Phase III, Multicenter, Double-Blind, Randomized Study
`of Letrozole, an Aromatase Inhibitor, for Advanced Breast
`Cancer Versus Megestrol Acetate
`
`By A. Buzdar, J. Douma, N. Davidson, R. Elledge, M. Morgan, R. Smith, L. Porter, J. Nabhollz, X. Xiang, and C. Brady
`
`Purpose: To compare two doses of letrozole (0.5 mg
`and 2.5 mg every day) and megestrol acetate (40 mg
`aid) as endocrine therapy in postmenopausal women
`with advanced breast cancer previously treated with
`antiestrogens.
`Patients and Methods: This double-blind, randomized,
`multicenter, multinational study enrolled 602 patients, all
`of whom were included in the primary analysis in the
`protocol. Patients had advanced or metastatic breast can-
`cer with evidence of disease progression while receiving
`continuous adiuvant antiestrogen therapy, had experi-
`enced relapse within 12 months of stopping adiuvant
`antiestrogen therapy given for at least 6 months, or had
`experienced disease progression while receiving anties-
`trogen therapy for advanced disease. Tumors were re-
`quired to be estrogen receptor- and/or progesterone
`receptor-positive or of unknown status. Confirmed objec-
`tive response rate was the primary efficacy variable.
`Karnofsky Performance Status and European Organiza-
`tion for Research and Treatment of Cancer quality-of-life
`assessments were collected for 1 year.
`
`NTTL A CURE can be found, the treatment of ad-
`
`vanced breast cancer focuses on slowing or stopping
`tumor growth for as long as possible and maintaining the
`patient’s quality of life. Endocrine therapy, an effective,
`minimally toxic, palliative treatment, represents the best
`therapeutic option for many patients. Tamoxifen is currently
`the most widely used endocrine therapy. Approximately
`40% to 50% of patients who relapse after tamoxifen may
`achieve
`clinical benefit
`from second—line
`endocrine
`
`agentsl'3 Progestins and nonspecific aromatase inhibitors
`have been the most commonly used second-line agents,
`with megestrol acetate and aminoglutethimide historically
`selected as the mainstay of second-line therapy. However,
`new molecules have been discovered that more specifically
`target aromatase.4 These include anastrozole, forrnestane,
`and letrozole, and all of them seem to provide better
`tolerability and more convenient administration than meges-
`trol acetate or aminoglutethimidefi"7 Response rates for the
`new options seem to be similar in metastatic breast cancer.
`About 20% to 30% of patients achieve an objective re-
`sponse with an additional 10% to 20% of patients achieving
`stable disease.4’6'9 Thus, the more specific aromatase inhib-
`itors are a reasonable choice for second-line therapy.
`Letrozole is a highly potent, orally active, nonsteroidal
`competitive inhibitor of the aromatase enzyme system
`
`
`Results: There were no statistically significant differ-
`ences among the three treatment groups for overall
`obiective tumor response. Patients treated with letro-
`zole 0.5 mg had improvements in disease progression
`(P = .044) and a decreased risk of treatment failure (P =
`.018), compared with patients treated with megestrol
`acetate. Letrozole 0.5 mg showed a trend (P = .053) for
`survival benefit when compared with megestrol ace-
`tate. Megestrol acetate was more likely to produce
`weight gain, dyspnea, and vaginal bleeding, and the
`letrozole groups were more likely to experience head-
`ache, hair thinning, and diarrhea.
`Conclusion: Given a favorable tolerability profile,
`once-daily dosing, and evidence of clinically relevant
`benefit, letrozole is equivalent to megestrol acetate and
`should be considered for use as an alternative treat-
`
`ment of advanced breast cancer in postmenopausal
`women after treatment failure with antiestrogens.
`J Clin Oncol 19:3357-3366. © 2001 by American
`Society of Clinical Oncology.
`
`that effectively inhibits the conversion of androgens to
`estrogens, both in vitro and in vivaw’11 1n postmeno-
`pausal patients with advanced breast cancer, daily doses
`of letrozole from 0.1 to 5 mg suppress plasma levels of
`estradiol, estrone, and estrone sulfate to more than 75%
`
`to 95% from baseline in all patients, with no clinically
`relevant effects on other hormones of the endocrine
`
`including glucocorticoids, mineralocorticoids,
`system,
`and thyroid hormones. 1 2'15
`Two large randomized, controlled, multinational studies
`were conducted to assess the efficacy and safety of letrozole
`
`
`
`From the University of Te<as MD. Anderson Cancer Center and
`Baylor College of Medicine, Houston, TX; St Thon'as Medical Group,
`Nashville, TN; Baptia Medical Center, Columbia, SC; Ziekenhuis
`Rijnstate, Arnhem, the Netherlands North Middlese< Hospital, Lon-
`don, and S Margaret’s Hospital, Em, United Kingdom; and Cross
`Cancer Institute, Edmonton, Alberta, Canada.
`Sibmitted August 4, 2000; accepted April 19, 2001.
`Supported by Novartis Pharn’aceuticals Corp, East Hanover, NJ.
`Address reprint requests to Aman Buzdar, MD, Department of
`Breast Medical Oncology, University of Texas MD. Anderson Cancer
`Center, Box 424, 1515 Holcombe Blvd, Houson, TX 77030; email:
`abuzdar@mdanderson.org.
`© 2001 by American Society of Clinical Oncology.
`0732-183X/01/1914—3357
`
`Journal of Clinical Oncology, Vol
`
`l 9, No 14 (July 15), 2001 : pp 3357-3366
`
`3357
`
`Downloaded from ascopubscrg by 151.194.33.114 on March 28,, 2017 from 151.194.033.114
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2140 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00900
`Fresenius-Kabi USA LLC v. AstraZeneca AB IPR2017-01913
`
`

`

`3358
`
`BUZDAR ET AL
`
`in postmenopausal women with advanced breast cancer who
`progressed despite antiestrogen therapy. Results from the
`first study indicated that once-daily treatment with letrozole
`2.5 mg demonstrated a significantly higher objective tumor
`response rate than both letrozole 0.5 mg every day (qd)
`(P = .004) and 160 mg of megestrol acetate qd (P = .04),
`with overall objective tumor response rates of 24%, 13%,
`and 16%,
`respectively.8 Letrozole 2.5 mg was also
`notably more effective than megestrol acetate, consider-
`ing the duration of objective response (median, 33
`months V median, 18 months; P = .02) and time to
`treatment failure (TTF) (P = .04).8"16
`Results from the second study indicated that once-daily
`treatment with letrozole 2.5 mg was superior to aminoglu-
`tethimide 250 mg given twice daily along with corticoste-
`roid supplementation for time to progression (TTP) (P =
`.008), TTF (P = .003), overall survival (P = .002), and
`duration of clinical benefit.17 The majority of adverse
`experiences were mild or moderate in severity. The five
`most frequently reported adverse events in letrozole-treated
`patients were musculoskeletal pain, fatigue, headache, nau-
`sea, and arthralgia.
`The present multicenter, intemational, double-blind, ran-
`domized study was conducted to compare two doses of
`once-daily letrozole, 0.5 mg and 2.5 mg,
`to megestrol
`acetate qid in postmenopausal women with advanced breast
`cancer previously treated with an antiestrogen. Previously
`published studies involving the new generation of aro-
`matase inhibitors had a limited follow-up period. Data
`reported here, beginning with the first visit of the first
`enrolled patient, cover a 4-year period that
`included a
`30-month enrollment period and 18 months of follow-up
`from the first visit of the last patient enrolled. In addition, a
`survival update was performed 37 months after the first Visit
`of the last patient enrolled. Fifty-six patients were still on
`treatment at the time of the primary analysis, which in-
`cluded objective response rate (ORR), duration of response,
`TTP, and TTF.
`
`PATIENTS AND METHODS
`
`Pati ents
`
`Postmenopausal women with histologically or cytologically con-
`firmed breast cancer who presented with either locally advanced or
`locoregionally recurrent disease or had metastatic disease were enrolled
`onto the study. Tumors were required to be either estrogen receptor
`(ER) and/or progesterone receptor (PgR) positive. Unknown status of
`ER and PgR was acceptable for study entry if no assay had been
`conducted. Patients were eligible if they had either relapsed while
`receiving continuous adjuvant antiestrogen therapy (eg, tamoxifen) or
`had relapsed within 12 months of stopping adjuvant antiestrogen
`therapy that had been administered for at least 6 months. Patients were
`also eligible if they progressed while receiving first-line antiestrogen
`
`therapy for advanced disease. Patients were permitted to have received
`up to two regimens of chemotherapy for advanced disease before trial
`entry provided that at least one had been administered before anties-
`trogen therapy. At the start of the study, patients were required to have
`the bulk (> 50%) of their tumor burden measurable and/or assessable.
`This criterion was found to unduly restrict patient enrollment, so
`inclusion criteria were amended to require patients to have at least one
`measurable and/or assessable tumor lesion. Patients were entered onto
`the study within 3 months of objective evidence of disease progression.
`Patients included women previously treated with chemotherapy,
`corticosteroids, iinrnunotherapy/biologic response modifiers (eg, inter-
`feron), antiestrogen treatment, either as adjuvant therapy or as therapy
`for advanced disease, or neoadjuvant treatment with endocrine therapy
`or chemotherapy. Patients were required to have discontinued any
`systemic anticancer treatment at the time of study entry. Any radiation
`therapy was completed at least 14 days before study entry. Patients had
`to have recovered from all reversible toxicities of any therapy admin-
`istered before study entry. All patients were required to be postmeno-
`pausal as defined by one of the following criteria: women 2 50 years
`of age who had not menstruated during the preceding 12 months or had
`castrate follicle-stimulating hormone levels (> 40 IU/L), women less
`than 50 years of age who had castrate follicle-stimulating hormone
`levels, or women who had undergone a bilateral oophorectomy.
`All patients were estimated to have, in the opinion of the investiga-
`tor, a life expectancy of at least 6 months and a Karnofsky performance
`status score of Z 50%. All laboratory results were required to be within
`the limits defined by the study protocol, which included creatinine less
`than 1.5 times the upper limit of normal (ULN), total billIllbiIl less than
`1.5 times ULN, transaminases less than 2.6 times ULN, WBC count 2
`3,000/mm3, granulocyte count 2 1,500/mm3, hemoglobin 2 8.5 g/dL,
`platelet count 2 75,000/mm3, and total calcium less than 11.6 mg/dL.
`Exclusion criteria included the existence of malignancies at other
`sites S 5 years before study entry or concurrent with study participa-
`tion, with the exception of cone-biopsied in situ carcinoma of the cervix
`or uterus and adequately treated basal and squamous cell carcinoma of
`the skin. Patients were also excluded if they had inflammatory breast
`cancer; extensive hepatic metastases, defined as more than 33% of the
`liver replaced by metastases noted on sonogram and/or computed
`tomography scan; metastases to the CNS; pulmonary lymphangitic
`metastases involving more than 50% of the lung; history of deep
`venous thrombosis or pulmonary embolism within 3 years unless the
`thrombosis was known to be directly related to tumor obstruction of
`circulation; severe uncontrolled cardiac disease (eg, congestive heart
`failure of the New York Heart Association 2 Class 1H); crescendo
`angina; myocardial infarction within 6 months before study entry; or
`uncontrolled diabetes mellitus.
`All patients gave written informed consent to participate in the study,
`which was approved by the local institutional review board or ethics
`committee for each study site. The study was conducted according to
`Good Clinical Practice guidelines.
`
`Sudy Design
`This was a randomized, double-blind, parallel-group, multicenter,
`international, comparative phase III study conducted in 120 centers
`throughout the United States, Canada, and Europe. Enrollment of 602
`patients occurred over a 30-month period. Patients were randomly
`assigned to one of three treatment arms: letrozole 0.5 mg qd, letrozole
`2.5 mg qd, or megestrol acetate 40 mg qid. Randomization was
`performed for each country without stratification by center. To preserve
`the double-blind design of the study, patients received either one tablet
`letrozole 0.5 mg or letrozole 2.5 mg once daily in the morning and one
`
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`
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`
`

`

`LETROZOLE VMEGESTROL ACETATE IN BREAST CANCER
`
`3359
`
`placebo capsule (matching a megestrol acetate tablet) qid, or one 40-mg
`capsule megestrol acetate qid plus one placebo tablet (matching a
`letrozole tablet) once daily. Changes in drug dosage were not
`permitted by the protocol; however, justifiable discontinuation of
`study medication for up to 3 consecutive weeks was acceptable
`under certain circumstances.
`Patients were allowed to receive radiotherapy to areas not being
`evaluated for tumor response or corticosteroids (topical or aerosol) for
`obstructive airway disease or nonmalignant skin lesions. Patients who
`received anticancer treatments, concomitant corticosteroid treatments
`other than those noted, bisphosphonates, or investigational drugs were
`not eligible participants for this study. A single treatment course of
`bisphosphonate, however, was permitted during the study for the
`treatment of hypercalcemia resulting from tumor
`flare,
`if saline
`hydration, diuretics, or calcitonin had been ineffective.
`Patient visits were scheduled at the beginning of study participation,
`at 2 weeks, 4 weeks, monthly through 6 months, and then every 3
`months. Patients who responded with either a complete response (CR)
`or partial response (PR) or had stable disease continued treatment until
`disease progession or withdrawal for another reason. On discontinu-
`ation from the study, patients were to be followed until death or until
`lost to follow-11p for a period of 60 months from their first study visit.
`Patient survival information was collected every 6 months.
`Patients were evaluated for tumor response at 3 months after the start
`of therapy and then every 3 months thereafter. An evaluation was also
`done if the patient discontinued treatment. Tumor response was
`evaluated by the investigator at the site according to International
`Union Against Cancer criteria specified by the protocol and by a
`designated central radiologist at each site who remained blinded.
`Measurable disease, whether bi- or unidimensional, was assessed either
`by palpation or on radiologic assessment (x-ray, abdominal ultrasound,
`or computed tomography scan). For multiple lesions, the tumor size
`equaled the sum of the products of the diameters of all
`lesions.
`Nonmeasurable, assessable tumors were not measurable by ruler or
`caliper but were assessed and evaluated by physical or radiologic
`evaluation. Response or increasing disease could only be estimated.
`Methodology for tumor assessment was to remain consistent through-
`out the course of the study. Full tumor evaluation, including the above
`procedures, was performed at baseline and at months 6 and 9. At month
`3 and at Visits subsequent to month 9, only areas positive for disease
`were evaluated unless warranted by the development of signs and
`symptoms indicating disease progression. All evaluations of objective
`tumor response (CR or PR) required confirmation after at least 4 weeks.
`Patients who did not show persistence ofthe initially observed response
`at the confirmatory evaluation were not considered to be responders.
`Response was defined as CR, PR, no change, or progressive disease.
`A CR was defined by the disappearance of all known disease,
`confirmed by two observations not less than 4 weeks apart. PR was
`defined as a decrease in tumor size of 50% or more (either measured or
`estimated in the case of measurable or assessable disease), confirmed
`by two observations not less than 4 weeks apart. In addition, there
`could be no appearance of any new lesions or progression of any
`known lesion(s). Objective tumor response included both confirmed
`CR and PR. Secondary efficacy measures included duration of re-
`sponse, duration of clinical benefit, TTF, TTP, and time to death
`(TTD). Duration of response was defined as the time from the date of
`randomization to the earliest date of documented disease progression or
`death from cancer or unknown cause. The time was censored at the
`cutoff date for analysis for patients still in response. Duration of clinical
`benefit was calculated only for those patients who had a confirmed
`objective tumor response or stable disease for Z 6 months. In these
`
`patients, duration of clinical benefit was calculated in the same manner
`as duration of response. TTP was defined as the time from randomiza-
`tion to the earliest date of disease progression, cancer-related death, or
`death from an unknown cause during therapy, or the time was censored
`at the cutoff date for analysis for patients without progressive disease.
`All deaths for which the reason was neither unknown cause nor
`malignant cause were reviewed before the treatment codes were
`unblinded so that the censoring mechanism could be identified on the
`database for analysis. TTP was censored if the patient remained on trial
`treatment at the date of the last patient’s last visit (data cutoff date)
`without any evidence of disease progression, or if she was withdrawn
`fi'om the trial for any reason other than unsatisfactory therapeutic effect
`or death from cancer or unknown cause. TTF was defined as the time
`from the date of randomization t0 the earliest date of disease progres-
`sion, discontinuation of therapy for any other reason, or death, or the
`time was censored at the cutoff date for analysis for patients still on
`therapy without evidence of disease progression. TTD was defined as
`the time from the date of randomization to the date of last known alive
`or death fi'om any cause.
`Tumor symptoms were evaluated at every visit. Assessments of
`Karnofsky performance status and measures of quality of life, including
`physical, role-related, emotional, cognitive, and social functioning;
`fatigue; nausea or vomiting; pain; dyspnea; insomnia; appetite loss;
`constipation; dialrhea; and financial difficulties, using the European
`Organization for Research and Treatment of Cancer quality-of-life
`questionnaire (EORTC QLQ-C30 version 2.0)18?” were obtained each
`month for the first 6 months and at 9 and 12 months. These
`assessments, though not part of the planned efficacy or safety analyses,
`were plarmed to support the safety and tolerability data collected during
`this trial. Patients received a complete physical examination at study
`initiation and at 3, 6, 9, and 12 months. Safety was assessed using the
`National Imstitutes of Health/National Cancer Institute comrnon tox-
`icity criteria and selected laboratory parameters to score severity of
`adverse experiences.20 Additionally, routine measurements of weight,
`blood pressure, pulse rate, ECG, chest x-ray, hematology/chemistries,
`and urinalysis were completed.
`
`Satisti cal Methodology
`The sample size for this trial was computed as the number of patients
`needed within one letrozole (0.5 mg or 2.5 mg daily) treatment group
`to detect at least a 13% difference from the megestrol acetate 160 mg
`treatment group for the confirmed ORRs (CR + PR). The sample size
`was calculated assuming 80% power, alpha level of 0.05, and two-
`sided, to show that either one of the two letrozole treatment groups was
`superior to the megestrol acetate treatment group, assuming a response
`rate for letrozole equal to 28% and a response rate for megestrol acetate
`equal to 15%. A total of 513 patients (171 per treatment arm) were
`required. Therefore, approximately 590 patients were planned in order
`to obtain the required 513 completed patients. Actual enrollment was
`closed at 602 patients.
`All analyses were based on the intent-to-treat approach. All statisti-
`cal tests perforrned were two-sided, with a .05 level of significance.
`Two-sided 95% confidence intervals for the odds ratio for each
`
`treatment comparison were also presented. No adjustments for multiple
`comparisons or multiple end points were made. The primary efficacy
`variable was the confirmed best overall objective tumor response rate
`and was analyzed using a logistic regression procedure both adjusted
`and unadjusted for prognostic baseline covariates (disease-free interval,
`dominant site of disease, prior antiestrogen therapy, stage of disease,
`and locally advanced,
`locoregionally recurrent, or metastatic breast
`cancer at study entry). Although there were two letrozole arms, the
`
`Downloaded from ascopubs.org by 151.194.33.114 011 March 28, 2017 from 151.194.033.114
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
`AstraZeneca Exhibit 2140 p. 3
`
`

`

`3360
`
`BUZDAR ET AL
`
`Table 1. Patient Demographics and Baseline Data
`Letrozole 0.5 mg
`Letrozole 2.5 mg
`Megestrol Acetate
`All Patients
`
`(n : 199)
`(n : 201)
`(n : 602)
`(n : 202)
`No. of
`No. of
`No. of
`No. of
`
`Baseline Prognostic Variable
`Patients
`%
`Patients
`5’6
`Patients
`°/o
`Patients
`96
`
`Age
`s 55 years
`56-69 years
`g 70 years
`Median, years
`Dominant site
`Viscera
`Bone
`Soit tissue
`No. of anatomic sites involved
`1
`2
`3
`Disease-tree interval
`Stage, IV
`< 24 months
`2 24 months
`Receptor status
`ER unk and PgR unk
`ERJr or PgRJr
`ER+ and PgR+
`ER’ and PgR’
`ER’ and PgR unl<
`Prior antiestrogen therapy
`Adiuvant only
`Advanced only
`Both
`Response to prior antiestrogen therapy
`Responder (CR+PR)
`SD W unk 2 6 months
`PD W unk < 6 months
`
`N/A (adiuvant only)
`Not assessable
`Previous chemotherapy
`None
`Adiuvant only
`Advanced only
`Both
`Kamolsky performance status
`1 00%
`< 100%
`Missing
`No. of prior endocrine therapies
`None (adiuvant only)
`1
`> 1
`
`32
`84
`86
`66.5
`
`1 01
`57
`44
`
`111
`73
`18
`
`24
`49
`129
`
`31
`57
`111
`1
`2
`
`83
`103
`16
`
`37
`61
`20
`83
`1
`
`130
`46
`15
`1 1
`
`66
`136
`0
`
`83
`1 16
`3
`
`16
`42
`43
`
`50
`28
`22
`
`55
`36
`9
`
`12
`24
`64
`
`15
`28
`55
`< 1
`1
`
`41
`51
`8
`
`18
`3O
`10
`41
`< 1
`
`64
`23
`7
`5
`
`33
`67
`O
`
`41
`57
`2
`
`33
`90
`76
`65.5
`
`95
`68
`36
`
`100
`70
`30
`
`33
`37
`129
`
`39
`48
`112
`0
`O
`
`7O
`1 12
`17
`
`42
`70
`16
`70
`1
`
`117
`48
`19
`15
`
`58
`140
`1
`
`70
`1 26
`3
`
`17
`45
`38
`
`48
`34
`18
`
`50
`35
`15
`
`17
`19
`65
`
`20
`24
`56
`O
`O
`
`35
`56
`9
`
`21
`35
`8
`35
`< 1
`
`59
`24
`10
`8
`
`29
`70
`< 1
`
`35
`63
`2
`
`38
`84
`79
`65.9
`
`97
`53
`51
`
`113
`64
`24
`
`16
`50
`135
`
`40
`57
`104
`0
`O
`
`78
`104
`19
`
`45
`62
`16
`78
`O
`
`115
`57
`24
`5
`
`51
`140
`O
`
`78
`1 20
`3
`
`19
`42
`39
`
`48
`26
`25
`
`56
`32
`12
`
`8
`25
`67
`
`20
`28
`52
`0
`O
`
`39
`52
`10
`
`22
`31
`8
`39
`O
`
`57
`28
`12
`3
`
`25
`75
`0
`
`39
`60
`2
`
`103
`258
`241
`66.0
`
`293
`1 78
`131
`
`324
`207
`71
`
`73
`136
`393
`
`110
`162
`3'27
`1
`2
`
`231
`319
`52
`
`124
`193
`52
`231
`2
`
`362
`1 51
`58
`31
`
`1 75
`426
`1
`
`231
`362
`9
`
`17
`43
`40
`
`49
`30
`22
`
`54
`34
`12
`
`12
`23
`65
`
`18
`27
`54
`< 1
`< 1
`
`38
`53
`9
`
`21
`32
`9
`38
`< 1
`
`60
`25
`10
`5
`
`29
`71
`< 1
`
`38
`60
`2
`
`Stage of disease
`3
`2o
`4
`7
`4
`7
`3
`6
`VII
`III
`1 1
`5
`11
`6
`1 1
`6
`33
`6
`
`IV
`185
`92
`181
`91
`183
`91
`549
`91
`
`Abbreviations: ER, estrogen receptor; PgR, progesterone receptor; unk, unknown.
`
`statistical significance was based only on pair comparison. Cochran
`Mantel-Haenszel tests were performed to compare ORRs according to
`the covariates that were thought to have an effect on overall objective
`response (disease-free interval, dominant site of disease, stage of
`disease at study entry, and history of antiestrogen therapy). A Cox
`proportional hazards regression analysis was performed on the intent-
`to-treat population for the median time to event and 95% confidence
`
`intervals for variables, including duration of response, duration of
`clinical benefit, time to response, TTP. TTF, and TTD. No adjustments
`for multiple comparisons or multiple end points were made. A
`longitudinal analysis on quality of life was performed using a pattern-
`mixture model. The criterion for the pattern classification was based on
`whether the patient was receiving the study drug 6 months or longer.
`Adverse experiences were summarized in terms of the number of
`
`Downloaded from ascopubs.org by 151.194.33.114 on March 28, 2017 from 151.194.033.114
`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
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`

`

`LETROZOLE VMEGESTROL ACETATE IN BREAST CANCER
`
`3361
`
`Table 2. Overall Tumor Response
`Letrozole 0.5 mg (n : 202)
`Letrozole 2.5 mg (n : 199)
`Megestrol Acetate (n : 201)
`No. of
`No. of
`No. of
`
`Variable
`Patients
`°/o
`Patients
`°/o
`Patients
`%
`
`Objective response
`95% CI
`
`42
`
`15.2-26.4
`
`21
`
`32
`
`11.0-21.2
`
`16
`
`30
`
`10.0-19.9
`
`15
`
`2.0
`4
`4.5
`9
`4.0
`8
`Complete response
`12.9
`26
`11.6
`23
`16.8
`34
`Partial response
`15.4
`31
`13.6
`27
`12.4
`25
`Stable disease < 6 months
`8.5
`17
`10.6
`21
`12.4
`25
`Stable disease 2 6 months
`50.7
`102
`51 .3
`102
`46.0
`93
`Disease progression
`
`Not assessable* 10.4 17 8.4 17 8.5 21
`
`
`
`
`
`
`*Patients with unconfirmed complete or partial response, patients not assessable, or tumor response evaluation not done.
`
`in each treatment arm, and by
`patients who experienced an event
`relationship to treatment, severity of the event, and duration of
`exposure to study medication.
`
`RESULTS
`
`Pati ents
`
`A total of 602 patients from 120 centers in seven
`countries were randomized in the study over a 30-month
`period, with approximately two thirds of the enrolled
`patients treated in the United States. All analyses were
`based on the intent-to-treat approach, where the intent-to-
`treat population was defined as the set of randomized
`patients who took at least one dose of trial medication. All
`patients, regardless of their length of trial treatment, were
`included in the intent—to-treat analysis.
`Of the 602 patients included in the intent-to-treat analy-
`ses, a total of 23 patients (3.8%) were considered noneli-
`gible and therefore were excluded from the acceptable
`patient analyses of tumor. A separate analysis of the primary
`end points conducted on the acceptable patient population
`showed no difference in results to the same analysis on the
`intent-to-treat population.
`The primary analysis was based on an unadjusted statis-
`tical model. An analysis adjusted for key baseline variables
`was also conducted, and results were consistent with the
`
`
`Table 3. Confirmed Best Overall Obiective Tumor Response
`Confirmed Best
`
`Treatment Comparisons
`Overall Objective
` Tumor Response 0.5 mg/MA 2.5 mg/MA 2.5 mg/O.5 mg
`
`
`
`Odds ratio
`1 .50
`1 .09
`0.73
`P
`.13
`.75
`.22
`
`95% CI 0.44-1.21 0.89-2.51 0.64-1.88
`
`
`
`NOTE. An odds ratio greater than 1 favors the treatment before the ratio
`symbol (/), whereas an odds ratio less than 1 favors the treatment after the
`ratio symbol.
`Abbreviations: 0.5 mg, letrozole 0.5 mg; 2.5 mg, letrozole 2.5 mg; MA,
`megestrol acetate 160 mg.
`
`presented unadjusted analysis. Randomization was similar
`in the three treatment arms (letrozole 0.5 mg, n = 202;
`letrozole 2.5 mg, n = 199', megestrol acetate, n = 201).
`Table 1 shows that the three treatment arms were similar
`
`with respect to demographics, disease characteristics, and
`extent of prior treatment at the beginning of the study. The
`median duration of treatment was approximately 5 to 7
`weeks longer for the letrozole 0.5 mg arm when compared
`to the letrozole 2.5 mg and megestrol acetate treatment arms
`(171.5 days, 120.0 days, and 136.0 days, respectively). The
`prognostic factors identified as having a significant impact
`on the various outcome variables for efficacy (age, disease-
`free interval, number of anatomic sites involved, best
`response to prior antiestrogen therapy, and stage of disease
`at study entry) were evenly distributed in all three arms and
`were present in frequencies expected in this population of
`patients. Results of X2 and Kruskal-Wallis tests showed no
`statistically significant difference among treatment groups
`at the .05 level of significance for any of the demographic,
`cancer history, or baseline prognostic variables. No patients
`had prior exposure to letrozole or megestrol acetate.
`
`Efficacy
`
`tumor response. Although the
`Best objective overall
`letrozole treatment groups had somewhat higher response
`rates than the megestrol acetate—treated group (Table 2), no
`statistically significant differences were noted when the
`groups were analyzed by logistic regression to compare the
`number of patients with a confirmed objective response (CR
`+ PR) (Table 3). Table 4 presents the response rates (CR +
`PR) by treatment within each baseline covariate. However,
`no statistically significant differences between treatments
`were detected within subgroups.
`Duration of response and clinical benefit. Median du-
`ration of objective tumor response was 23 months for
`letrozole 0.5 mg, 25 months for letrozole 2.5 mg, and 30
`months for megestrol acetate (Table 5). Median duration of
`
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`Copyright © 2017 American Society of Clinical Oncology. All rights reserved.
`
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`

`3362
`
`BUZDAR ET AL
`
`Table 4. Confirmed Overall Obiective Response Rate—Important Baseline Covariates
`Letrozole 0.5 mg Megestrol Acetate Letrozole 2.5 mg
`
`
`
`No.
`CR + PR
`No.
`CR + PR
`No.
`CR + PR
`Baseline Covariate
`Treated
`No.
`°/o
`Treated
`No.
`°/o
`Treated
`No.
`°/o
`
`
`Disease-Free interval
`Stage IV
`< 24 months
`2 24 months
`Dominant site of disease
`Solt tissue
`Bone
`Viscera
`
`24
`49
`129
`
`44
`57
`101
`
`2
`13
`27
`
`18
`7
`17
`
`8.3
`26.5
`20.9
`
`40.9
`12.3
`16.8
`
`33
`37
`129
`
`36
`68
`95
`
`3
`7
`22
`
`14
`4
`14
`
`9.1
`18.9
`17.1
`
`38.9
`5.9
`14.7
`
`16
`50
`135
`
`51
`53
`97
`
`3
`9
`18
`
`17
`3
`10
`
`18.8.
`18.0
`13.3
`
`33.3
`5.7
`10.3
`
`Prior antiestrogen therapy
`Adiuvant only
`Advanced only
`Both adiuvant and advanced
`Stage of disease at entry
`50.0
`9
`18
`55.6
`10
`18
`52.9
`9
`17
`|/||/|||
`
`
`
`
`
`
`
`
`
`185 33 17.8 181 22 12.2 183 21IV 11.5
`
`83
`103
`16
`
`14
`25
`3
`
`16.9
`24.3
`18.8
`
`70
`1 12
`17
`
`9
`20
`3
`
`12.9
`17.9
`17.6
`
`78
`104
`19
`
`10
`20
`O
`
`12.8
`19.2
`0
`
`clinical benefit (objective response and stable disease last-
`ing at least 6 months) was 21 months for letrozole 0.5 mg,
`18 months for letrozole 2.5 mg, and 15 months for meges-
`trol acetate. There were no statistically significant differ-
`ences noted in any of the pair comparisons for duration of
`response nor duration of clinical benefit (Table 6).
`TTP. At the time of the analysis, 158 patients (78%) in
`the letrozole 0.5 mg treatment arm, 163 (82%)
`in the
`letrozole 2.5 mg arm, and 162 (80%) in the megestrol
`acetate arm had progressed or died. Figure 1 shows the
`Kaplan-Meier estimates for TTP. Median TTP was longer
`for letrozole 0.5 mg—treated patients (6 months), compared
`with both the letrozole 2.5 mg and megestrol acetate
`treatment arms (3 months). Patients treated with letrozole
`0.5 mg had a significantly lower risk of disease progression
`(hazard ratio, 0.80; P = .044) than patients treated with
`megestrol acetate. The differences in TTP between the
`letrozole treatment groups and the letrozole 2.5 mg—treated
`patients and megestrol acetate—treated patients were not
`statistically significant (Table 6).
`
`Table 5. Duration of Obiective (CR + PR) Response and Clinical Benefit
`Letrozole
`Letrozole
`Megestrol
`
`0.5 mg
`2.5 mg
`Acetate
`
`n : 30
`n : 32
`n : 42
`Duration of response (CR + PR)
`13
`16
`20
`No. of events
`29.7
`24.9
`23.4
`Median, months
`12.2-—
`17.3-—
`20.7-—
`95% CI, months
`n : 49
`n : 55
`n : 68
`Duration of clinical loenelit
`25
`34
`40
`No. of events
`15.4
`17.5
`20.7
`Median, months
`
`95% CI, months 14.3-32.8 16.9-23.4 12.3-24.9
`
`
`
`'ITF. Median TTF of 5 months was longer for the
`letrozole 0.5 mg treatment group, compared with 3 months
`for both the letrozole 2.5 mg and megestrol acetate treat-
`ment arms. A statistically significant lower risk of treatment
`failure was detected in patients treated with letrozole 0.5 mg
`when compared with patients treated with megestrol acetate
`(hazard ratio, 0.78; P = .018). No significant difference was
`found when comparisons were made between the letrozole
`treatment groups or between letrozole 2.5 mg and megestrol
`acetate (Table 6).
`TTD. Two thirds of the patients were deceased at the
`time of the survival update. There were fewer deaths in the
`letrozole 0.5 mg arm (61%) than in the letrozole 2.5 mg arm
`(69%) or in the megestrol acetate arm (70%). Figure 2
`shows the Kaplan-Meier estimates for TTD. Median TTD
`was 33 months for letrozole 0.5 mg, 29 months for letrozole
`2.5 mg, and 26 months for megestrol acetate. There were no
`statistically significant differences in TTD among the three
`treatment groups, although a trend is noted for letrozole 0.5
`mg in comparison to megestrol acetate (P = .053) (Table 6).
`Siject assessments. Treatment groups were similar in
`the time trend for the Kamofsky performance scale or
`global health status/quality-of—life scale based on an explor-
`atory longitudinal analysis of the two scores. In general,
`decreases from baseline in performance status w