730
`
`A Phase III Trial Comparing Anastrozole
`(1 and 10 Milligrams), a Potent and Selective Aromatase
`Inhibitor, with Megestrol Acetate in Postmenopausal
`Women with Advanced Breast Carcinoma
`
`Aman U. Buzdar, M.o.1
`Stephen E. Jones, M.o.2
`Charles L. Vogel, M.o.3
`Janet Wolter, MD.4
`Paul Plourde, M.o.5
`Alan Webster, M.Sc.6
`for the Arimidex Study Group
`
`‘ Department of Medical Oncology, M. D. An-
`derson Cancer Center, University of Texas Medi-
`cal Center, Houston, Texas.
`
`2Simmons Cancer Center, Baylor University
`Medical Center, Dallas, Texas.
`
`3 The South Florida Comprehensive Cancer Cen-
`ter at Parkway Regional Medical Center, North
`Miami Beach, Florida.
`
`4 Department of Medicine, Rush—Presbyterian—
`St. Luke's Medical Center, Chicago, Illinois.
`
`5Zeneca Pharmaceuticals, Wilmington, Dela-
`ware.
`
`6Zeneca Pharmaceuticals, Medical Affairs,
`Alderly Park, Macclesfield, Chesire, United King-
`dom.
`
`Supported by a grantfrom Zeneca Pharmaceuti-
`cals, Wilmington, Delaware.
`
`The authors thank Gary DorreII, M. S., for edito-
`rial assistance.
`
`the Arimidex Study
`Additional members of
`Group who participated in this trial were Harvey
`B. Sher, University Professional Center, Jack-
`sonville, FL; David B. Myers, BIOP, Billings, MT;
`Carol J. Fabian, University of Kansas Medical
`Center, Kansas City, KS; Rayna Kneuper-Hall,
`Medical University of South Carolina, Charles-
`ton, SC; Andrew G. Glass, Kaiser Foundation
`Hospital, Portland, OR; Nicholas James Robert,
`Fairfax Hospital, Annandale, VA; Irving M. Ber-
`kowitz, Medical Center of Delaware, Newark, DE;
`
`© 1997 American Cancer Society
`
`BACKGROUND. Anastrozole is a new oral aromatase inhibitor with highly potent
`and selective activity for the aromatase enzyme. In a Phase III trial, the efficacy
`and tolerability of anastrozole, given in doses of 1 and 10 mg orally once daily,
`and megestrol acetate, given in doses 0f40 mg orally 4 times daily, were compared
`in 386 postmenopausal women with advanced breast carcinoma who progressed
`after tamoxifen therapy.
`METHODS. The trial was randomized, double blind for anastrozole, open label for
`megestrol acetate, parallel group, and multicenter. Patients were randomly as—
`signed to receive anastrozole, 1 mg (n = 128); anastrozole, 10 mg (n = 130); or
`megestrol acetate (11 = 128). The primary efficacy measures were time to progres—
`sion and tumor response; secondary measures were time to treatment failure,
`duration of response, quality of life, and time to death.
`RESULTS. With a median duration offollow—up of 6 months, there was no statistical
`evidence of a difference between either 1 or 10 mg doses of anastrozole and
`megestrol acetate for any efficacy endpoint. According to rigid response criteria,
`10%, 6%, and 6% of patients in the anastrozole 1 mg, anastrozole 10 mg, and
`megestrol acetate groups, respectively, had an objective response (complete re—
`sponse or partial response) and 27%, 24%, and 30% of patients in the respective
`groups had stable disease for a duration of 24 weeks or longer. Quality—of—life
`assessments revealed that anastrozole in a 1—mg dose was associated with better
`physical scores and anastrozole in a 10—mg dose with better psychologic scores
`than megestrol acetate. Both anastrozole and megestrol acetate were generally
`well tolerated. Among anticipated adverse events, gastrointestinal disturbance was
`more common among patients in the anastrozole groups, whereas weight gain
`occurred more frequently among patients in the megestrol acetate groups. Weight
`increases of 5% or more and 10% or more were more common among megestrol
`acetate—treated patients; moreover, patients in this group continued to gain weight
`over time.
`
`CONCLUSIONS. Anastrozole, given in doses of1 and 10 mg once daily, represents a
`well tolerated and effective therapeutic option for the treatment ofpostmenopausal
`women with advanced breast carcinoma who progress after tamoxifen treatment.
`Cancer 1997; 79:730—9. © 1997 American Cancer Society.
`
`KEYWORDS: anastrozole, megestrol acetate, aromatase inhibition, progestin, breast
`carcinoma, postmenopausal.
`
`
`
`StuartJ. Tipping, Marshfield Clinic, Marshfield,
`WI; Gershon Y. Locker, The Evanston Hospital,
`Evanston, IL; Michael Meshad, Providence Can-
`cer Center, Mobile, AL, Peter D. Eisenberg,
`
`Incorporated,
`Marin Oncology Associates
`Greenbrae, CA; Harold A. Harvey, Milton Her-
`shey Medical Center, Hershey, PA; James W.
`Lynch, University of Florida, Gainesville, FL;
`
`AstraZeneca Exhibit 2137 p. 1
`InnoPharma Licensing LLC v. AstraZeneca AB IPR2017-00905
`
`

`

`Anastrozole vs. Megestrol Acetate in Advanced Breast Cancer/Buzdar et al.
`
`731
`
`Hormonal therapy is well established as a primary
`therapy for postmenopausal women with ad-
`vanced breast carcinoma. The antiestrogen tamoxifen
`citrate (Nolvadex, Zeneca Pharmaceuticals, Wilming-
`ton, DE), is regarded as the first-line therapy for this
`group of patients;1 however, a percentage of patients
`will have a recurrence and require additional palliative
`treatment for their disease. Progestins are frequently
`used as second-line therapy for patients who have pro-
`gressed after tamoxifen therapy, but their appeal is
`limited by the occurrence of weight gain and edema,
`as well as cardiovascular and thromboembolic side
`effects.2
`
`The class of compounds known as aromatase inhibi-
`tors offers potential benefits in the management of breast
`carcinoma, particularly for postmenopausal patients with
`advanced disease. Although aminoglutethimide, a nonse-
`lective aromatase inhibitor, was the first to be evaluated
`
`extensively in clinical trials, its acceptance was limited by
`an association with a wide spectrum of adverse events,
`as well as a requirement for the concomitant administra-
`tion of hydrocortisone.3’5 Since the development of ami-
`noglutethimide, new generations of aromatase inhibitors
`have been synthesized; all these compounds are substan-
`tially more potent than aminoglutethimide as inhibitors
`of the aromatase enzyme.6
`One of the new aromatase inhibitors is anastrozole
`
`(Arimidex, Zeneca Pharmaceuticals), an achiral benzytria-
`
`zole derivative, which has highly effective and selective
`activity for the aromatase enzyme? Clinical trials have
`demonstrated that circulating serum estradiol concentra-
`tions, measured by a sensitive assay, are consistently sup-
`pressed to the limit of quantification of the assay with
`daily anastrozole doses of 1 mg and higher.7 Doses of
`up to 10 mg daily have no effect on glucocorticoid or
`mineralocorticoid secretion as indicated by normal re-
`sponses to adrenocorticotropic hormone stimulation
`tests.7 Anastrozole is rapidly absorbed after oral adminis-
`tration, with maximal plasma concentrations occurring
`within 2 hours, and it possesses a half-er that supports
`once-daily oral administration?
`In the current trial, the authors compared the efficacy
`and tolerability of anastrozole and megestrol acetate in
`postmenopausal women with advanced breast carcinoma
`who progressed after tamoxifen treatment. Two daily
`doses of anastrozole, 1 and 10 mg, were selected for evalu-
`ation. The l-mg daily dose provides the lowest dose of
`anastrozole to give maximum detectable reduction of se-
`rum estradiol concentrations, whereas the 10 mg daily
`dose offers the potential for enhanced antitumor activity
`and increased clinical benefit.
`
`MATERIALS AND METHODS
`
`Patient Population
`To enter the trial, patients were required to have pro-
`gressed while receiving tamoxifen or other antiestro-
`
`Barbara A. Parker, University of California at San Diego Cancer Center, San Diego, CA; Debu Tripathy, Mount Zion Medical Center, San Francisco, CA;
`Reginald P. Pugh, Allegheny General Hospital, Pittsburgh, PA; Hernan I. Vargas and Stanley R. Klein, Harbor-UCLA Medical Center, Torrance, CA; Lucille
`A. Leong, City of Hope Medical Center, Duarte, CA; Gregory B. Smith, Hematology and Oncology Group, Santa Rosa, CA; John K. Erban and Susan A.
`Sajer, New England Medical Center, Boston, MA; Leo L. Stolbach, Saint Vincent's Hospital, Worcester, MA; Steven Perkins, Dallas, TX; Kathleen I.
`Pritchard, Toronto-Bayview Regional Cancer Centre, North York, Ontario, Canada; Nikolay V. Dimitrov, Michigan State University, East Lansing, MI; Karl
`K. Boatman, Baptist Medical Center of Oklahoma, Oklahoma City, OK; Jacob Amir, Little Rock Diagnostic Clinic PA, Little Rock, AR; Aroop Mangalik,
`University of New Mexico Cancer Center, Albuquerque, NM; Francis J. Cummings, Roger Williams General Hospital, Providence, RI; Joseph Aisner,
`University of Maryland Cancer Center, Baltimore, MD; Joseph A. Sparano, Montefiore Medical Center, Bronx, NY; Gary B. Fleishman, Research for Health
`Incorporated, Houston, TX; David N. Krag, University of Vermont Cancer Center, Burlington, VT; Fredric C. Kass, Cancer Foundation of Santa Barbara,
`Santa Barbara, CA; Mary A. Simmonds, Cowley Associates, Camp Hill, PA; James A. Mailliard, Creighton Cancer Center, Omaha, NE; Lori J. Goldstein,
`Fox Chase Cancer Center, Philadelphia, PA; Ellis G. Levine, Roswell Park Cancer Center, Buffalo, NY; Harvey J. Lerner, Oncology Associates, Philadelphia,
`PA; Thomas G. Frazier, Bryn Mawr, PA; Kenneth E. Gale, Syracuse, NY; Ishmael A. Jaiyesimi, Cancer Care Associates, PC, Royal Oak, MI; Sanford Jay
`Kempin, and Gary A. Palmer, Cooperative Cancer Center, Palm Springs, CA; Gregory P. Sarna, Comprehensive Cancer Center, Cedars Sinai, Los Angeles,
`CA; Martin Wiesenfeld, Cedar Rapids Oncology Project, Cedar Rapids,
`IA; Dala J. R. Jarolim, International Medical Technical Consultants,
`Inc., Tulsa,
`OK; Rebecca L. Moroose, Altamonte Springs, FL; Susan N. Rosenthal, Rochester General Hospital, Rochester, NY; Joseph M. Koenig, Akron City Hospital,
`Akron, OH; David Prager, Allentown, PA; John Showel, West Suburban Hospital, Oak Park,
`IL; Elizabeth C. Reed, University of Nebraska Medical Center,
`Omaha, NE; John R. Feagler, Immanuel Cancer Center, Omaha, NE; Gamini S. Soori, Maryland Plaza, Omaha, NE; Robert W. Warner, Heartland Oncology
`and Hematology, PC, Council Bluffs, IA; James A. Stewart, University of Wisconsin, Hospital and Clinics, Madison, WI; Robert A. Johnson, The Memphis
`Cancer Center, Inc., Memphis, TN; Silvana Martino, Westlake Comprehensive Cancer Center, Westlake Village, CA; James R. Borst, Butterworth Hospital,
`Grand Rapids, MI; Howard L. Ritter, The Toledo Clinic, Toledo, OH; Robert C. Hermann, Marrietta, GA; Barry S. Berman, and Michael S. Robert, Regional
`Oncology and Hematology Associates, Kissimmee, FL; Peter Todd Silberstein, Mercy Cancer Center, Mason City,
`IA; John M. Bennett, University of
`Rochester Cancer Center, Rochester, NY; and Daniel Booser, Gabriel Hortobagyi, Richard Therault, and Frankie Holmes, M. D. Anderson Cancer Center,
`Houston, TX.
`
`The trademarks Arimidex and NoIvadex are the property of Zeneca Limited.
`
`Address for reprints: Aman Buzdar, M. D., Department of Breast Medical Oncology, Box 56, The University of Texas, M. D. Anderson Cancer Center,
`1515 Holcombe Blvd., Houston, TX 77030.
`
`Received September 19, 1996; accepted October 28, 1996.
`
`AstraZeneca Exhibit 2137 p. 2
`
`

`

`732
`
`CANCER February 15, 1997 / Volume 79 / Number 4
`
`gen therapy for advanced breast carcinoma or to have
`had a recurrence during adjuvant tamoxifen treat-
`ment; be postmenopausal, defined as having nonfunc-
`tioning ovaries through natural menopause or surgi-
`cal, radiation-induced, or chemical castration (women
`
`older than 50 who did not menstruate during the pre-
`ceding 12 months were considered postmenopausal,
`whereas women younger than 50 had to have a follicle-
`stimulating hormone concentration of >40 lU/L to
`enter); and have World Health Organization (WHO)
`performance status score of :2. Patients were ex-
`cluded if they had estrogen receptor negative breast
`carcinoma (except when a patient had showed a previ-
`ous response to tamoxifen treatment), exposure to
`more than one previous course of cytotoxic therapy
`for advanced disease (except adjuvant chemotherapy),
`exposure to more than one previous hormonal therapy
`for advanced breast carcinoma, or any concurrent
`medical illness or laboratory abnormalities that would
`compromise their safety or prevent interpretation of
`results. Written informed consent was obtained from
`
`all patients, and the trial was approved at each site by
`an Institutional Review Board.
`
`Trial Design
`The trial design was randomized, double blind for an-
`astrozole, open label for megestrol acetate, and paral-
`lel group. The primary efficacy measures were time to
`progression and tumor response; secondary efficacy
`measures were time to treatment failure, duration of
`
`response, quality of life, and time to death.
`Anastrozole was supplied as film-coated, white
`tablets containing either 1 or 10 mg of the medication.
`Megestrol acetate was supplied as white, circular,
`scored tablets containing 40 mg of the medication.
`Patients were randomly allocated to 1 of 3 oral treat-
`ment regimens: 1 mg of anastrozole once daily, 10 mg
`of anastrozole once daily, or 40 mg of megestrol ace-
`tate 4 times daily. Treatment continued until disease
`progression or until withdrawal from treatment for any
`reason other than progression. Patients who had dis-
`ease progression were permitted to receive either cyto-
`toxic therapy or other hormonal treatments. When pa-
`tients withdrew before having progression, they were
`monitored for time to progression.
`Baseline screening assessments were completed
`within the 4 weeks before randomization. On Day 1,
`the date of randomization, eligible patients underwent
`a complete physical examination. Each patient’s dis-
`ease was assessed clinically every 4 weeks for the first
`24 weeks of treatment, and then every 12 weeks until
`Week 48. After Week 48, assessments were performed
`every 3 months until disease progression was detected.
`Bone scans were repeated every 24 weeks until disease
`progression or withdrawal. Radiographic examination
`
`of confirmed metastatic lesions was repeated every
`12 weeks (or earlier when clinically indicated) during
`treatment and at withdrawal.
`Patients were withdrawn from active treatment for
`
`a serious adverse event, noncompliance with protocol
`procedures, unwillingness or inability to continue in
`the trial, withdrawal by an investigator, or clinically
`significant breast carcinoma progression. All patients
`who were withdrawn were monitored for survival.
`
`Efficacy Assessments
`Time to progression, time to treatment failure, time
`to death, and duration of response were calculated
`from the date of randomization. Time to progression
`represented the time to objective disease progression
`or death, whichever occurred first. Patients who had
`not reached progression at the time of data cutoff were
`right-censored in the analysis at the time of their latest
`visit. Time to treatment failure was the time to earliest
`
`occurrence of progression, death, or withdrawal. Time
`to death represented the number of days until death
`from any cause. Duration of response, which was re-
`corded for those with either a complete or partial re-
`sponse, was the time to objective progression or death.
`Assessments of tumor response included both
`measurable and nonmeasurable disease. Measurable
`
`disease was defined as the presence of metastatic le-
`sions measurable in one or two dimensions using
`physical or radiographic methods (including com-
`puted tomography scan) and osteolytic bone lesions.
`For measurable lesions, only the physical or radiologic
`measurements were recorded. To ensure consistency
`and objectivity in the assignment of response catego-
`ries, a computerized algorithm was used to assign re-
`sponses based on the measurements. The program
`strictly applied the protocol definition of response
`based on the International Union Against Cancer
`(UICC) criteria.8 Nonmeasurable disease was defined
`as single metastatic lesions smaller than 0.5 cm, malig-
`nant pleural effusion or ascites, a positive bone scan,
`and osteoblastic bone lesions. For nonmeasurable le-
`
`sions, partial responses were not permitted to be as-
`signed, in accordance with the strict criteria for assess-
`ment. Therefore, responses were assigned only in the
`categories of complete response, stable disease, or
`progressive disease.
`The best objective response over time was deter-
`mined on the basis of objective responses at each visit.
`Complete or partial responses were assigned only
`when noted on successive visits at least 4 weeks apart.
`Measurable lesions of bone, chest, and abdomen were
`
`assessed at 12-week intervals. Abest response of stable
`disease was assigned when responses of stable disease
`or better were observed for at least 24 weeks. If such
`
`responses had been observed for <24 weeks because
`
`AstraZeneca Exhibit 2137 p. 3
`
`

`

`Anastrozole vs. Megestrol Acetate in Advanced Breast Cancer/Buzdar et al.
`
`733
`
`a patient did not have measurements for 24 weeks at
`the time of data cutoff, then a best response of stable
`disease for <24 weeks was recorded.
`
`Quality-ot-Lite Assessments
`The primary quality-of-life assessment was the vali-
`dated Rotterdam Symptom Checklist,9 which was
`completed by the patients before treatment, every 4
`weeks for 24 weeks, and subsequently every 12 weeks
`until disease progression, for up to 1 year. Other qual-
`ity-of-life variables that were scored and recorded
`were the types of analgesics used, severity of bone
`pain, and performance status or level of daily activity.
`
`Pharmacokinetic Assessments
`
`Blood samples for determination of anastrozole con-
`centrations were collected before therapy and at se-
`lected times during therapy. Plasma concentrations
`of anastrozole were determined using a validated gas
`chromatographic method that employed capillary gas
`chromatographic separation with electron capture de-
`tection. The assay method was validated over a con-
`centration range of 3 to 100 ng/mL, using 0.5-mL
`plasma samples. The quantitation limit for anastrozole
`using this method was 3 ng/mL.
`
`Tolerability Assessments
`Any detrimental change in a patient’s condition after
`the trial began and during any follow-up period, unless
`related to disease progression, was considered an ad-
`verse event. Patients were solicited indirectly for ad-
`verse events; prompted by a question, each patient
`described anything that had bothered her. In addition
`to monitoring for adverse events, routine laboratory
`tests results were performed at baseline, at selected
`times during therapy, and at withdrawal. The results
`of clinical laboratory tests were reviewed for clinically
`relevant changes. Physical examinations were per-
`formed and weight, blood pressure, and pulse were
`recorded at baseline, at selected times during therapy,
`and at withdrawal.
`
`Statistical Analysis
`A population of 300 patients was deemed sufficient to
`detect a treatment difference of approximately 14
`weeks in median time to progression with 80% power
`and a 2—sided alpha level of 0.05, assuming a median
`time to progression of 26 weeks, a uniform recruitment
`over a 1-year period, and a minimum follow-up of 6
`months. To protect against an imbalance in treatment
`allocation across centers, the randomization scheme
`was stratified for center. In addition, treatments were
`
`allocated in blocks of three patients at each center.
`Efficacy analyses were performed on the basis on
`an intention to treat basis: data were included in the
`
`analysis according to randomized treatment. The Cox
`proportional hazards model was used to analyze time
`to disease progression, time to treatment failure, and
`time to death. For each of the treatment comparisons,
`the results were expressed as hazard ratios, with corre-
`sponding confidence intervals (CI) of 97.7% for time
`to progression and 97.5% for time to treatment failure
`and death. The model included variables for treat-
`
`ment, estrogen receptor status, progesterone receptor
`status, and hormonal treatment history. Time to pro-
`gression, treatment failure, and death were also sum-
`marized using Kaplan—Meier curves, which were used
`to estimate the median time for each endpoint. Logis-
`tic regression was used to analyze response data. Be-
`cause of the low number of patients with response
`data, the analysis was performed with treatment as
`the only covariate. Duration of response was summa-
`rized for patients who had a best objective response
`of complete or partial response and using Kaplan—
`Meier curves. Rotterdam Symptom Checklist scores
`were analyzed by analysis of covariance, the Wilcoxon
`rank sum test, and logistic regression; the physical and
`psychologic scores were analyzed by the first
`two
`methods, whereas the functional score was analyzed
`by logistic regression.
`Data on adverse events were recorded according
`to the treatment actually received. Adverse events that
`might be expected to occur on the basis of the pharma-
`cology of anastrozole and megestrol acetate were pro-
`spectively identified and the incidence for each group
`was recorded; these adverse events included weight
`gain, edema, thromboembolic disease, gastrointesti-
`nal disturbance, hot flushes, and vaginal dryness.
`
`RESULTS
`Patient Characteristics
`
`Three hundred and eighty-six patients from 49 centers
`in North America were entered and randomized to 1
`
`of the 3 treatment groups (Table 1). One patient was
`randomized to receive anastrozole 10 mg but elected
`not to receive therapy; she was included in the analysis
`of efficacy but not in the analysis of safety.
`The median duration of follow-up time for pa-
`tients was 179 days for the anastrozole 1 mg group,
`182 days for the anastrozole 10 mg group, and 176
`days for the megestrol acetate group.
`
`Efficacy
`Table 2 summarizes the analysis of time to progres-
`sion, time to treatment failure, and time to death for
`the anastrozole groups and the megestrol acetate
`group. Kaplan—Meier curves for time to progression
`and time to death are displayed in Figures 1 and 2.
`The results for time to disease progression, time to
`treatment failure, and time to death showed both
`
`AstraZeneca Exhibit 2137 p. 4
`
`

`

`Anastrozole 1 mg
`(n = 128)
`
`Anastrozole 10 mg
`(n = 130)
`
`Megestrol acetate
`(n = 128)
`
`65
`
`29—93
`
`70
`
`31—112
`
`66
`
`41—91
`
`70
`
`40— 31
`
`66
`
`39—90
`
`67
`
`42— 1
`
`
`
`55
`
`1
`
`3
`
`
`
`
`
`122 95)
`57 [5
`76 59
`
`7
`17
`14
`3 2
`8 6
`16
`
`
`
`47
`6
`51 40
`15
`2
`1
`1
`
`39)
`5
`78 61)
`
`734
`
`CANCER February 15, 1997 / Volume 79 / Number 4
`
`TABLE 1
`
`Demographic and Pretreatment Characteristics
`
`Parameter
`
`Age (yrs)
`Mean
`
`Range
`Weight“ (kg)
`Mean
`
`Range
`Previous treatment (no., %)
`Surgery
`Cytotoxic chemotherapy
`Radiotherapy
`Receptor status (no., %)
`3R+,PR+
`3R+, PR—
`3R+, PR unknown
`3R—, PR+
`3R—, PR—
`nknown
`WHO performance status score (no., %)
`0
`
`
`
`2
`3
`4
`Previous treatment (no., %)
`Adjuvant tamoxifen
`"amoxifen for advanced disease
`DL at'on of tamoxifen treatment for advanced diseaseb'C
`o. of patients
`e 'an duration of treatment (wks)
`Re apsed during adjuvant tamoxifen treatmentC
`o. of patients
`e 'an disease free interval (wks)
`Previous best response to tamoxifen (no., %) for advanced disease
`Comolete
`)ar 'al
`isease
`S ab e
`3 0g ession
`nkiown
`Measu ab e disease (no., %)
`No neastrable disease (no., %)
`Sites 0 metastatic disease (no., %)d
`Soft
`'ssue
`Bone
`Viscera
`Liver
`No evi ence of liver involvement
`No eva uable metastatic disease8
`Extent of metastatic disease (no., %)f
`Soft tissue only
`Bone Oily
`Viscera only
`Mixed
`No eva uable metastatic disease8
`
`
`
`124 (97)
`58 45)
`72 56)
`
`
`
`80 63)
`25 20)
`4 (3)
`2 (2)
`1()
`16 13)
`
`69 54)
`41 32)
`18 14)
`0
`0
`
`
`
`126 97)
`59 ([5)
`74 (57)
`
`76 (59)
`20( 5)
`6 (5
`0
`8 (6
`20( 5)
`
`59 (45)
`55 (42)
`13 ( 0)
`3 (2
`0
`
`60 (47)
`68 (53)
`
`60
`100
`
`57
`136
`
`54 (42)
`76 (58)
`
`69
`105
`
`47
`158
`
`3 (4)
`6 (9)
`31 46)
`3 (f)
`25 37)
`82 64)
`z6 36)
`
`
`
`
`
`42 33)
`87 68)
`51 40)
`8 14)
`10 (86)
`5 (f)
`
`7 13)
`45 35)
`4 11)
`47 37)
`5 (f)
`
`76
`86
`
`50
`189
`
`7 (9)
`12 (15)
`27 (35)
`5 (6)
`27 (35)
`81 (63)
`47 (37)
`
`39 (31)
`79 (62)
`60 (47)
`18 (14)
`110 (86)
`3 (2)
`
`16 (13)
`41 (32)
`22 (17)
`46 (36)
`3 (2)
`
`5 (7)
`8 ( 1)
`34 45)
`5 (7)
`24 32)
`79 61)
`51 39)
`
`45 35)
`83 64)
`51 39)
`17 13)
`113 (87)
`12 9)
`
`11)
`14
`37 29)
`15 12)
`52 40)
`12 9)
`
`
`
`Er: estrogen receptor; PR: progesterone receptor; WHO: World Health Organization.
`a Weight was not recorded for all patients.
`b For treatment of primary disease (after mastectomy or lumpectomy) and metastatic lesions.
`“ Patients who did not receive tamoxifen and for whom duration of treatment could not be calculated are not included.
`
`d Patients maybe in more than one category.
`9 Includes patients with excised or irradiated local or distant disease at entry, patients with local or distant metastases that were excised or eradicated before entry, and one patient who had no evaluable disease.
`fCategories are mutually exclusive.
`
`AstraZeneca Exhibit 2137 p. 5
`
`

`

`Anastrozole vs. Megestrol Acetate in Advanced Breast Cancer/Buzdar et al.
`
`735
`
`TABLE 2
`
`Analysis of Time to Progression, Time to Treatment Failure, and
`Time to Death
`
`100
`
`ono
`
`
`
`
`
`mo
`
`
`
`
`
`Percentagesurviving
`
`Anastrozole 1 mg
`“vs. megestrol
`acetate”
`
`Anastrozole 10 mg
`“vs. megestrol
`acetate”
`
`Endpoint
`
`Time to disease progression
`Hazard ratioa
`97.7% CI
`Pvalueb
`Time to treatment failure
`Hazard ratio
`97.5% CI
`Pvalueb
`Time to death
`Hazard ratio
`97.5% CI
`Pvalueb
`
`0.89
`0.61—1.30
`0.49
`
`0.85
`0.59—1.23
`0.33
`
`0.96
`0.45—2.08
`0.91
`
`1.00
`.69—1.45
`.99
`
`.99
`.70—1.41
`.97
`
`.50
`.21—1.21
`.09
`
`
`
`CI: confidence interval.
`a Hazard ratios > 1.00 indicate that the first treatment is associated with a shor er time to progression,
`treatment failure, or death than the second treatment.
`b 0.025 represents the critical P value for statistical significance.
`
`— anastrozole 1 mg
`
`anastrozole 10 mg
`_ _ .- megestrol acetate
`
`100
`
`
`
`80 —
`
`60*
`I
`
`40—-
`
`20—
`
`
`
`
`Percentageprogression-free
`
`.s.o l
`
`20 —
`
`— anastrozole1 mg
`----- anastrozole 10 mg
`» — -- megestrol acetate
`
`Month
`
`FIGURE 2. Kaplan—Meier probability of time to death in patients in the
`anastrozole 1 mg, anastrozole 10 mg, and megestrol acetate groups.
`
`TABLE 3
`
`Objective Tumor Response in Patients in the Anastrozole 1 mg,
`Anastrozole 10 mg, and Megestrol Acetate Groups
`
`No. of patients (%)
`
`Anastrozole
`1 mg
`(n = 128)
`
`Anastrozole
`10 mg
`(n = 130)
`
`Megestrol
`acetate
`(n = 128)
`
`4 (3)
`9 (7)
`34 (27)
`19 (15)
`62 (48)
`
`1 (1)
`6 (5)
`31 (24)
`27 (21)
`65 (50)
`
`2 (2)
`5 (4)
`38 (30)
`17 (13)
`66 (52)
`
`Objective response
`
`Complete response
`Partial response
`Stable disease 2 24 wks
`Stable disease < 24 wksa
`Progression
`
`a Represents patients who had stable disease but had tumor assessments taken at <24 weeks at the
`time of data cutoff.
`
`Month
`
`FIGURE 1. Kaplan—Meier probability of time to progression in patients
`in the anastrozole 1 mg, anastrozole 10 mg, and megestrol acetate groups.
`
`doses of anastrozole to be similar to megestrol acetate.
`Disease progression occurred in 69 patients (54%) in
`the anastrozole 1 mg group, 75 patients (58%) in the
`anastrozole 10 mg group, and 78 patients (61%) in the
`megestrol acetate group. Median times to progression
`were 170 days for the anastrozole 1 mg group, 143
`days for the anastrozole 10 mg group, and 151 days
`for the megestrol acetate group. Treatment failure oc-
`curred in 74 (58%), 82 (63%), and 85 patients (66%) in
`the anastrozole 1 mg, anastrozole 10 mg, and meges-
`trol acetate groups,
`respectively. Median times to
`treatment failure were 168 days, 133 days, and 125
`
`days for the respective groups. Seventeen patients in
`the anastrozole 1 mg group, 10 patients in the an-
`astrozole 10 mg groups, and 19 patients in the meges-
`trol acetate group died. Because of the low number of
`deaths occurring at the time of data cutoff, median
`times to death could not be calculated.
`
`The best objective responses for the 1 and 10 mg
`anastrozole groups were similar to that for the meges-
`trol acetate group (Table 3). The estimated odds ratio
`for response for anastrozole 1 mg versus megestrol
`acetate was 1.95 (97.7% C1, 0.65—5.91). Similarly, the
`estimated odds ratio for response for anastrozole 10
`mg versus megestrol acetate was 0.98 (97.7% Cl, 0.28—
`3.43). Overall, 37%, 29%, and 35% of patients in the
`anastrozole 1 mg, anastrozole 10 mg, and megestrol
`acetate groups, respectively, had either an objective
`response or stable disease for a duration of 24 weeks
`or longer. Responses occurred in all sites of disease,
`with the best responses in patients with soft tissue
`
`AstraZeneca Exhibit 2137 p. 6
`
`

`

`736
`
`CANCER February 15, 1997 / Volume 79 / Number 4
`
`TABLE 4
`
`TABLE 5
`
`Common Adverse Events, Regardless of Causality, Reported in 15% of
`Patients in the Anastrozole 1, Anastrozole 10 mg, and Megestrol
`Acetate Groups
`
`Incidence of Anticipated Adverse Events, Regardless of Causality, in
`Patients in the Anastrozole 1 mg, Anastrozole 10 mg, and Megestrol
`Acetate Groups
`
`Adverse event
`
`Anastrozole 1
`mg (n = 128)
`
`No. (%)
`
`Anastrozole
`10 mg
`(n = 129)
`
`Megestrol
`acetate 160
`mg (n = 128)
`
`Adverse event
`
`Anaastrozole Anastrozole
`
`1 mg
`(n = 128)
`
`10 mg
`(n = 129)
`
`Megestrol acetate
`160 mg (n = 128)
`
`No. (%)
`
`(32)
`41
`(21)
`27
`(27)
`35
`Asthenia
`(11)
`14
`(16)
`21
`(16)
`20
`Back pain
`(13)
`16
`(26)
`33
`(17)
`22
`Headache
`(15)
`19
`(22)
`28
`(16)
`20
`Pain
`(12)
`15
`(16)
`20
`(22)
`28
`Hot flushes
`(16)
`21
`(25)
`32
`(20)
`25
`Nausea
`(24)
`31
`(15)
`19
`(13)
`17
`Dyspnea
`
`Weight gain (16) 1 (1) 6 (5) 20
`
`
`
`
`
`
`20 (16)
`6 (5)
`1 (1)
`Weight gain
`22 (17)
`14 (11)
`15 (12)
`Edema
`6 (5)
`3 (2)
`4 (3)
`Thromboembolic disease
`34 (27)
`55 (43)
`48 (38)
`Gastrointestinal disturbance
`27 (21)
`23 (18)
`29 (23)
`Hot flushes
`
`Vaginal dryness 1 (1) 4 (3) 2 (2)
`
`
`
`50
`
` AO
`Percentageofpatients MO
`
`(A)0
`
`10
`
`5% or more
`
`- anastrozole1 mg
`anastrozole 10 mg
`megestrol acetate
`
`
`
`10% or more
`
`Weight gain (kg)
`
`
`
`FIGURE 3. Weight gain of 25% and 210% in patients in the anastrozole
`1 mg, anastrozole 10 mg, and megestrol acetate groups.
`
`mg and from 350 to 450 ng/mL for anastrozole 10 mg.
`There were no apparent notable age-related trends in
`mean Cmin values. Plasma anastrozole concentrations
`were slightly higher in patients without renal or he-
`patic impairment.
`
`Tolerability
`Both 1 and 10 mg of anastrozole and 160 mg of meges-
`trol acetate were generally well tolerated (Table 4).
`Among anticipated adverse events (Table 5),weight
`gain and edema were reported more frequently among
`patients treated with megestrol acetate, whereas gas-
`trointestinal disturbances (nausea, vomiting, change
`in bowel habits, or anorexia) were more common
`among patients who received 1 or 10 mg of an-
`astrozole. Weight increases of 5% or more, as well as
`10% or more, occurred more frequently in patients
`treated with megestrol acetate compared with those
`treated with 1 or 10 mg of anastrozole (Fig. 3). More-
`
`AstraZeneca Exhibit 2137 p. 7
`
`disease (complete or partial responses of 24% in the
`anastrozole 1 mg group, 14% in the anastrozole 10
`mg group, and 31% in the megestrol acetate group).
`Responses were observed in patients who progressed
`after receiving adjuvant tamoxifen and in patients who
`received tamoxifen for advanced disease.
`
`For patients with a partial or complete response,
`the duration of response ranged from approximately
`3 to 16.5 months in the 3 treatment groups. The num-
`ber of patients who had an objective response in each
`treatment group was too small to provide a meaningful
`median for duration of response.
`
`Quality of Life
`Anastrozole 1 mg was associated with better physical
`scores and anastrozole 10 mg with better psychologic
`scores than megestrol acetate. The difference in physi-
`cal scores was significant (P < 0.025) at Week 24 be-
`tween the anastrozole 1 mg and megestrol acetate
`groups. With respect to psychologic scores, the differ-
`ence was significant (P < 0.025) between the an-
`astrozole 1 mg and megestrol acetate groups at Week
`12 and between both the 1 mg and 10 mg anastrozole
`groups at Week 24. Subjective symptom scores re-
`vealed no differences between the anastrozole groups
`and the megestrol acetate group in analgesic use, bone
`pain, or performance status.
`
`Pharmacokinetics
`
`After daily administration of anastrozole 1 mg, individ-
`ual steady state concentrations ranged mostly from 20
`to 60 ng/mL. Steady-state concentrations of plasma
`anastrozole increased 10-fold with the 10-mg dose;
`most of
`the values ranged from 200 to 600 ng/mL.
`The majority of minimum concentration of drug (Cmin)
`values ranged from 30 to 45 ng/mL for anastrozole 1
`
`

`

`Anastrozole vs. Megestrol Acetate in Advanced Breast Cancer/Buzdar et al.
`
`737
`
`that although administration of an-
`limitation is
`astrozole was double blinded, administration of meg-
`estrol acetate was open label. The trial was initially
`planned with a double blind design for both an-
`astrozole and megestrol acetate; however, the oral tab-
`let formulation of megestrol acetate developed for use
`in the trial had greater bioavailability than the com-
`mercially available formulation. Given the lack of a
`suitable trial formulation of megestrol acetate, a deci-
`sion was made to utilize a