V O L U M E 3 1 䡠 N U M B E R 2 䡠 J A N U A R Y 1 0 2 0 1 3
`
`JOURNAL OF CLINICAL ONCOLOGY
`
`O R I G I N A L R E P O R T
`
`Randomized Phase III Placebo-Controlled Trial of Letrozole
`Plus Oral Temsirolimus As First-Line Endocrine Therapy in
`Postmenopausal Women With Locally Advanced or
`Metastatic Breast Cancer
`Antonio C. Wolff, Ann A. Lazar, Igor Bondarenko, August M. Garin, Stephen Brincat, Louis Chow, Yan Sun,
`Zora Neskovic-Konstantinovic, Rodrigo C. Guimaraes, Pierre Fumoleau, Arlene Chan, Soulef Hachemi,
`Andrew Strahs, Maria Cincotta, Anna Berkenblit, Mizue Krygowski, Lih Lisa Kang, Laurence Moore,
`and Daniel F. Hayes
`See accompanying editorial on page 171
`
`A
`
`B
`
`S
`
`T
`
`R
`
`A
`
`C
`
`T
`
`Purpose
`Recent data showed improvement in progression-free survival (PFS) when adding everolimus
`to exemestane in patients with advanced breast cancer experiencing recurrence/progression
`after nonsteroidal aromatase inhibitor (AI) therapy. Here, we report clinical outcomes of
`combining the mammalian target of rapamycin (mTOR) inhibitor temsirolimus with letrozole in
`AI-naive patients.
`Patients and Methods
`This phase III randomized placebo-controlled study tested efficacy/safety of first-line oral letrozole
`2.5 mg daily/temsirolimus 30 mg daily (5 days every 2 weeks) versus letrozole/placebo in 1,112
`patients with AI-naive, hormone receptor–positive advanced disease. An independent data
`monitoring committee recommended study termination for futility at the second preplanned
`interim analysis (382 PFS events).
`Results
`Patients were balanced (median age, 63 years; 10% stage III, 40% had received adjuvant
`endocrine therapy). Those on letrozole/temsirolimus experienced more grade 3 to 4 events (37%
`v 24%). There was no overall improvement in primary end point PFS (median, 9 months; hazard
`ratio [HR], 0.90; 95% CI, 0.76 to 1.07; P ⫽ .25) nor in the 40% patient subset with prior adjuvant
`endocrine therapy. An exploratory analysis showed improved PFS favoring letrozole/temsirolimus
`in patients ⱕ age 65 years (9.0 v 5.6 months; HR, 0.75; 95% CI, 0.60 to 0.93; P ⫽ .009), which was
`separately examined by an exploratory analysis of 5-month PFS using subpopulation treatment
`effect pattern plot methodology (P ⫽ .003).
`Conclusion
`Adding temsirolimus to letrozole did not improve PFS as first-line therapy in patients with AI-naive
`advanced breast cancer. Exploratory analyses of benefit in younger postmenopausal patients
`require external confirmation.
`
`J Clin Oncol 31:195-202. © 2012 by American Society of Clinical Oncology
`
`INTRODUCTION
`
`The selective estrogen receptor (ER) modulator
`tamoxifen has been the primary choice for treat-
`ing ER-positive metastatic breast cancer (MBC),
`but ultimately most patients have disease progres-
`sion.1,2 Aromatase inhibitors (AIs), like the non-
`steroidal inhibitor letrozole, significantly inhibit
`estrogen biosynthesis3 and improve clinical out-
`comes at least temporarily.4,5 Endocrine responsive-
`ness may be lost by upregulating proliferation/
`
`survival signal transduction pathways, like upstream
`signaling transmembrane growth factor receptors
`such as the human epidermal growth factor receptor
`2 (HER2)6 and downstream intracellular signaling
`such as the PI3K/Akt/mammalian target of rapamy-
`cin (mTOR) pathways.7,8 Modulation of these path-
`ways may circumvent resistance mechanisms when
`combined with antiestrogens.6,9-13
`Temsirolimus, an inhibitor of mTOR, has
`clinical activity as intravenous (IV) monotherapy
`in heavily pretreated locally advanced breast
`
`Antonio C. Wolff, the Johns Hopkins
`Kimmel Comprehensive Cancer Center,
`Baltimore, MD; Ann A. Lazar, University of
`California San Francisco, San Francisco,
`CA; Igor Bondarenko, Municipal Clinical
`Hospital #4, State Medical Academy,
`Dnepropetrovsk, Ukraine; August M. Garin,
`Russian Oncological Research Center,
`Moscow, Russia; Stephen Brincat, Sir Paul
`Boffa Hospital, Floriana, Malta; Louis
`Chow, UNIMED Medical Center, Wan
`Chai, Hong Kong; Yan Sun, Cancer Hospi-
`tal, Chinese Academy of Medical Sciences,
`Beijing, China; Zora Neskovic-
`Konstantinovic, Institute of Oncology and
`Radiology of Serbia, Belgrade, Serbia;
`Rodrigo C. Guimaraes, Hospital Vera Cruz,
`Belo Horizonte, Brazil; Pierre Fumoleau,
`Centre Georges-Francois Leclerc Service
`Oncologie, Dijon; Soulef Hachemi, Pfizer,
`Paris, France; Arlene Chan, Mount Medical
`Center, Perth, Australia; Andrew Strahs,
`Maria Cincotta, Anna Berkenblit, Mizue
`Krygowski, Lih Lisa Kang, and Laurence
`Moore, Pfizer, Cambridge, MA; and Daniel
`F. Hayes, University of Michigan Compre-
`hensive Cancer Center, Ann Arbor, MI.
`
`Published online ahead of print at
`www.jco.org on December 10, 2012.
`
`Authors’ disclosures of potential conflicts
`of interest and author contributions are
`found at the end of this article.
`
`Clinical trial information: NCT00083993.
`
`Corresponding author: Antonio C. Wolff,
`MD, the Johns Hopkins Kimmel Compre-
`hensive Cancer Center, 1650 Orleans St,
`CRB1-189, Baltimore, MD 21287; e-mail:
`awolff@jhmi.edu.
`
`© 2012 by American Society of Clinical
`Oncology
`
`0732-183X/13/3102-195/$20.00
`
`DOI: 10.1200/JCO.2011.38.3331
`
`© 2012 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on August 25, 2015. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`195
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`NOVARTIS EXHIBIT 2176
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`

`
`Wolff et al
`
`cancer or MBC.14 In a randomized phase II study in postmeno-
`pausal women,9 an intermittent 30-mg oral temsirolimus schedule
`(daily for 5 days every 2 weeks) added to daily oral letrozole 2.5 mg
`was safe and reached desired blood levels with a slightly higher mean
`relative dose-intensity than with a 10-mg daily temsirolimus schedule.
`Here, we report a prospective phase III study (HORIZON) testing the
`efficacy/safety of adding temsirolimus to letrozole in postmenopausal
`women with ER-positive and/or progesterone receptor (PR) –positive
`(hereon described just as ER-positive) locally advanced breast cancer
`or MBC with no prior exposure to AIs.
`
`PATIENTS AND METHODS
`
`Study Design
`In this multinational, randomized, double-blind phase III study of letro-
`zole/temsirolimus or letrozole/placebo, patients were stratified by geography
`(United States; Western Europe, Australia, New Zealand, India, and Canada;
`or Asia-Pacific, Eastern Europe, Africa, and South America) and according to
`presence or absence of bone metastasis. Patients were randomly assigned (1:1)
`to letrozole 2.5 mg once daily continuously plus oral temsirolimus 30 mg or
`placebo once daily for 5 days every 2 weeks (one cycle). Treatment was stopped
`in the event of excessive toxicity or disease progression.
`The study was designed by the sponsor (Wyeth) and representatives of
`the academic investigators. Data were collected by the sponsor’s data manage-
`ment team and initially analyzed by the sponsor’s statistical team. A medical
`writer contributed to the first manuscript draft. A separate independent statis-
`tical review was recommended by the academic first and last authors of this
`article, who then prepared all subsequent drafts aided by the statistician coau-
`thors. All coauthors made additional contributions to the interpretation of the
`data and subsequent editing. No one else contributed to the manuscript.
`Eligibility Criteria
`Patients had histologically and/or cytologically confirmed ER-positive
`breast cancer with evidence of locally advanced or metastatic disease (stage
`IIIB/C or IV) and one or more measurable lesions by Response Evaluation
`Criteria in Solid Tumors (RECIST).15 Baseline ER/PR status (and HER2 ex-
`
`pression status, when available) was based on local testing of the most recently
`analyzed tissue. Patients were ineligible if they had prior adjuvant AI within 12
`months before study day 1, if disease recurrence occurred during the first 6
`months of adjuvant endocrine therapy, or if prior endocrine therapy (includ-
`ing AIs) was administered for locally advanced/MBC. Patients must have
`been ⱖ 18 years old, had a Karnofsky performance status ⱖ 60, life expectancy
`ⱖ 6 months, and have been postmenopausal (ie, age ⱖ 60 years, age ⬍ 60 and
`amenorrheic for ⱖ 12 months, age ⬍ 60 and amenorrheic for ⬍ 12 months
`before day 1 if luteinizing hormone/follicle-stimulating hormone values
`within menopausal range assuming no use of drugs that affect luteinizing
`hormone/follicle-stimulating hormone values, and/or prior bilateral oopho-
`rectomy or radiation castration with subsequent amenorrhea for ⱖ 6 months).
`Baseline labs required absolute neutrophil count (ANC) ⱖ 1,500/␮L, platelet
`count ⱖ 100,000/␮L (ⱖ 80,000/␮L in patients in China), hemoglobin ⱖ 8.0
`g/dL, serum creatinine ⱕ 1.5⫻ upper limit of normal (ULN), total bilirubin ⱕ
`1.5⫻ ULN, AST/ALT ⱕ 3⫻ ULN (ⱕ 5⫻ ULN if liver metastases present),
`fasting cholesterol ⱕ 350 mg/dL, serum triglycerides ⱕ 400 mg/dL, and cal-
`cium ⱕ 12.5 mg/dL. Patients were excluded if bone was the only site of disease,
`in the event of inflammatory breast cancer, or in the event of one or more prior
`chemotherapy regimens or more than 14 consecutive days of endocrine ther-
`apy for locally advanced/MBC.
`
`Safety
`Adverse events (AEs) were coded using the Coding Thesaurus for Ad-
`verse Reactions Terminology (COSTART) and graded according to National
`Cancer Institute Common Terminology Criteria, version 3.0. All patients who
`received one or more dose of drug were included in the safety analysis. Tem-
`sirolimus or placebo administration was withheld if ANC was less than
`1,000/␮L or platelet counts were less than 50,000/␮L and for any grade 3 to 4
`nonhematologic toxicity with the exception of hyperglycemia and hypercho-
`lesterolemia (for which patients should be receiving concomitant therapy) and
`nausea/vomiting (unless already receiving optimal antiemetic therapy). Treat-
`ment could be reinitiated within 3 weeks if ANC was ⱖ 1,000/␮L, platelets
`were ⱖ 50,000/␮L, and nonhematologic toxicities recovered to grade ⱕ 2.
`First dose reduction was to temsirolimus/placebo 30 mg daily for 4 days every
`2 weeks and second was to 3 days every 2 weeks. Protocol therapy stopped if
`recovery was not achieved within 3 weeks. Letrozole dose reduction was not
`permitted but could be held for ⱕ 3 consecutive weeks if associated toxicities
`
`Assessed for eligibility
`(N = 1,375)
`
` dedulcxE
` Did not meet inclusion criteria,
` declined to participate, or
` other reasons
`
`)362 = n(
`
`Random assignment
`(n = 1,112)
`
`Allocated to letrozole plus
`temsirolimus
` Received allocated intervention
` Did not receive allocated intervention
` eruliaf neercS
` Requested to discontinue the
` treatment
` EA
` nruter ot eruliaF
`
`(n = 556)
`
`(n = 550)
`(n = 6)
`)1 = n(
`(n = 3)
`
`)1 = n(
`)1 = n(
`
`Fig 1. CONSORT flow diagram. AE, ad-
`verse event.
`
`Allocated to letrozole plus placebo
` Received allocated intervention
` Did not receive allocated intervention
` eruliaf neercS
` EA
` htaeD
`
`(n = 556)
`(n = 553)
`(n = 3)
`)1 = n(
`)1 = n(
`)1 = n(
`
`Included in the intent-to-treat analysis (n = 556)
`Included in the safety analysis
`(n = 550)
`
`Included in the intent-to-treat analysis (n = 556)
`Included in the safety analysis
`(n = 553)
`
`196
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2012 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on August 25, 2015. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`NPC02237301
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`NOVARTIS EXHIBIT 2176
`Par v Novartis, IPR 2016-00084
`Page 2 of 8
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`

`
`Letrozole Plus Oral Temsirolimus in Advanced Breast Cancer
`
`Table 1. Demographic and Baseline Characteristics
`
`Table 2. Summary of Efficacy End Points
`
`Letrozole
`Plus
`Temsirolimus
`(n ⫽ 555)
`
`Letrozole
`Plus
`Placebo
`(n ⫽ 555)
`
`Characteristic
`
`No.
`
`%
`
`No.
`
`%
`
`Age, years
`Median
`Range
`n
`ⱕ 65
`⬎ 65
`Histologic gradeⴱ
`Well differentiated
`Moderately differentiated
`Poorly differentiated
`Undifferentiated
`Unknown
`Estrogen receptor status
`Positive
`Negative
`Unknown
`Progesterone receptor status
`Positive
`Negative
`Unknown
`HER2 status
`Positive
`Negative
`Unknown
`Karnofsky performance statusⴱ
`ⱖ 60
`⬍ 60
`Unknown
`Prior chemo-, immuno-, hormonal therapyⴱ
`Yes
`No
`Unknown
`Prior endocrine therapy†
`Yes
`No
`Duration, months
`Median
`Range
`Time from last endocrine therapy to
`study day 1, months
`Median
`Range
`
`63
`36-98
`553
`322
`231
`
`47
`197
`101
`8
`197
`
`534
`19
`2
`
`411
`125
`19
`
`130
`224
`201
`
`547
`1
`2
`
`358
`0
`192
`
`238
`318
`
`58
`42
`
`9
`36
`18
`1
`36
`
`96
`3
`1
`
`74
`23
`3
`
`23
`40
`36
`
`99
`1
`1
`
`65
`
`35
`
`43
`57
`
`63
`28-91
`553
`326
`227
`
`45
`184
`114
`9
`201
`
`530
`25
`0
`
`399
`143
`13
`
`101
`259
`195
`
`552
`0
`3
`
`327
`0
`226
`
`223
`333
`
`59
`41
`
`8
`33
`21
`2
`36
`
`95
`5
`
`72
`26
`2
`
`18
`47
`35
`
`99
`
`1
`
`59
`
`41
`
`40
`60
`
`34
`0.03-126
`
`33
`0.03-186
`
`5
`0-284
`
`6
`0.03-159
`
`Abbreviation: HER2, human epidermal growth factor receptor 2.
`ⴱFor patients who received at least one dose of drug, 550 in the letrozole/
`temsirolimus group and 553 in the letrozole/placebo group.
`†For the intent-to-treat population of 556 patients per group.
`
`were present. The protocol was approved by the ethics committees/institu-
`tional review boards of each site. The study was conducted according to
`international standards of good clinical practice. All patients gave written
`informed consent.
`Assessment of Outcomes
`RECIST criteria were used for efficacy assessment (measurable lesions
`had to be two times the size of the scan reconstruction interval). Staging was
`done at screening and every 8 weeks.
`End Points and Statistical Analysis
`The primary efficacy end point was progression-free survival (PFS) of the
`intent-to-treat population as assessed by independent review. PFS was the time
`
`Parameter
`
`Total population
`Progression-free survival
`No. censored
`%
`Median, months
`95% CI
`Hazard ratioⴱ
`95% CI
`P†
`Overall survival
`No. censored
`%
`Median, months
`Hazard ratioⴱ
`95% CI
`P†
`Tumor response
`Complete response
`No.
`%
`Partial response
`No.
`%
`Objective response rate, %
`Subgroups
`Prior endocrine therapy, progression-free
`survival
`No.
`%
`Median, months
`95% CI
`Hazard ratioⴱ
`95% CI
`P†
`No prior endocrine therapy, progression-
`free survival
`No.
`%
`Median, months
`95% CI
`Hazard ratioⴱ
`95% CI
`P†
`Age ⱕ 65 years, progression-free
`survival
`No.
`No. censored
`%
`Median, months
`95% CI
`Hazard ratioⴱ
`95% CI
`P†
`Age ⬎ 65 years, progression-free
`survival
`No.
`No. censored
`%
`Median, months
`95% CI
`Hazard ratioⴱ
`95% CI
`P†
`
`Letrozole Plus
`Temsirolimus
`(n ⫽ 556)
`
`Letrozole Plus
`Placebo
`(n ⫽ 556)
`
`270
`49
`9.0
`7.2 to 9.4
`
`475
`85
`NE
`
`10
`2
`
`139
`25
`27
`
`221
`40
`5.2
`3.7 to 6.5
`
`332
`60
`9.4
`9.1 to 11.1
`
`326
`146
`45
`5.6
`4.8 to 9.0
`
`227
`124
`55
`10.1
`9.0 to 11.4
`
`290
`52
`8.9
`7.4 to 9.6
`0.90
`0.76 to 1.07
`.25
`
`483
`87
`NE
`0.89
`0.65 to 1.23
`.50
`
`14
`3
`
`137
`25
`27
`
`237
`43
`6.5
`5.5 to 8.5
`0.84
`0.66 to 1.08
`.17
`
`316
`57
`11.0
`9.2 to 12.9
`0.87
`0.69 to 1.11
`.27
`
`322
`168
`52
`9.0
`7.3 to 10.9
`0.75
`0.60 to 0.93
`.009
`
`231
`122
`53
`8.5
`5.6 to 10.6
`1.21
`0.92 to 1.59
`.17
`
`Abbreviation: NE, not estimable.
`ⴱLetrozole plus temsirolimus compared with letrozole plus placebo based on
`Cox proportional hazards model stratified by prior bone disease status and
`geographic region.
`†Letrozole plus temsirolimus compared with letrozole plus placebo based on
`log-rank test stratified by prior bone disease status and geographic region.
`
`www.jco.org
`
`© 2012 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on August 25, 2015. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
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`

`
`Wolff et al
`
`from first treatment to earliest time of disease progression, symptomatic dete-
`rioration, or death. As independent assessments of progression were not com-
`pleted at the time the study was stopped, investigator-assessed PFS is reported.
`Secondary end points included overall survival (OS), tumor response and
`clinical benefit, time to tumor progression, duration of response, time to
`treatment failure, safety, and quality of life using European Organisation for
`Research and Treatment of Cancer Quality of Life Questionnaire Cancer-30
`and Q-TwiST (Quality-Adjusted Time Without Symptoms of Disease or Tox-
`icity of Treatment) methodologies. This article reports only OS, tumor re-
`sponse, and safety. Key predefined covariate analyses included prior adjuvant
`tamoxifen. Analyses of molecular markers phosphatase and tensin homolog
`and p27 on tissues (⬃20% of patients) did not comply with Reporting Rec-
`ommendations for Tumor Marker Prognostic Studies (REMARK) criteria and
`are not reported.
`A sample size of 1,236 patients (expecting 15% nonevaluable) and
`726 events were needed to detect a PFS hazard ratio (HR) of 0.8 (median
`PFS, 11.75 v 9.4 months) favoring the investigational arm (85% power,
`two-sided log-rank test, 5% significance). Expected accrual time was
`⬃16.4 months.
`The patients and whole study team were blinded, as were Wyeth senior
`management personnel. An independent statistician (not part of the study
`team) generated the randomization sequence list with different seed numbers
`using SAS with proc plan procedure (SAS v9; SAS Institute, Cary, NC; Rv2.10).
`The generated list (with random number, stratification, and treatment infor-
`mation) was sent to a central computerized randomization enrollment system.
`
`Formal review and approval processes were in place before the random allo-
`cation sequence could be released. Each site received temsirolimus/placebo
`without treatment information directly from a group independent of the study
`team. In cases of emergency, the patient was unblinded via the computerized
`randomization enrollment system. When this occurred, the investigator noti-
`fied the sponsor medical monitor immediately and documented the reason
`for unblinding.
`Two preplanned interim analyses evaluating safety and efficacy
`would occur after 145 (⬃20%) and after 363 (⬃50%) events (disease
`progression or death) with appropriate adjustments and predefined terms
`for early success or futility. PFS/OS were estimated using the Kaplan-Meier
`method.16 HRs and 95% CIs were calculated using a stratified Cox propor-
`tional hazards model. The proportional hazards assumption was assessed
`using a standard approach based on the Cox extended model (ie, time-
`dependent covariates).
`A planned subset analysis based on the subject’s age (age ⱕ 65 v ⬎ 65
`years) was intended but not prospectively documented before the interim
`analyses. Age findings reported in a 2006 San Antonio Breast Cancer Sympo-
`sium poster then led the first and last academic authors to conduct exploratory
`and independent statistical analyses using the subpopulation treatment effect
`pattern plot (STEPP) methodology to illustrate graphically the relationship
`between age and outcome (PFS or OS) across the age continuum. Significance
`of treatment-effect heterogeneity as a function of age was calculated using a
`permutation test.17,18 Planning for the STEPP analyses was locked before
`analyses, and the 5-month PFS analysis (y-axis of Fig 4) was designated as the
`
`Stratified log-rank test P = .25
`HR, 0.90; 95% CI, 0.76 to 1.07
`
`LET + TEMSR
`LET + placebo
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Progression-Free Survival
`
`(probability)
`
`A
`
`0
`
`2
`
`4
`
`6
`
`8
`
`12
`10
`Time (months)
`
`14
`
`16
`
`18
`
`20
`
`22
`
`387/79 278/63 193/43 149/19
`553
`553 365/110 276/58 211/35 154/18
`
`102/21
`110/21
`
`61/19
`65/21
`
`40/10
`37/9
`
`22/2
`18/6
`
`5/4
`6/2
`
`0/3
`2/0
`
`0/0
`0/0
`
`No. at risk/events
`LET + TEMSR
`LET + placebo
`B
`
`1.0
`
`(A)
`Fig 2. Kaplan-Meier estimates of
`progression-free survival and (B) overall
`survival. HR, hazard ratio; LET, letrozole;
`TEMSR, temsirolimus.
`
`Stratified log-rank test P = .50
`HR, 0.89; 95% CI, 0.65 to 1.23
`
`LET + TEMSR
`LET + placebo
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Overall Survival
`
`(probability)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`
`12
`14
`16
`Time (months)
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`No. at risk/events
`LET + TEMSR
`LET + placebo
`
`556
`527/7 472/17 417/15 341/10 265/7 194/7 132/5 88/1
`556 524/10 463/15 410/7 335/12 271/15 202/5 137/7 91/5
`
`46/2 24/1
`48/3 23/0
`
`9/1
`9/2
`
`1/0
`3/0
`
`0/0
`1/0
`
`0/0
`0/0
`
`198
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2012 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on August 25, 2015. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`NPC02237303
`
`NOVARTIS EXHIBIT 2176
`Par v Novartis, IPR 2016-00084
`Page 4 of 8
`
`

`
`Letrozole Plus Oral Temsirolimus in Advanced Breast Cancer
`
`primary STEPP analysis. The additional STEPP analyses looking at 6-, 7-, 8-,
`and 9-month PFS percentages were conducted to check consistency and fol-
`lowed established recommendations.17 Two-sided P values were reported for
`all statistical tests, and P ⱕ .05 was considered significant.
`
`RESULTS
`
`Patients
`Between May 2004 and March 2006, 1,112 patients (Fig 1)
`from 263 centers were randomly assigned to receive letrozole plus
`temsirolimus (550 treated) or letrozole plus placebo (553 treated), and
`⬃10% (51 and 65 patients, respectively) had stage III disease that was
`considered not amenable to curative surgery and/or radiation. In
`March 2006, the Independent Data Monitoring Committee con-
`cluded at the second predefined interim analysis (382 events) that the
`study was unlikely to reach its PFS primary end point and recom-
`mended its termination. Data reported herein correspond to the final
`December 2006 data lock (median follow-up, 9.5 months; range, 0 to
`27.2 months).
`Demographic and disease characteristics were balanced (Ta-
`ble 1). Patients had ER-positive (96%) and/or PR-positive (73%)
`disease, whereas 23% in the letrozole/temsirolimus group and 18%
`
`in the letrozole/placebo group were HER2 positive. No patients
`had prior endocrine therapy for locally advanced/MBC. Although
`⬃40% received adjuvant endocrine therapy (median duration,
`⬃34 months; median time since last endocrine therapy, ⬃5
`months), none had cancer recurrence during the first 6 months,
`nor did any patient receive adjuvant AI within 12 months of study
`entry. Therefore, although data on specific type of adjuvant endo-
`crine therapy were not prospectively collected, it is assumed that
`they would have received tamoxifen.
`
`Efficacy
`The retrospective independent assessment of progression was
`not complete when the trial was stopped. Therefore, the PFS data are
`based on investigator assessment with a randomly assigned intent-to-
`treat population of 1,112 patients. Overall, PFS was comparable in
`both groups (HR, 0.90; 95% CI, 0.76 to 1.07; P ⫽ .25; Table 2; Fig 2A).
`Median PFS (8.9 and 9.0 months, respectively) and OS were also
`comparable (HR, 0.89; 95% CI, 0.65 to 1.23; P ⫽ .50; Table 2; Fig 2B).
`There was no evidence of nonproportional hazards (PFS, P ⫽ .43; OS,
`P ⫽ .51). Few death events occurred by the time of this analysis
`because of early study termination. Most patients were censored, and
`median survival could not be calculated. Objective response rate (RR)
`
`Stratified log-rank test P = .009
`HR, 0.75; 95% CI, 0.60 to 0.93
`
`LET + TEMSR
`LET + placebo
`
`1.0
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Progression-Free Survival
`
`(probability)
`
`A
`
`of
`estimates
`3. Kaplan-Meier
`Fig
`progression-free survival by patient’s age:
`(A) ⱕ 65 years and (B) older than 65 years.
`HR, hazard ratio; LET, letrozole; TEMSR,
`temsirolimus.
`
`0
`
`2
`
`4
`
`6
`
`8
`
`12
`10
`Time (months)
`
`14
`
`16
`
`18
`
`20
`
`22
`
`322
`326
`
`231/47 169/33 118/27
`199/80 145/38 103/22
`
`88/11
`76/8
`
`63/15
`55/10
`
`40/11
`37/11
`
`28/5
`22/4
`
`15/1
`13/3
`
`2/0
`4/2
`
`0/0
`1/0
`
`0/1
`0/0
`
`No. at risk/events
`LET + TEMSR
`LET + placebo
`B
`
`1.0
`
`Stratified log-rank test P = .17
`HR, 1.21; 95% CI, 0.92 to 1.59
`
`LET + TEMSR
`LET + placebo
`
`0.8
`
`0.6
`
`0.4
`
`0.2
`
`Progression-Free Survival
`
`(probability)
`
`0
`
`2
`
`4
`
`6
`
`8
`
`10
`12
`Time (months)
`
`14
`
`16
`
`18
`
`20
`
`22
`
`No. at risk/events
`LET + TEMSR
`LET + placebo
`
`231
`227
`
`75/16
`156/32 109/30
`166/30 131/20 108/13
`
`61/8
`78/10
`
`39/6
`55/11
`
`21/8
`28/10
`
`12/5
`15/5
`
`7/0
`5/3
`
`3/0
`2/0
`
`0/0
`1/0
`
`0/0
`0/0
`
`www.jco.org
`
`© 2012 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on August 25, 2015. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`199
`
`NPC02237304
`
`NOVARTIS EXHIBIT 2176
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`Page 5 of 8
`
`

`
`Wolff et al
`
`Letrozole + temsirolimus
`Letrozole + placebo
`
`49
`(n = 207)
`
`72
`68
`65
`61
`57
`53
`(n = 216) (n = 240) (n = 208) (n = 228) (n = 205) (n = 216)
`Median Age (years)
`
`78
`(n = 195)
`
`P = .003
`
`49
`(n = 207)
`
`72
`68
`65
`61
`57
`53
`(n = 216) (n = 240) (n = 208) (n = 228) (n = 205) (n = 216)
`Median Age (years)
`
`78
`(n = 195)
`
`100
`
`80
`
`60
`
`40
`
`20
`
`0
`
`
`
`
`60
`
`40
`
`20
`
`0
`
`-20
`
`-40
`
`-60
`
`
`
`A
`
`5-Month Progression-Free
`
`Survival (%)
`
`B
`
`Progression-Free Survival (%)
`
`Difference in 5-Month
`
`Fig 4. STEPP analysis of the treatment effect of letrozole plus temsirolimus
`versus letrozole plus placebo as measured by (A) 5-month progression-free
`survival (PFS) and (B) difference (letrozole plus temsirolimus) – (letrozole plus
`placebo) in 5-month PFS with corresponding 95% pointwise CIs (dashed blue
`lines). The values on the x-axis indicate the median age for patients in each of the
`overlapping subpopulations. Each subpopulation contains approximately 200
`patients and approximately 100 overlapping patients. (B) Solid horizontal black
`line indicates overall treatment effect, and dotted horizontal black line indicates
`no effect. A difference in 5-month PFS greater than 0 suggested letrozole plus
`temsirolimus treatment was better; otherwise, letrozole plus placebo was better
`(P ⫽ .003 represents the P value from the interaction test).
`
`RR, PFS, or OS. The primary efficacy end point of PFS was not met,
`and the Independent Data Monitoring Committee recommended
`study termination after the second planned interim analysis. The
`investigational arm had more toxicities.
`These findings contrast with PFS benefit observed in the
`Breast Cancer Trials of Oral Everolimus-2 (BOLERO-2) study that
`tested another mTOR inhibitor, everolimus, plus the steroidal AI
`exemestane. BOLERO-2 described 84% of patients as having
`endocrine-sensitive disease (ie, ⱖ 24 months of endocrine therapy
`before recurrence in the adjuvant setting or stabilization for ⱖ 24
`weeks on endocrine therapy for advanced disease).19 Although
`HORIZON did not prospectively define endocrine sensitivity, 40%
`of our patients previously received adjuvant endocrine therapy
`(and most such recurrences occurred during adjuvant therapy),
`and essentially none had received an AI as adjuvant therapy. Con-
`sequently, despite the limitations of cross-trial comparisons, key
`
`was the same (27%), and 17% and 19% of patients, respectively, had
`stable disease ⱖ 24 weeks.
`In a prospectively planned subset analysis, no interaction was
`observed between prior adjuvant endocrine therapy and treatment
`(P ⫽ .80). PFS was comparable for both arms in patients with/without
`prior adjuvant endocrine therapy (HR, 0.84; 95% CI, 0.66 to 1.08;
`HR, 0.87; 95% CI, 0.69 to 1.11, respectively; Table 2).
`An exploratory subset analysis by age (age ⱕ 65 v ⬎ 65 years)
`showed an interaction between age and treatment outcome (test
`for interaction, P ⫽ .007). Patients age ⱕ 65 years had longer PFS
`with letrozole/temsirolimus (median, 9.0 v 5.6 months; HR, 0.75;
`95% CI, 0.60 to 0.93; P ⫽ .009; Table 2; Fig 3A), whereas PFS was
`comparable for patients older than 65 years (median, 8.5 v 10.1
`months; HR, 1.21; 95% CI, 0.92 to 1.59; P ⫽ .17; Table 2; Fig 3B).
`Consequently, exploratory STEPP analyses to further examine
`possible interaction of age and mTOR inhibition were performed.
`Figure 4 summarizes the 5-month PFS percentage for letrozole/
`temsirolimus versus letrozole/placebo for subpopulations with in-
`creasing age. STEPP analyses showed a consistent PFS benefit
`favoring the investigational arm for younger (but not older) post-
`menopausal women (P ⫽ .003 for interaction), and results were
`consistent across different time points (5-, 6-, 7-, 8-, or 9-month
`PFS). STEPP analyses of 5-month OS percentage across the con-
`tinuum of age suggested heterogeneity in the treatment effect
`across varying levels of age. However, no significant treatment-
`effect heterogeneity was found (P ⫽ .38 for interaction at 5-month
`OS) regardless of the time-point (5-, 6-, 7-, 8-, or 9-month OS).
`
`Safety
`Treatment-emergent AEs (TEAEs) were mostly observed in the
`investigational arm (91% v 79%, respectively). Some of the most
`meaningful TEAEs (all grades) observed in the temsirolimus versus
`placebo arms, respectively, included asthenia (27% v 21% of patients),
`mucositis/stomatitis (up to 26% v 4%), diarrhea (21% v 9%), head-
`ache (19% v 12%), anorexia (15% v 7%), and rash (15% v 4%; Table
`3). Grade 3 to 4 TEAEs were more common in the temsirolimus arm
`(37% v 24%), like hyperglycemia (4% v 1%), diarrhea (2% v 1%),
`mucositis/stomatitis (up to 2% v ⬍ 1%), and hyperlipemia (2% v
`⬍ 1%).
`More patients in the temsirolimus arm seem to have had a per-
`manent dose reduction for AEs (24 or 4% v 10 or 1%). AEs leading to
`protocol therapy discontinuation in least two patients in the investi-
`gational arm were stomatitis (n ⫽ 3), pulmonary embolus, increased
`␥-glutamyl transpeptidase, pneumonitis, and respiratory failure (n ⫽
`2 each), compared with back pain and pneumonia (n ⫽ 2 each) in the
`control arm. Median number of cycles in the investigational arm was
`10 (range, one to 42 cycles) with a mean temsirolimus relative dose-
`intensity (pill count and patient diary) of 0.96. Patients in both arms
`received a median of 10 cycles of letrozole (mean letrozole relative
`dose-intensity of 1.0).
`
`DISCUSSION
`
`The HORIZON randomized placebo-controlled study tested the ad-
`dition of oral temsirolimus to the nonsteroidal AI letrozole as first-line
`therapy in postmenopausal women with ER-positive locally ad-
`vanced/MBC and did not identify any meaningful improvement in
`
`200
`
`JOURNAL OF CLINICAL ONCOLOGY
`© 2012 by American Society of Clinical Oncology
`Downloaded from jco.ascopubs.org on August 25, 2015. For personal use only. No other uses without permission.
`Copyright © 2013 American Society of Clinical Oncology. All rights reserved.
`
`NPC02237305
`
`NOVARTIS EXHIBIT 2176
`Par v Novartis, IPR 2016-00084
`Page 6 of 8
`
`

`
`Letrozole Plus Oral Temsirolimus in Advanced Breast Cancer
`
`Table 3. Treatment-Emergent Adverse Events That Occurred in at Least
`12% of Patients
`
`Letrozole Plus
`Temsirolimus (n ⫽ 550)
`
`Letrozole Plus Placebo
`(n ⫽ 553)
`
`All
`Grades
`
`Grade 3
`or 4
`
`All
`Grades
`
`Grade 3
`or 4
`
`Adverse Event
`
`No. % No.
`
`%
`
`No. % No.
`
`%
`
`Any adverse event
`Asthenia
`Diarrhea
`Headache
`Nausea
`Pain
`Cough increased
`Anorexia
`Peripheral edema
`Rash
`Mucositis
`Fever
`Hyperglycemia
`Dyspnea
`Vomiting
`Hypercholesterolemia
`Pruritus
`Stomatitis
`Infection
`Hyperlipemia
`Arthralgia
`Anemia
`Back pain
`Abdominal pain
`Vasodilation
`
`499
`148
`115
`102
`87
`82
`84
`81
`83
`82
`78
`78
`72
`69
`63
`67
`66
`65
`62
`61
`60
`59
`57
`56
`28
`
`91
`27
`21
`19
`16
`15
`15
`15
`15
`15
`14
`14
`13
`13
`12
`12
`12
`12
`11
`11
`11
`11
`10
`10
`5
`
`37
`203
`3
`14
`2
`13
`2 ⬍ 0.5
`3
`1
`6
`1
`2 ⬍ 0.5
`4
`1
`0
`1
`7
`1
`6
`1
`4
`4
`20
`3
`16
`1
`4
`1
`4
`1
`5
`1
`6
`1
`7
`2
`9
`1
`5
`1
`7
`1
`7
`2
`8
`1 ⬍ 0.5
`
`439
`115
`52
`66
`90
`59
`56
`39
`33
`23
`11
`41
`26
`54
`50
`33
`29
`13
`43
`28
`78
`27
`60
`50
`59
`
`79
`21
`9
`12
`16
`11
`10
`7
`6
`4
`2
`7
`5
`10
`9
`6
`5
`2
`8
`5
`14
`5
`11
`9
`11
`
`24
`134
`2
`10
`1
`4
`2 ⬍ 0.5
`3
`1
`4
`1
`2 ⬍ 0.5
`3
`1
`0
`1 ⬍ 0.5
`1 ⬍ 0.5
`3
`1
`5
`1
`15
`3
`4
`1
`1 ⬍ 0.5
`0
`1 ⬍ 0.5
`3
`1
`2 ⬍ 0.5
`4
`1
`7
`1
`7
`1
`5
`1
`2 ⬍ 0.5
`
`differences in patient characteristics may explain the different PFS
`observed in the two trials. HORIZON essentially excluded patients previ-
`ously to AIs, whereas BOLERO-2 eligibility required progression on a
`nonsteroidal AI during or within 12 months of completing adjuvant
`therapy or within 1 month if in the metastatic setting.19 This may also
`explainthedifferentresponseratesobservedintheircontrolarms(27%in
`HORIZON v 0.4% in BOLERO-2).
`Temsirolimus itself or its dosing, route, and/or schedule of ad-
`ministration are alternative reasons to explain the different outcomes
`of these trials. Single-agent IV temsirolimus weekly at 75 or 300 mg IV
`weekly was modestly active (RR, 9%) in breast cancer (n ⫽ 109),14
`with no responses seen in a smaller study (n ⫽ 31, 25 mg IV weekly).20
`Regarding toxicity as a proxy for pharmacodynamic effects, a small
`randomized, open-label, three-arm phase II study (n ⫽ 92) of letro-
`zole ⫾ oral temsirolimus 10 mg daily or 30 mg intermittently showed
`similar toxicity profiles in both temsirolimus arms (⬃42% and 57% of
`patients with any mucositis, respectively), with a doubling of the PFS
`in the intermittent arm compared with letrozole.9 Finally, an indirect
`and limited comparison of
`the observed toxicities between
`BOLERO-2 (see its Table 219) and HORIZON (Table 3 of this article)
`suggests a similar proportional increase over placebo in the frequency
`of