CENTER FOR DRUG EVALUATION AND RESEARCH
`
`APPROVAL PACKAGE FOR:
`
`APPLICATION NUMBER
`
`21-344
`
`Medical / Statistical Review(s)
`
`

`

`
`
`NDA 21-344:
`
`New Drug Application
`
`Fulvestrant (FASLODEXTM)
`
`FDA Center for Drug Evaluation and
`Research
`
`Division of Oncology Drug Products
`
`Combined Medical/Statistical
`
`NDA Review
`
`Medical Reviewer: Peter Bross, MD
`
`Medical Team Leader: Grant Williams, MD
`
`Statistical Reviewer: Peiling Yang, Ph.D
`
`Statistical Team Leader: Gang Chen, Ph.D
`
`

`

` CLINICAL REVIEW
`
`Table of Contents
`
`Executive Summary ........................................................................... . 5
`
`Recommendations ................................................................................................. 5
`
`i.
`
`ii.
`
`Recommendation on Approvability ............................................................ 5
`
`Recommendation on Phase 4 Studies and/or Risk Management Steps ...... 5
`
`Summary of Clinical Findings ............................................................................. 6
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`v.
`
`Brief Overview of Clinical Program ........................................................... 6
`
`Efficacy ....................................................................................................... 7
`
`Safety ........................................................................................................... 8
`
`Dosing ......................................................................................................... 9
`
`Special Populations ..................................................................................... 9
`
`Clinical Review ................................................................... ................ 9
`
`Introduction and Background ............................................................................. 9
`
`i.
`
`ii.
`
`iii.
`
`Drug Established and Proposed Trade Name, Drug Class, Applicant’s
`Proposed Indication(s), Dose, Regimens, Age Groups ............................... 9
`
`Drug Chemical Structure ........................................................................... 10
`
`State of Armamentarium for Indication(s) ................................................ 10
`
`Important Milestones in Product Development ............................................... 16
`
`Important Issues with Pharmacologically Related Agents .............................. 18
`
`Clinically Relevant Findings From Chemistry, Animal Pharmacology and
`Toxicology, Microbiology, Biopharmaceutics, Statistics and/or Other
`Consultant Reviews ............................................................................................. 18
`
`i.
`
`Pharmacology/Toxicology ........................................................................ 18
`
`Human Pharmacokinetics and Pharmacodynamics ........................................ 21
`
`i.
`
`Phannacokinetics ...................................................................................... 2]
`
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` CLINICAL REVIEW
`
`ii.
`
`Pharmacodynamics .................................................................................... 23
`
`IV. Description of Clinical Data and Sources ................................................... 29
`
`i.
`
`Overall Data .............................................................................................. 29
`
`ii.
`
`iii.
`
`Tables Listing the Clinical Trials .............................................................. 29
`
`Literature Review ...................................................................................... 33
`
`Clinical Review Methods .................................................................................... 34
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`v.
`
`How the Review was Conducted .............................................................. 34
`
`Overview of Materials Consulted in Review ............................................ 34
`
`Overview of Methods Used to Evaluate Data Quality and Integrity ........ 34
`
`Were Trials Conducted in Accordance with Accepted Ethical Standards 35
`
`Evaluation of Financial Disclosure ........................................................... 35
`
`Integrated Review of Efficacy ......................................................... 36
`
`Brief Statement of Conclusions .......................................................................... 36
`
`General Approach to Review of the Efficacy of the Drug ............................... 37
`
`i.
`
`ii.
`
`Phase 2 studies of efficacy ........................................................................ 37
`
`Phase 3 studies reviewed in detail ............................................................. 38
`
`iii.
`
`Ongoing studies in first line indication ..................................................... 39
`
`Detailed Review of Trials by Indication ............................................................ 39
`
`i.
`
`ii.
`
`Proposed indication ................................................................................... 39
`
`Overview of the clinical trial program ...................................................... 40
`
`iii.
`
`Phase 3 clinical trials ................................................................................. 4]
`
`iv.
`
`v.
`
`vi.
`
`Efficacy assessments ................................................................................. 45
`
`Statistical plan ........................................................................................... 49
`
`Study conduct ............................................................................................ 52
`
`vii.
`
`Combined Results of Randomized Trials ................................................. 55
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`CLINICAL REVIEW
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`viii.
`
`Efficacy results by trial: Trial #20 (European open label) ........................ 60
`
`ix.
`
`x.
`
`xi.
`
`Efficacy results by trial: Trial #21 (North American — double blind double
`dummy) ..................................................................................................... 72
`
`Preliminary Results of trial #0025 in first line indication ......................... 85
`
`Overall Efficacy Conclusions .................................................................... 87
`
`Integrated Review of Safety ............................................................................... 90
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`v.
`
`Brief Statement of Conclusions ................................................................ 90
`
`Description of Patient Exposure ................................................................ 90
`
`Methods and Specific Findings of Safety Review .................................... 92
`
`Adequacy of Safety Testing ...................................................................... 96
`
`Summary of Critical Safety Findings and Limitations of Data ................. 97
`
`Dosing, Regimen, and Administration Issues ................................................... 97
`
`Use in Special Populations .................................................................................. 98
`
`i.
`
`.
`
`ii.
`
`iii.
`
`iv.
`
`Evaluation of Applicant’s Gender Effects Analyses and Adequacy of
`Investigation .............................................................................................. 98
`
`Evaluation of Evidence for Age, Race, or Ethnicity Effects on Safety or
`Efficacy ..................................................................................................... 98
`
`Evaluation of Pediatric Program ............................................................... 98
`
`Comments on Data Available or Needed in Other Populations ................ 99
`
`Conclusions and Recommendations .................................................................. 99
`
`i.
`
`ii.
`
`iii.
`
`iv.
`
`Conclusions ............................................................................................... 99
`
`Dosing ..................................................................................................... 100
`
`Tradename issues .................................................................................... 100
`
`Recommendations ................................................................................... 100
`
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` CLINICAL REVIEW
`
`Executive Summary Section
`
`Clinical Review for NDA 21-344
`
`1.
`
`Executive Summary
`
`a.
`
`Recommendations
`
`i.
`
`Recommendation on Approvability
`
`We recommend the approval of fulvestrant (FASLODEX), 250 mg monthly by the intramuscular
`route, for the treatment of.
`_
`Pro F 050i La 19 at i n Y
`
`. n. This recommendation is
`based on a review of clinical and non clinical studies submitted in support of the NDA
`application as well as a review ofthe literature.
`
`ii.
`
`Recommendation on Phase 4 Studies and/or Risk
`
`Management Steps
`
`We recommend the following phase 4 commitments:
`
`To update survival data on the randomized studies #20 and #21 and to submit a study report
`when the data are mature.
`
`To perform a study of the effect of ketoconazole on fulvestrant pharmacokinetics. This study
`may be conducted using the intravenous formulation of fulvestrant. to allow for fewer
`patients (the IV route has less inter—individual variability than the IM route) and to increase
`safety during performance of the study.
`
`The sponsor will submit all error reports, both potential and actual, that occur with the drug
`Faslodex for a period of two years following the date of drug approval. Potential errors
`include any reports of potential circumstances or events that have the capacity to cause error
`and should be reported in a quarterly summary. Actual errors include any preventable event
`that reached the patient and caused harm or reached the patient and did not cause harm.
`Additionally, the sponsor will report actual errors that occurred but did not reach the patient,
`such as if the wrong drug was prepared but system checks prevented the drug from reaching
`the patient or being administered to the patient. All actual errors should be submitted as a 15-
`day report regardless of patient outcome. The sponsor will agree to provide yearly reports of
`potential and actual errors occurring with the drug, Faslodex, to the Agency for two years
`following the date of drug approval.
`
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`CLINICAL REVIEW
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`Executive Summary Section
`
`b.
`
`Summary of Clinical Findings
`
`This NDA includes information on two randomized (phase 3) trials and 24 supportive
`clinical trials. The phase 3 randomized trials were designed to compare the effectiveness and
`safety of Faslodex (fulvestrant) with that of Arimidex (anastrozole) in the treatment of advanced
`breast cancer in postmenopausal women. The supportive trials were designed to provide
`supplementary information such as data on the pharmacokinetics and effects of fulvestrant in
`different populations and the mechanism of action of fulvestrant on breast tumors. Fulvestrant
`and anastrozole are manufactured by Astra Zeneca Pharmaceuticals, the NDA applicant.
`Fulvestrant is a monthly injection and anastrozole is a tablet given daily by mouth. The applicant
`claims that the data submitted demonstrate that fulvestrant is safe and effective in the treatment
`
`of advanced breast cancer in postmenopausal women, and that fulvestrant works by a different
`mechanism than tamoxifen and represents a new class of drugs for the hormonal treatment of
`breast cancer.
`
`i.
`
`Brief Overview of Clinical Program
`
`The Faslodex clinical trial program consisted of 26 trials in which 854 subjects received
`formulations and schedules of fulvestrant. One thousand fourteen patients were
`various
`randomized to treatment in the pivotal efficacy trials, and data from 851 postmenopausal women
`with advanced breast cancer was included in the primary efficacy intent to treat (ITT) analyses.
`Four hundred twenty three patients received monthly injections of 250 mg of fulvestrant for a
`median of six months and an equal number received anastrozole tablets. 163 patients were
`randomized to receive fulvestrant 125mg, however this dose was shown in a planned interim
`analysis to be less effective than 250 mg and these patients were not
`included in the ITT
`population efficacy analysis. A total of 1277 subjects received treatment in the clinical trials and
`were included in the evaluations of safety and tolerability.
`
`The trial population for randomized efficacy trials #0020 and #002] consisted of
`postmenopausal women with advanced breast cancer who had recurrence or progression of
`disease and required treatment because of either relapse after adjuvant tamoxifen therapy or
`progression after first-line treatment with tamoxifen for advanced disease. Entry characteristics
`were similar between treatment arms in both trials. Approximately 75% of the patients were
`reported to be estrogen receptor positive, with slightly higher percentages in the North American
`trial #0021and in the anastrozole arm of the European trial #0020. The remainder of the patients
`showed clinical evidence of hormone sensitivity. The median age was 63, the population was
`predominantly Caucasian, and 90% had a relatively good activity tolerance with a WHO
`performance status of 0 or 1. Over 96% had been previously treated with Tamoxifen, either in
`the adjuvant setting or as treatment for metastatic disease. Sixty-two percent of patients on the
`North American trial #002] and 42% of patients on the European trial #0020 had been
`previously treated with conventional cytotoxic chemotherapy.
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`CLINICAL REVIEW
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`Executive Summary Section
`
`ii.
`
`Efficacy
`
`
`
`
`
`
`
`Estimated % difference in Resonse Ratesa
`
`
`7.35
`0.29
`
`
`
`
`
`
`Table l: Summa
`Trial 0020
`Eurme - o nen label
`
`of Efficac results
`Trial 0021
`US -double blind
`
`Fulvestrant
`Anastrozole
`Fulvestrant Anastrozole 1mg
`250 mg
`I mg
`250 mg
`n=222
`n=229
`n=206
`n= 194
`
`Overall Res onse Rates (ITT Poulation)
`
`
`
`
`
`-0.39, 17.98
`95.4% CI
`-6.51, 10.36
`
`
`
`Median Time to Pro_ ession (ITT)
`
`156
`Median TTP da 5
`103
`
`0.98 .=0.84
`
`
`(0.74 to 1. 14
`(0.79 to 1.21)
`2-sided 95.4% CI
`' A difference in response rates greater than 0 indicates that fulvestrant 250 mg is associated with
`higher response rate compared with anastrozole lmg.
`b A hazard ratio ofless than 1 indicates that fulvestrant 250 mg is associated with a longer time to
`disease progression, as compared with anastrozole lmg.
`
`0.92 .=0.43
`
`Efficacy end points were evaluated in the randomized trials 0020 and 0021, the Phase 1]]
`controlled trials submitted for registration. Patients received either the long acting intramuscular
`injection (I.M.). formulation of fulvestrant or daily anastrazole tablets. The primary objective of
`the studies was to demonstrate that patients treated with fulvestrant had a decreased time to
`disease progression (superiority in time to progression) compared with anastrozole. Afier initial
`data analysis revealed that the study data failed to show a significantly longer TTP in the
`fulvestrant treatment group, the applicant proposed a non-inferiority analysis of TTP and
`response rate, to demonstrate that fulvestrant was no worse than anastrozole in terms of TTP and
`response rate. When evaluating hormonal drugs for the treatment of breast cancer, demonstration
`of non-inferiority based on the endpoint of TTP can not provide sufficient basis for marketing
`approval, because the effect of the active control drugs on TTP is not known with any degree of
`certainty. Therefore, demonstration of non-inferiority in response rates has provided the basis for
`previous NDA approvals for the hormonal treatment for advanced breast cancer. The FDA
`agreed to the applicant’s proposed analysis, provided that TTP was considered to be a supportive
`endpoint and not the primary objective.
`
`Results
`
`Superiority in any endpoint was not shown for fulvestrant over anastrozole. The FDA medical
`reviewer analyzed the submitted NDA response data using the primary electronic datasets and
`the results were similar to those reported by the applicant. FDA—adjudicated response rates in the
`European trial #0020 were 20.3 % in the fulvestrant arm and 14.9% in the anastrozole arm. In the
`North American trial #0021, the FDA response rates were 17% in both arms. A few patients with
`
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`Executive Summary Section
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`tumors that tested negative for estrogen or progesterone receptors or receptor status unknown
`also appeared to respond to therapy with fulvestrant or anastrozole. Although median time to
`progression (TTP) was somewhat longer in the fulvestrant arm in trial #0021, analysis of Kaplan
`— Meier survival curves were similar between arms in both trials and did not suggest any
`clinically meaningful differences between treatment arms. Analysis of the difference in response
`rates by both the applicant and FDA demonstrated that in each of the 2 pivotal trials for the NDA
`a deficiency in response of greater than 10% with respect to anastrozole was ruled out with two-
`sided 95.4% confidence intervals (CI’s) thereby achieving the accepted criterion for non
`inferiority. Some patients with unknown hormone receptor status and a few patients who were
`estrogen and progesterone receptor negative responded to fulvestrant in these trials. Faslodex
`may be effective in an occasional patient who is hormone receptor negative.
`
`The FDA and applicant agreed that the upper l-sided 97.5% confidence limit for the hazard ratio
`for TTP did not exceed 1.25 and a potential deficiency in time to progression of more than 25%
`for the experimental treatment was also ruled out. The applicant claimed that this showed that
`fulvestrant was “non-inferior” to anastrozole for TTP. However there is no accepted standard for
`non-inferiority of time to progression in this setting and therefore this analysis was considered
`supportive of, but not definitive proof of, fulvestrant efficacy. No statistically significant
`differences were found between treatment arms in any of the secondary endpoints including
`survival, duration of response, clinical benefit, and deterioration of quality of life.
`
`Preliminary results of trial #25 comparing fillvestrant with tamoxifen in the
`initial treatment of metastatic breast cancer showed a trend toward longer time to progression in
`the tamoxifen treatment group. Therefore, fulvestrant should not be used for the initial treatment
`of hormone-sensitive breast cancer.
`
`iii.
`
`Safety
`
`Overall, fulvestrant 250 mg was well tolerated in postmenopausal women with locally
`advanced or metastatic breast cancer. Relatively few serious adverse events were considered
`drug-related in either treatment group. The most common drug-related events (>10%) were
`injection site reactions and hot flashes. Common events (l-10%) included asthenia, headache,
`and gastrointestinal disturbances including nausea, vomiting, and diarrhea. Rash and urinary tract
`infections were also reported. An increase in joint disorders reported in patients treated with
`anastrozole was the only specific finding. The most common side effects noted were weakness
`or asthenia, headache, flushing or vasodilatation, back pain and gastrointestinal disturbances
`including nausea, vomiting, and diarrhea.
`
`Both the number and types of adverse events were similar between fulvestrant- and
`anastrozole- treated patients in the pivotal controlled efficacy trials. Local injection reactions
`with mild transient pain and inflammation were more common in patients given the 2 x 2.5 mL
`injections compared with patients given the single 5 mL injection (27% vs. 8%). An increase in
`thromboembolic phenomena (blood clots) reported at interim analysis in the fulvestrant
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`CLINICAL REVIEW
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`Executive Summary Section
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`treatment group was not found in the final safety analysis. Most serious adverse events (SAE’s)
`occurred within the first 24 weeks of fulvestrant treatment, and there was no obvious relationship
`between the occurrence of SAE‘s and patient age.
`
`iv.
`
`Dosing
`
`The proposed dose of 250 mg monthly by intramuscular injection is supported by
`preclinical, pharmacokinetic, phannacodynamic, and clinical efficacy data. Higher doses were
`not tested because of solubility factors and the necessity to keep the volume of injection below
`Scc. The 125mg dose was not efficacious. Comparability between two 2.5cc injections and the
`single 5cc monthly injection were supported by pharmacokinetic and clinical efficacy data. The
`250 mg intramuscular dose was well tolerated, except for reports of local injection site reactions,
`which were increased in the group in which two 2.5 m1 injections were administered.
`
`v.
`
`Special Populations
`
`Fulvestrant was studied in a population consisting primarily of elderly postmenopausal
`women. Because this drug blocks the action of estrogen, it is contraindicated in pregnancy.
`Short-term phamiacokinetic and endocrine studies were completed in a small number of normal
`male volunteers and healthy premenopausal women. Fulvestrant has not been studied in the
`pediatric population. Because fulvestrant is metabolized primarily in the liver, a study of
`pharrnacokinetics in patients with severe liver impairment would be helpful to determine the
`safety of fulvestrant in these populations. The predominant population was Caucasian. A study
`of efficacy in other populations might provide data to confirm efficacy in different ethnic
`populations.
`
`2.
`
`Clinical Review
`
`21.
`
`Introduction and Background
`
`i.
`
`Drug Established and Proposed Trade Name, Drug Class,
`Applicant’s Proposed Indicati0n(s), Dose, Regimens, Age
`Groups
`
`FASLODEX® (fulvestrant) (ICI 182,780) injection for intramuscular administration is a
`steroidal antiestrogen. The proposed indication is for
`
`The recommended dose is 250 mg to be
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`CLINICAL REVIEW
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`Clinical Review Section
`
`administered intramuscularly into the buttock at intervals of one month as either a single 5
`mL injection or two concurrent 2.5 mL injection.
`
`ii.
`
`Drug Chemical Structure
`
`Figure 1: FASLODEX® (fulvestrant) (ICl 182,780)
`
`OH
`
`7
`
`H0
`
`(CH2)SSO(CH2)SCF2CF3
`
`iii.
`
`State of Armamentarium for Indication(s)
`
`Existing hormonal treatments for advanced breast cancer
`
`The goals of treating patients with metastatic breast cancer are to prolong survival, slow
`or halt disease progression, and enhance the patient‘s quality of life. In patients with estrogen
`receptor (ER)-positive cancers that are not progressing rapidly, hormonal therapy is generally
`the first treatment option. If a patient initially responds to an endocrine agent and then
`progresses, or if a patient has been previously treated in a adjuvant setting and then recurs,
`another endocrine agent may still provide benefit‘. There are 3 main classes of hormonal
`treatments for breast cancer: antiestrogens such as tamoxifen and toremifene; progestins such as
`megesterol; and aromatase inhibitors such as anastrozole, letrozole, and exemestane. The
`applicant has suggested that fulvestrant represents a new class of hormonal treatments for breast
`cancer: estrogen receptor downregulators.
`
`Tamoxifen.
`
`The most clinical experience in the hormonal treatment for breast cancer is with the
`nonsteroidal antiestrogen tamoxifen (NOLVADEXN), which has been used not only as first-line
`treatment in advanced disease but as an adjuvant treatment following surgery. Tamoxifen has
`been used as first-line therapy for metastatic breast cancer for many years. Until recently, no
`other endocrine agent has shown superiority to tamoxifen in this setting. At usual daily doses of
`20 to 40 mg, tamoxifen is effective in patients of different ages and different stages of disease, in
`
`’ Buzdar A., Semin Oncol. 2001 Jun;28(3):291-304.
`
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`Clinical Review Section
`
`both pre- and postmenopausal women, in patients with tumors designated as ER positive and
`unknown.2 Although tamoxifen competes with endogenous estrogen for binding to ERs, its
`precise mechanism of action is elusive. The biological activity of tamoxifen ranges from full
`estrogen agonist to partial agonist to full antagonist which may account for undesirable effects,
`such as increased endometrial proliferation and a slightly increased risk of endometrial cancer. 3’
`Several researchers postulate that tamoxifen’s ability to stimulate the estrogen receptor is partly
`responsible for the tamoxifen resistance that develops in some patients (as demonstrated in
`preclinical models). 5
`
`4
`
`Treatment following progression on tamoxifen
`
`In postmenopausal patients with disease progression following treatment with tamoxifen (or
`related nonsteroidal antiestrogens), the choice of next-step treatment includes progestins (eg,
`megestrol acetate and medroxyprogesterone) or aromatase inhibitors (eg, aminogluthetimide and
`anastrozole).
`
`(a)
`
`Progestins
`
`The beneficial effects of progestins in the treatment of advanced breast cancer are attributed to
`their ability to counteract or oppose the stimulatory effects of estradiol on tumor. However,
`drug-related adverse effects, notably weight gain, edema, and thromboembolic complications,
`pose additional health concerns and raise compliance issues.
`
`(b)
`
`Aromatase inhibitors
`
`Aromatase inhibitors offer an effective means of reducing estrogen production by inhibiting the
`enzyme aromatase (estrogen synthetase), which serves as the catalyst in the conversion of
`androgens to estrogens. In post-menopausal women, the principal source of circulating estrogen,
`estradiol,
`is conversion of adrenally-generated androstenedione to estrone by aromatase in
`peripheral tissues, such as adipose tissue, with further conversion of estrone to estradiol.The
`presence of aromatase in human breast tumors and surrounding stromal tissue may provide a
`local source as well.
`
`2 Buzdar, AU. Tamoxifen's clinical applications: old and new. Arch Fam Med. 9:906-12, 2000.
`3 Jordan VC, Murphy CS. Endocrine pharmacology of antiestrogens as antitumor agents.
`Endocrinology Review 11:578-610, 1990.
`4 Graham JD, Bain DL, Richer JK, Jackson TA, Tung L, Horwitz KB. J Steroid Biochem Mol
`Biol742255-9, 2000.
`5 Howell A, DeFriend D, Anderson E. Mechanisms of response and resistance to endocrine
`therapy for breast cancer and the development of new treatments. Rev Endocrine-Related Cancer
`43:5-21,1993.
`
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`(i)
`
`Aminoglutethimide
`
`The nonspecific aromatase inhibitor aminoglutethimide has well-established efficacy, but even at
`conventional doses, it causes moderate toxicity and inhibits production of corticosteroids,
`making it necessary for patients to take supplemental corticosteroids. In addition, approximately
`one third of patients require mineralocorticoid replacement because of inhibited aldosterone
`production, and 5% require thyroxyine replacement because of reduced synthesis.6 In the United
`States, aminoglutethimide is not approved for use in the treatment of breast cancer.
`
`(ii)
`
`Anastrozole:
`
`The nonsteroidal aromatase inhibitor anastrozole was the first to receive marketing approval
`from the FDA, “for the treatment of advanced breast cancer in postmenopausal women with
`disease progression following tamoxifen therapy.” Two randomized double blinded phase 3 trials
`comparing 2 doses of anastrozole with megace were submitted for registration. A total of 764
`postmenopausal women who had disease progression after treatment with tamoxifen for
`metastatic disease or as adjuvant therapy were enrolled. Some patients had also received prior
`chemotherapy as adjuvant or for metastatic disease. Most patients were ER +, a smaller fraction
`were ER unknown or negative. 262 patients were treated with anastrozole 1 mg; 248 patients
`with anastrozole 10 mg; and 253 patients with Megace 160 mg.
`
`The primary endpoints of the two trials were objective response rate and TTP. Only
`patients with measurable disease could be considered partial responders. Objective response rates
`were calculated based on the Union Internationale Contre le Cancer (UICC) criteria.7 Both trials
`included over 375 patients; demogra hics and other baseline characteristics were similar for the
`three treatment groups in each trial. The efficacy results from the 2 trials showed no statistical
`differences between treatment arms in TTP, objective response rate, TTF or survival (see Table
`2). Anastrozole subsequently received marketing approval for the first-line indication after it was
`shown to have at least non-inferior efficacy compared with tamoxifen.
`
`Statistical Issues:
`
`0
`
`Sample size calculations were based on the assumption of anastrozole superiority over
`megestrol acetate in both endpoints; however, superiority was not shown.
`
`(iii)
`
`Letrozole:
`
`6 Manni A. Clinical use of aromatase inhibitors in the treatment of breast cancer. Joumal of
`
`Cellular Biology 1993;176:242—6.
`7 UTCC response criteria were incorporated into WHO (bidimensional) response criteria — see
`World Health Organization (WHO) Handbook for Reporting Results of Cancer Treatment.
`Geneva, WHO. l979;48:7.
`8 Buzdar AU, Jonat W, Howell A, Jones SE, Blomqvist CP, Vogel CL, et al. Anastrozole versus
`megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma:
`results of a survival update based on a combined analysis of data from two mature phase III
`trials. Arimidex Study group. Cancer 1998;83:1142-52.
`
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`CLINICAL REVIEW
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`Clinical Review Section
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`Letrozole (Femara® - Novartis) is a nonsteroidal aromatase inhibitor which was granted
`marketing approval in 1997 in the second line indication “for the treatment of advanced breast
`cancer in postmenopausal women with disease progression following antiestrogen therapy.”
`Registration trials consisted of two randomized phase 3 multinational trials comparing 2 doses of
`letrozole (0.5, 2.5) with megestrol acetate in one study, and aminoglutethimide 250 mg b.i.d.
`(with corticosteroid supplementation) in the other study. A total of 552 postmenopausal women
`with disease progression after treatment with antiestrogens for metastatic disease or as adjuvant
`therapy were enrolled in the megestrol acetate trial and 557 patients in the aminoglutethimide
`study. Fifty-seven percent of patients were ER +, 43% were ER unknown or negative. The
`primary endpoints of the two trials were objective response rate and TTP. Response rate was
`significantly higher in the letrozole 2.5 mg arm compared with letrozole 0.5mg, with a trend for
`superiority (p = 0.08) compared with megestrol acetate. The comparison of letrozole 2.5 mg
`with aminoglutethimide did not show any significant difference in tumor response. The risk of
`progression was significantly lower for letrozole in both trials with a hazard ratio (letrozole to
`megesterol) of 0.77 (p = 0.03) in the megestrol acetate trial and a hazard ratio (letrozole to
`aminoglutethimide) of 0.74 (p= 0.02) in the aminoglutethimide trial. Letrozole therefore
`received marketing approval “for the treatment of advanced breast cancer in postmenopausal
`women with disease progression following antiestrogen therapy.”
`
`(iv)
`
`Exemestane:
`
`Exemestane (AROMASIN® ~ Pharmacia \& Upjohn) is an orally bioavailable
`irreversible steroidal aromatase inactivator. Examestane received marketing approval in 1999
`“for the treatment of advanced breast cancer in postmenopausal women whose disease has
`progressed following tamoxifen therapy.” One pivotal multicenter, randomized, double-blind
`trial and 2 supportive phase 2 studies supported approval. The pivotal trial compared
`exemestane 25 mg administered once daily to megestrol acetate 40 mg four times daily. A total
`of 769 postmenopausal women who had disease progression after treatment with tamoxifen for
`metastatic disease or as adjuvant therapy were enrolled in the pivotal trial. Some patients had
`also received prior chemotherapy as adjuvant (28%) or for metastatic disease (16%). Sixty-seven
`percent of the women were ER positive and 32% were receptor unknown.
`The primary endpoint of the trials was objective response rates, which were found to
`be 15% in the examestane arm and 12% in the megace arm. Response rates from the single-
`ann trials were a little higher: 23.4% and 28%. These efficacy results failed to show that the
`exemestane response rate was significantly greater than that of megace. The pivotal trial was
`powered to show non-inferiority, defined in the protocol in terms of the difference between
`the tumor objective response in the two groups: registration was to be allowed on the basis of
`demonstration that the upper limit of the two-sided 90% CI. for the difference in response
`rates (Megace minus Exemestane) was < 25% of megace response rate. The difference in
`response rate, megace minus exemestane, was 2.6%, and the upper limit of the corresponding
`confidence interval did not exceed the pre-specified margin. Therefore, the criterion for non-
`inferiority was met.
`
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` CLINICAL REVIEW
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`Clinical Review Section
`
`Secondary endpoints included multiple time to event measures (TTP, TTF, Time to
`response), duration of response and survival. The protocol stated t