0025 demonstrated evidence of the antitumor activity of fulvestrant in
`postmenopausal women with advanced breast cancer, as shown by a 32% objective response
`rate. The trial did not, however, achieve its primary objectives, demonstrating neither superiority
`nor noninferiority of fulvestrant relative to tamoxifen for the primary end point of time to
`
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`
`progression. Survival data are not yet mature and have not yet been analyzed. The study
`population in registration trials 0020 and 0021 showed resistance to prior endocrine therapy,
`whereas patients in Trial 0025 were endocrine therapy naive or showed no evidence of resistance
`to prior endocrine therapy. Because of the difference in patient populations, FDA agrees with the
`applicant that the review of data from Trials 0020 and 0021 can be viewed independently of the
`efficacy results of Trial 0025.
`
`Reviewer Comment: Although the results of this trial have not been reviewed, the reported
`results suggest that fulvestrant may not be equally efficacious as tamoxifen in the first line
`setting.
`
`xi.
`
`Overall Efficacy Conclusions
`
`(1)
`
`Trial Population
`
`The trial population for Trials 0020 and 0021 consisted of postmenopausal women with
`advanced breast cancer who had either recurrence or progression of disease and required
`hormonal treatment because of relapse after adjuvant endocrine therapy or progression after first-
`line treatment for advanced disease. Evidence of hormone sensitivity was an additional trial
`requirement and was defined as (a) at least 12 months of adjuvant hormonal therapy before
`relapse, (b) tumor remission or stabilization after at least 3 months of hormonal therapy before
`progression, or (c) a tumor status of estrogen—receptor positive (ER+) or progesterone-receptor
`positive (PgR+). Patients with a tumor status of ER negative or ER unknown were permitted to
`enter the trials as long as they fulfilled either criteria.
`The baseline disease characteristics appeared similar between treatment groups, despite
`lack of stratification for prognostic factors. Over 97% of patients had metastatic disease at entry,
`and over 75% of patients in each treatment group had ER+ tumors. The population studied
`appears fairly well to reflect the proposed indication except that it is not clear how many patients
`had artificially-induced menopause, and over 95% of patients were previously treated with
`tamoxifen. Previous second line approvals in advanced breast cancer have specified ‘disease
`progression after tamoxifen.’ Treatment arms were well balanced for prognostic characteristics,
`except that in trial 0020 slightly more patients in the fulvestrant arm had an unknown receptor
`status, and fewer patients were known estrogen receptor positive. This might have biased the trial
`results against fulvestrant.
`
`(2)
`
`Efficacy endpoints
`
`(a)
`
`Time to Progression
`
`The original primary objective was demonstration of superiority of time to progression.
`Response rate was a secondary endpoint. After data analysis revealed that the original objective
`was not met, 'I'TP was considered as a secondary endpoint for review. Although the FDA
`statistical reviewer used a slightly different confidence level and the PP population was slightly
`different from the Applicant’s, the FDA concured with the Applicant’s finding that, using a non-
`inferiority margin of 25%, fulvestrant 250-mg was non-inferior to anastrozole with respect to
`
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`
`time to progression. Results of the FDA statistical reviewer’s analysis of time to progression are
`summarized in the table below:
`
`Table 56: Time to Progression
`
`
`
`Euro - e - o u en label
`US -double blind
`
`Fulvestrant
`Anastrozole
`Fulvestrant
`
`
`250 mg
`I mg
`250 mg
`
`
`(n=206)
`(n= 194)
`(n=222)
`(n=229
`
` Median Time to Proression ITT
`
`
`
`l56
`165
`l03
`Median TTP da 5
`
`
`Hazard ratio'
`0.98 (-=0.84
`2-slded 95.4% CI
`(0.74 to l. 14
`(0.79 to 1.21)
`
`
`Median Time to Pro_ression Per Protocol
`
`—n_--n--z_
`
`
`
`Anastrozole lmg
`
`0.92 =0.43
`
`
`
`
`'Cox proportional—hazards model with baseline covariates: age, performance status, measurable compared with non-
`measurable disease, receptor status, previous response to hormone therapy, previous use of cytotoxic chemotherapy,
`and use of bisphosphonate therapy for bone disease.
`
`Although median time to progression was slightly longer for patients treated with fulvestrant in
`trial # 2] , examination of the Kaplan-Meier curves did not suggest any lasting difference in time
`to progression between treatment arms. Analysis of covariates suggested that patients with
`measurable disease only, or worse performance status, appeared to have a somewhat higher risk
`for progression. Patients whose hormone receptor status was unknown appeared to have a lower
`risk ofprogression.
`
`(b)
`
`Response rate
`
`In the pivotal efficacy trials, treatment with fulvestrant produced objective response rates
`comparable to or greater than those achieved with anastrozole, however, superiority of
`fulvestrant over anastrozole was not shown. Whether analyses were performed on the ITT or PP
`population, adjusted or unadjusted analysis, the estimated hazard ratio was not significantly
`different from 1 in either trial. When the applicant requested approval based on non-inferiority
`because of failure to demonstrate superiority, the Division’s response was to focus on non-
`inferiority of response rate, since the control effect on time to progression is unknown.
`Regulatory precedent has allowed registration on the basis of non inferiority in response rates in
`previous NDA’s for the hormonal treatment of breast cancer. Results of the FDA statistical
`reviewer’s analysis of response data is summarized in the table below:
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`
`Table 57: Response data from phase 3 trials
`
`Trial 0020
`Trial 0021
`Euro u e - o - en label
`US —double blind
`
`Fulvestrant
`Anastrozole
`Fulvestrant
`Anastrozole
`t
`1m
`250 m
`I m
`250 m_
`
`
`n=222
`
`
`End point
`
`NumbEr (%) CR
`PR
`CR+PR
`
`10 (4.5)
`36 (16.2)
`46 20.7
`45 (20.3%)
`
`— .4-1 “Uc E.D3 c :1aI-
`
`4 (1.7)
`32 (14.0)
`36 (15.7
`
`10 (14.9)
`26 (12.6)
`36(17.5
`
`7 (3.6)
`27 (13.9)
`34 17.5
`
`
`
`
`
`
`
`
`
`
`
`-I———-I_
`
`min-m-
`Estimated % difference in Res u onse Rates ‘
`-0.02
`5.42
`
`95.4% C1
`
`(-6.28, 8.87
`(-1.44,14.77
`Per Protocol Po - ulation
`
`
`m 2
`
`9 (15%)
`
`Estimated "/9 difference in Res - onse Rates ‘
`
`
`
`
`—_—
`
`
`
`‘ logistic-regression model with baseline covariates.
`b logisticqegression model without baseline covariates.
`c unadjusted analysis. A difference in response rates greater than 0 indicates that fulvestrant 250 mg is
`associated with higher response rate compared with anastrozole 1mg. See appendix for discussion of
`statistical sensitivity analysis.
`
`Reviewer comment: The FDA statistical reviewer concurred with the applicant’s finding that,
`using the non-inferiority margin of 10% for response rate, fulvestrant 250-mg was non-inferior
`to anastrozole l-mg with respect to objective response rate in both the ITT and PP populations
`for each trial.
`
`(c)
`
`Other efficacy endpoints
`
`There was no apparent difference in the Kaplan Meier survival curves in trial 20. There
`was a slight trend in Kaplan-Meier curves in favor of anastrozole in survival analysis in Trial
`0021. However, since the data were not mature and the trial was not powered for survival
`analysis, no conclusion regarding survival should be drawn. No statistical significant differences
`between arms were found in other efficacy and QOL endpoints.
`
`(d)
`
`Overall Efficacy Conclusions
`
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`Each of the two pivotal trials for the NDA supported noninferiority of fulvestrant versus
`the comparator, anastrozole, in both response rate and time to progression, in postmenopausal
`women with disease progression following antiestrogen therapy. Fulvestrant exhibited a slightly
`higher response rate compared with anastrozole in trial #20 and a slightly longer time to
`progression in trial #21. No statistical significant differences between arms were found in other
`efficacy and QOL endpoints.
`(1.
`Integrated Review of Safety
`
`I.
`
`Brief Statement of Conclusions
`
`Overall, fulvestrant 250 mg was well tolerated in postmenopausal women with locally advanced
`or metastatic breast cancer. The number and types of adverse events were similar between
`fulvestrant- and anastrozole-treated patients in the 2 pivotal controlled efficacy trials. Adverse
`reactions commonly reported in the clinical trial program are summarized as follows:
`
`Commonly reported adverse reactions
`0 whole body: asthenia, usually mild or moderate in nature
`
`0
`
`0
`
`0
`
`0
`
`o
`
`0
`
`injection- site reactions, including mild transient pain and inflammation in 27% of
`patients (5% of treatment courses) when given as 2 x 2.5- ml injections;
`
`injection- site reactions including mild transient pain and inflammation in 8% of
`patients (1% of injections) when given as a single 5— ml injection;
`
`hot flashes (predominately mild and usually occur within the first 2 months of
`therapy);
`
`headache, mostly mild;
`
`gastrointestinal disturbance, including nausea, vomiting, diarrhea, and anorexia that
`are usually mild in nature;
`
`urinary tract infections, usually mild in nature.
`
`ii.
`
`Description of Patient Exposure
`
`A total of 1178 patients were exposed to various doses and schedules of fulvestrant. The
`largest group included the 588 patients who were included in the pivotal efficacy trials, and these
`patients also received the longest exposures to fulvestrant. The safety follow-up period was
`similar for all trials (8 weeks following the last injection). Patients receiving either the LA
`formulation, SA formulation, oral formulation or iv formulation were followed for 8 weeks after
`the last dose. Patient exposure to anastrozole and fulvestrant in the clinical trials submitted to
`NDA 21-344 are summarized in the table below:
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`Table 58: Fulvestrant and Anastrozole patient exposure in NBA 21-344
`
`Trial category
`
`Fulvestrant'I
`
`Anastrozole
`
`(all doses and
`formulations)
`
`Efficacy Trials
`588
`
`2
`
`1 mg
`
`423
`
`Clinical harmacolo_ trials
`
`I' ivotal controlled efficacy
`rials (Trials 0021, 0020)
`
`I n postmenopausal women
`ith breast cancer (Trials
`I002, 0018, 0039
`
`I023, 0024, 0026, 0029, 0031,
`
`I034, 0036, 0038, 0-1 5-1 1)
`breast cancer
`
`’ Includes patients given fulvestrant 125 mg (all trials, including Trials 0021
`and 0020).
`
`The exposure of patients to single doses of fulvestrant is summarized below:
`
`Table 59: Single dose patient exposure to fulvestrant
`
`Formulation
`
`Predominant
`Po . ulation
`
`Healthy Males
`
`Number of patients
`ex - osed
`
`Intravenous
`
`Healthy
`volunteers
`
`SA —
`intramuscualr
`
`Healthy
`Volunteers
`
`LA —
`intramuscular
`
`Postmenopausal
`women with
`
`Patients in the pivotal trials had the greatest cumulative exposure. While some of the 423
`subjects in the 2 pivotal trials (LA formulation) were exposed to fulvestrant 250 mg for long
`periods (up to approximately 3 years), the median exposure was about 6 months. More than half
`of the 19 patients in the Phase I] efficacy trial were exposed to the LA formulation of fulvestrant
`250 mg for at least 7 months. The 165 subjects given fulvestrant 125 mg in the 2 pivotal trials
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`were exposed for a median of less than 4 months, although at least] subject was treated for
`nearly 2 years. The exposure to fulvestrant outside of the 2 pivotal trials was greatest in
`postmenopausal women with breast cancer in Trial 0004, in which the median duration of
`treatment was 196 days. Peak exposure ‘Cmax achieved) was greatest in the phannacokinetic trial
`of the iv formulation. Overall, patients in the pivotal trials had the greatest cumulative exposure
`(Table 54).
`
`Table 60: Patient exposure to fulvestrant (LA formulation) in e