T h e ne w e ngl a nd jou r na l o f m e dicine
`
`original article
`
`Everolimus in Postmenopausal Hormone-
`Receptor–Positive Advanced Breast Cancer
`José Baselga, M.D., Ph.D., Mario Campone, M.D., Ph.D.,
`Martine Piccart, M.D., Ph.D., Howard A. Burris III, M.D., Hope S. Rugo, M.D.,
`Tarek Sahmoud, M.D., Ph.D., Shinzaburo Noguchi, M.D., Michael Gnant, M.D.,
`Kathleen I. Pritchard, M.D., Fabienne Lebrun, M.D., J. Thaddeus Beck, M.D.,
`Yoshinori Ito, M.D., Denise Yardley, M.D., Ines Deleu, M.D.,
`Alejandra Perez, M.D., Thomas Bachelot, M.D., Ph.D., Luc Vittori, M.Sc.,
`Zhiying Xu, Ph.D., Pabak Mukhopadhyay, Ph.D., David Lebwohl, M.D.,
`and Gabriel N. Hortobagyi, M.D.
`
`Abs tr act
`
`Background
`Resistance to endocrine therapy in breast cancer is associated with activation of the
`mammalian target of rapamycin (mTOR) intracellular signaling pathway. In early
`studies, the mTOR inhibitor everolimus added to endocrine therapy showed antitu-
`mor activity.
`Methods
`In this phase 3, randomized trial, we compared everolimus and exemestane versus
`exemestane and placebo (randomly assigned in a 2:1 ratio) in 724 patients with hor-
`mone-receptor–positive advanced breast cancer who had recurrence or progression
`while receiving previous therapy with a nonsteroidal aromatase inhibitor in the
`adjuvant setting or to treat advanced disease (or both). The primary end point was
`progression-free survival. Secondary end points included survival, response rate,
`and safety. A preplanned interim analysis was performed by an independent data
`and safety monitoring committee after 359 progression-free survival events were
`observed.
`Results
`Baseline characteristics were well balanced between the two study groups. The median
`age was 62 years, 56% had visceral involvement, and 84% had hormone-sensitive
`disease. Previous therapy included letrozole or anastrozole (100%), tamoxifen (48%),
`fulvestrant (16%), and chemotherapy (68%). The most common grade 3 or 4 adverse
`events were stomatitis (8% in the everolimus-plus-exemestane group vs. 1% in the
`placebo-plus-exemestane group), anemia (6% vs. <1%), dyspnea (4% vs. 1%), hyper-
`glycemia (4% vs. <1%), fatigue (4% vs. 1%), and pneumonitis (3% vs. 0%). At the
`interim analysis, median progression-free survival was 6.9 months with everolimus
`plus exemestane and 2.8 months with placebo plus exemestane, according to assess-
`ments by local investigators (hazard ratio for progression or death, 0.43; 95% confi-
`dence interval [CI], 0.35 to 0.54; P<0.001). Median progression-free survival was 10.6
`months and 4.1 months, respectively, according to central assessment (hazard ratio,
`0.36; 95% CI, 0.27 to 0.47; P<0.001).
`Conclusions
`Everolimus combined with an aromatase inhibitor improved progression-free survival
`in patients with hormone-receptor–positive advanced breast cancer previously treated
`with nonsteroidal aromatase inhibitors. (Funded by Novartis; BOLERO-2 ClinicalTrials
`.gov number, NCT00863655.)
`
`From Massachusetts General Hospital
`Cancer Center, Harvard Medical School,
`Boston (J.B.); Institut de Cancérologie de
`l’Ouest/René Gaudu cheau, Nantes Saint
`Herblain, France (M.C.); Institute Jules
`Bordet, Brussels (M.P., F.L.); Sarah Can-
`non Research Institute, Nashville (H.A.B.,
`D.Y.); University of California, San Francis-
`co, Helen Diller Family Comprehensive
`Cancer Center, San Francisco (H.S.R.);
`Novartis, East Hanover, NJ (T.S., Z.X.,
`P.M., D.L.); Osaka University, Depart-
`ment of Breast and Endocrine Surgery,
`Osaka, Japan (S.N.); the Department of
`Surgery, Comprehensive Cancer Center,
`Medical University of Vienna, Vienna
`(M.G.); Sunnybrook Odette Cancer Cen-
`tre and the University of Toronto, Toronto
`(K.I.P.); Highlands Oncology Group, Fay-
`etteville, AR (J.T.B.); Cancer Institute Hos-
`pital of Japanese Foundation for Cancer
`Research, Ariake, Tokyo (Y.I.); Oncology
`Center, AZ Nikolass, Sint-Niklaas, Bel-
`gium (I.D.); Memorial Cancer Institute,
`Hollywood, FL (A.P.); Centre Léon-Bérard,
`Lyon, France (T.B.); Novartis Pharma, Ba-
`sel, Switzerland (L.V.); and the University
`of Texas M.D. Anderson Cancer Center,
`Houston (G.N.H.). Address reprint re-
`quests to Dr. Baselga at the Division of
`Hematology/Oncology, Massachusetts
`General Hospital Cancer Center, 55 Fruit
`St., Lawrence House 108, Boston, MA
`02114, or at jbaselga@partners.org.
`
`This article (10.1056/NEJMoa1109653) was
`published on December 7, 2011, and up-
`dated on December 13, 2011, at NEJM.org.
`
`N Engl J Med 2012;366:520-9.
`Copyright © 2011 Massachusetts Medical Society.
`
`520
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0001
`
`

`
`everolimus in advanced breast cancer
`
`Endocrine therapy is the cor­
`
`nerstone of treatment for patients with
`hormone-receptor (HR)–positive advanced
`breast cancer. In postmenopausal patients, aroma-
`tase inhibitors (e.g., letrozole and anastrozole)
`have become the treatment of choice in first-line
`therapy.1­5 Unfortunately, not all patients have a
`response to first-line endocrine therapy (primary
`or de novo resistance), and even patients who have
`a response will eventually relapse (acquired resis-
`tance). On disease progression, second-line treat-
`ment options include other classes of aromatase
`inhibitors (steroidal or nonsteroidal) and the es-
`trogen-receptor (ER) antagonists fulvestrant and
`tamoxifen.6,7
`The study of resistance to endocrine therapies
`in HR-positive breast cancer has aimed at iden-
`tifying new therapeutic strategies that would en-
`hance the efficacy of endocrine therapies.8 An
`emerging mechanism of endocrine resistance is
`aberrant signaling through the phosphatidylino-
`sitol 3-kinase (PI3K)–Akt–mammalian target of
`rapamycin (mTOR) signaling pathway.9­11 Grow-
`ing evidence supports a close interaction between
`the mTOR pathway and ER signaling. A substrate
`of mTOR complex 1 (mTORC1), called S6 kinase 1,
`phosphorylates the activation function domain 1
`of the ER, which is responsible for ligand-inde-
`pendent receptor activation.12,13
`Everolimus (Afinitor, Novartis) is a sirolimus
`(formerly called rapamycin) derivative that inhib-
`its mTOR through allosteric binding to mTORC1.14
`In preclinical models, the use of everolimus in
`combination with aromatase inhibitors results in
`synergistic inhibition of the proliferation and in-
`duction of apoptosis.15 In a randomized, phase 2
`study comparing neoadjuvant everolimus plus let-
`rozole with letrozole alone in patients with newly
`diagnosed ER-positive breast cancer, the response
`rate for the combination was higher than that
`for letrozole alone.16 The Breast Cancer Trials of
`Oral Everolimus-2 (BOLERO-2) study reported here
`evaluated the efficacy and safety of the combina-
`tion of everolimus and exemestane in patients
`with HR-positive breast cancer refractory to non-
`steroidal aromatase inhibitors.
`
`Methods
`
`Roles of the Sponsor and Authors
`The study was designed by the academic investi-
`gators and by representatives of the sponsor, No-
`vartis. The data were collected with the use of the
`
`sponsor’s data-management systems and were
`analyzed by the sponsor’s statistical team. All au-
`thors vouch for the accuracy and completeness of
`the reported data and attest that the study con-
`formed to the protocol and statistical analysis plan,
`available with the full text of this article at NEJM
`.org. Contributions to the interpretation of data
`and the subsequent writing, reviewing, and amend-
`ing of the manuscript were made by all authors.
`The first draft of the manuscript was prepared by
`the first and last authors and by the trial’s lead
`physician at Novartis. No one who is not an au-
`thor contributed to writing the manuscript.
`
`Patients
`Eligible patients were postmenopausal women with
`ER-positive, human epidermal growth factor re-
`ceptor type 2 (HER2)–nonamplified advanced
`breast cancer whose disease was refractory to
`previous letrozole or anastrozole, defined as re-
`currence during or within 12 months after the end
`of adjuvant treatment or progression during or
`within 1 month after the end of treatment for ad-
`vanced disease. Letrozole or anastrozole did not
`have to be the most recent treatment before ran-
`domization, but recurrence or progression during
`receipt of the most recent systemic therapy had
`to be documented before randomization. Other
`previous anticancer endocrine treatments and a
`single prior chemotherapy regimen for advanced
`disease were also allowed.
`Patients had to have at least one measurable
`lesion or mainly lytic bone lesions in the absence
`of measurable disease. Patients also had to have
`an Eastern Cooperative Oncology Group (ECOG)
`performance status of 2 or less (on a scale from
`0 to 5, with 0 indicating that the patient is fully
`active, 1 indicating that the patient is restricted
`in physically strenuous activity but is ambulatory
`and able to carry out work of a light or sedentary
`nature, and 2 indicating that the patient is am-
`bulatory and capable of all self-care but unable to
`work) and adequate organ and hematologic func-
`tions.17 Exclusion criteria included a history of
`brain metastases and previous treatment with ex-
`emestane or mTOR inhibitors.
`Written informed consent was obtained from
`all patients before enrollment. The institutional
`review board at each participating center approved
`the study, which was conducted in accordance
`with the principles of Good Clinical Practice, the
`provisions of the Declaration of Helsinki, and
`other applicable local regulations. A steering com-
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`521
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`The New England Journal of Medicine
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`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0002
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`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`mittee supervised the conduct of the study, and
`an independent data and safety monitoring com-
`mittee performed semiannual safety reviews and
`reviewed the interim efficacy results.
`
`Study Design and Treatment
`In this international, double-blind, phase 3 study,
`patients were randomly assigned to treatment with
`oral everolimus or matching placebo (at a dose of
`10 mg daily), in conjunction with exemestane
`(25 mg daily). Randomization, at a 2:1 ratio in
`
`favor of the everolimus–exemestane group, was
`stratified according to the presence of visceral
`metastasis and previous sensitivity to endocrine
`therapy. The latter was defined as at least 24 months
`of endocrine therapy before recurrence in the ad-
`juvant setting or a response or stabilization for at
`least 24 weeks of endocrine therapy for advanced
`disease.
`The primary end point was progression-free
`survival, on the basis of radiographic studies as-
`sessed by the local investigators, with central as-
`
`Table 1. Patient and Tumor Characteristics at Baseline.*
`
`Characteristic
`
`Age (yr)
`
`Median
`
`Range
`
`Race (%)†
`
`White
`
`Black
`
`Asian
`
`Other
`
`Disease-free interval‡
`
`Median (mo)
`
`Range (mo)
`
`<12 mo (%)
`
`12–24 mo (%)
`
`>24 mo (%)
`
`No adjuvant therapy (%)
`
`Previous sensitivity to endocrine therapy (%)
`
`Visceral disease (%)
`
`Measurable disease (%)§
`
`Metastatic site (%)
`
`Lung
`
`Liver
`
`Bone
`
`No. of metastatic sites (%)
`
`1
`
`2
`
`≥3
`
`ECOG performance status (%)¶
`
`0
`
`1
`
`2
`
`Everolimus
`and Exemestane
`(N = 485)
`
`Placebo
`and Exemestane
`(N = 239)
`
`62
`
`34–93
`
`74
`
`3
`
`20
`
`3
`
`58
`
`61
`
`28–90
`
`78
`
`1
`
`19
`
`2
`
`57
`
`1–340
`
`5–316
`
`2
`
`5
`
`56
`
`31
`
`84
`
`56
`
`70
`
`29
`
`33
`
`76
`
`32
`
`31
`
`36
`
`60
`
`36
`
`2
`
`4
`
`6
`
`54
`
`31
`
`84
`
`56
`
`68
`
`33
`
`30
`
`77
`
`29
`
`34
`
`37
`
`59
`
`35
`
`3
`
`522
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0003
`
`

`
`everolimus in advanced breast cancer
`
`Table 1. (Continued.)
`
`Characteristic
`
`Purpose of most recent treatment (%)
`
`Adjuvant therapy
`
`Treatment of advanced or metastatic disease
`
`Previous treatment with letrozole or anastrozole (%)
`
`Letrozole or anastrozole as most recent treatment (%)
`
`Previous treatment with antiestrogen (%)
`
`Any antiestrogen
`
`Tamoxifen
`
`Fulvestrant
`
`Previous chemotherapy (%)
`
`Neoadjuvant or adjuvant therapy only
`
`Treatment of metastatic disease (with or without neoad-
`juvant or adjuvant therapy)
`
`No. of previous therapies (%)‖
`
`1
`
`2
`
`≥3
`
`Everolimus
`and Exemestane
`(N = 485)
`
`Placebo
`and Exemestane
`(N = 239)
`
`21
`
`79
`
`100
`
`74
`
`57
`
`47
`
`17
`
`44
`
`26
`
`16
`
`30
`
`54
`
`16
`
`84
`
`100
`
`75
`
`59
`
`49
`
`16
`
`40
`
`26
`
`18
`
`30
`
`53
`
`* There were no significant differences in baseline characteristics between the two treatment groups.
`† Race was determined by self-report.
`‡ Disease-free interval is defined as the time from diagnosis of breast cancer to first relapse in patients who received ad-
`juvant therapy (308 patients in the combination-therapy group and 153 patients in the exemestane-alone group).
`§ All other patients had at least one mainly lytic bone lesion.
`¶ Scores for Eastern Cooperative Oncology Group (ECOG) performance status range from 0 to 5, with 0 indicating that
`the patient is fully active, 1 indicating that the patient is restricted in physically strenuous activity but is ambulatory and
`able to carry out work of a light or sedentary nature, and 2 indicating that the patient is ambulatory and capable of all
`self-care but unable to work.
`‖ Previous therapies include those used in the adjuvant setting or to treat advanced disease.
`
`sessment by an independent radiology commit-
`tee used in a supportive analysis. Secondary end
`points included overall survival, overall response
`rate, clinical benefit rate, time to deterioration
`of ECOG performance status, safety, and quality
`of life, with the use of the European Organization
`for Research and Treatment of Cancer quality-of-
`life core questionnaire (QLQ-C30) and the breast
`cancer module (QLQ-BR23). Blood levels of evero-
`limus and plasma levels of exemestane were as-
`sessed 4 weeks after randomization (both before
`and 2 hours after the medications were taken) in
`a subgroup of 80 patients. Plasma levels of estra-
`diol were assessed at screening or day 1 before
`starting trial therapy and at week 4 for the same
`patients.
`Treatment continued until disease progression,
`the development of unacceptable toxicity, or with-
`
`drawal of consent. The protocol provided detailed
`guidelines for dose interruptions or reductions
`for everolimus and matched placebo for adverse
`events. In such cases, two reductions in the evero-
`limus or placebo dose were permitted: an initial
`reduction to 5 mg daily and a subsequent reduc-
`tion to 5 mg every other day.
`
`Efficacy and Safety Assessments
`Tumor assessment included computed tomograph-
`ic (CT) scanning or magnetic resonance imaging
`(MRI) of the chest, abdomen, and pelvis at base-
`line and every 6 weeks until disease progression.
`Patients who discontinued one or both study treat-
`ments for any reason other than progression were
`required to follow the same schedule of assess-
`ments until progression. All imaging studies were
`required to be sent for central radiologic review.
`
`n engl j med 366;6 nejm.org february 9, 2012
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`523
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`The New England Journal of Medicine
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`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
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` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0004
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`A bone scan or skeletal survey was required with-
`in 6 weeks before randomization. Abnormalities
`shown on bone scans were assessed by radiogra-
`phy, CT scanning with bone windows, or MRI be-
`fore randomization and were assessed using the
`same method every 6 weeks. Hematologic func-
`tion, biochemical measures, and vital signs were
`assessed at baseline and at each visit, and the lipid
`profile was assessed every 6 weeks. Adverse events
`were monitored continuously throughout the study
`and graded according to the National Cancer In-
`stitute Common Terminology Criteria for Adverse
`Events, version 3.0.18
`
`Statistical Analysis
`The primary efficacy analysis (progression-free
`survival), based on local assessment, was a log-
`rank test stratified according to visceral metasta-
`ses and previous hormone sensitivity. A total of
`528 progression-free survival events were required
`for the final analysis, in order to detect a hazard
`ratio of 0.74 with 90% power with the use of a
`log-rank test and a two-look Lan–DeMets group-
`sequential design with an O’Brien–Fleming-type
`boundary19 at a one-sided cumulative 2.5% level
`of significance. Further assuming a median pro-
`gression-free survival of 3.7 months in the con-
`trol group,6 18 months of recruitment, a 10% rate
`of loss to follow-up, and a 2:1 randomization ra-
`tio in favor of the everolimus–exemestane group,
`705 patients were to be randomly assigned. The
`study had a prespecified interim analysis after
`the observation of approximately 60% of the pro-
`gression-free survival events (the event count was
`359). At the time of the interim analysis, the data
`and safety monitoring committee was to disclose
`that the trial met its primary end point only if
`both analyses of progression-free survival (local
`and central assessments) crossed the thresholds
`of significance, as prospectively defined in the
`charter of the committee.
`
`R esults
`
`Patients
`A total of 724 women at 189 centers in 24 coun-
`tries were randomly assigned to the combination
`either of everolimus and exemestane (485 patients,
`hereafter called the combination-therapy group)
`or exemestane and placebo (239 patients, hereaf-
`ter called the exemestane-alone group), from June
`2009 through January 2011 (Fig. 1 in the Supple-
`
`mentary Appendix, available at NEJM.org). Base-
`line characteristics were well balanced. The me-
`dian age was 62 years, 56% of the patients had
`visceral involvement, and 76% had bone metasta-
`sis. Sixty-nine percent of the patients had mea-
`surable disease, and all other patients had at least
`one mainly lytic bone lesion. Thirty-six percent
`had metastases in at least three organs. Accord-
`ing to local assessment, all patients had ER-pos-
`itive tumors, and 72% had progesterone-receptor–
`positive disease. All patients had HER2-negative
`tumors (by protein or gene analysis), except 2 for
`whom the result was missing. Earlier therapies
`included letrozole or anastrozole (100%), tamox-
`ifen (48%), fulvestrant (16%), and chemotherapy
`(68%), with a median of three previous therapies.
`The most recent therapy before randomization
`was letrozole or anastrozole in 74% of the patients
`(Table 1). By the protocol definition, 84% of the
`patients had previous sensitivity to endocrine
`therapy.
`
`Treatment
`At the cutoff date (February 11, 2011), 296 pa-
`tients were still receiving study treatment: 227
`(47%) in the combination-therapy group and 69
`(29%) in the exemestane-alone group. The median
`duration of exposure to everolimus was 14.6 weeks,
`as compared with 12.0 weeks of exposure to pla-
`cebo; as for exposure to exemestane, the median
`duration was 17.4 weeks in the combination-
`therapy group versus 12.0 weeks in the exemes-
`tane-alone group. The most frequent primary rea-
`son for discontinuation was disease progression
`(37% in the combination-therapy group and 66%
`in the exemestane-alone group).
`Data from the patients in the clinical phar-
`macology component of the trial showed that
`everolimus does not affect plasma concentrations
`of endogenous estradiol, and estradiol levels were
`not different between the two treatment groups
`(data not shown).
`
`Safety
`Serious adverse events, as defined in the proto-
`col, were reported among 23% of patients in the
`combination-therapy group (11% attributed to
`study treatment) and 12% in the exemestane-alone
`group (1% attributed to study treatment). A high-
`er percentage of patients discontinued everoli-
`mus in the combination-therapy group than dis-
`continued placebo in the control group because
`
`524
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0005
`
`

`
`everolimus in advanced breast cancer
`
`Table 2. Adverse Events Irrespective of Relationship to Study Treatment (with at Least 10% Incidence
`in the Everolimus–Exemestane Group).
`
`Adverse Event
`
`Everolimus and Exemestane
`(N = 482)
`
`Placebo and Exemestane
`(N = 238)
`
`Stomatitis
`
`Rash
`
`Fatigue
`
`Diarrhea
`
`Decreased appetite
`
`Any Event
`
`Grade 3
`Event
`
`Grade 4
`Event
`
`Any Event
`
`Grade 3
`Event
`
`Grade 4
`Event
`
`56
`
`36
`
`33
`
`30
`
`29
`
`8
`
`1
`
`3
`
`2
`
`1
`
`<1
`
`percent
`
`11
`
`6
`
`26
`
`16
`
`10
`
`27
`
`0
`
`0
`
`<1
`
`<1
`
`0
`
`<1
`
`1
`
`0
`
`1
`
`1
`
`0
`
`1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Nausea
`
`Cough
`
`Dysgeusia
`
`Headache
`
`Decreased weight
`
`Dyspnea
`
`Arthralgia
`
`Anemia
`
`27
`
`22
`
`21
`
`19
`
`19
`
`18
`
`16
`
`16
`
`1
`
`<1
`
`<1
`
`1
`
`4
`
`1
`
`5
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`1
`
`11
`
`5
`
`13
`
`5
`
`9
`
`16
`
`4
`
`0
`
`0
`
`0
`
`0
`
`1
`
`0
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`<1
`
`0
`
`<1
`
`Epistaxis
`
`Vomiting
`
`Peripheral edema
`
`Pyrexia
`
`Aspartate aminotransferase level
`increased
`
`Constipation
`
`Hyperglycemia
`
`15
`
`14
`
`14
`
`14
`
`13
`
`13
`
`13
`
`0
`
`<1
`
`1
`
`<1
`
`3
`
`<1
`
`4
`
`0
`
`<1
`
`0
`
`0
`
`<1
`
`0
`
`<1
`
`1
`
`11
`
`6
`
`6
`
`6
`
`11
`
`2
`
`0
`
`<1
`
`<1
`
`<1
`
`1
`
`<1
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Pneumonitis
`
`Thrombocytopenia
`
`Asthenia
`
`Alanine aminotransferase level
`increased
`
`Pruritus
`
`Insomnia
`
`Back pain
`
`12
`
`12
`
`12
`
`11
`
`11
`
`11
`
`11
`
`3
`
`2
`
`2
`
`3
`
`<1
`
`<1
`
`0
`
`0
`
`1
`
`0
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`<1
`
`3
`
`3
`
`3
`
`8
`
`8
`
`0
`
`0
`
`2
`
`0
`
`0
`
`1
`
`<1
`
`0
`
`0
`
`0
`
`0
`
`0
`
`of adverse events (19% vs. 4%) and withdrawal of
`consent (5% vs. 2%). For exemestane discontinu-
`ation, the corresponding numbers were 7% ver-
`sus 3% and 7% versus 2%. In the combination-
`therapy group, seven deaths attributed to adverse
`events (1%) were reported during treatment or
`within 28 days after stopping treatment: two deaths
`from sepsis and one each from pneumonia, tu-
`mor hemorrhage, cerebrovascular incident, renal
`
`failure, and suicide. In the exemestane-alone group,
`one death from pneumonia (<1%) was reported
`during treatment.
`The most common grade 3 or 4 adverse events
`were stomatitis (8% in the combination-therapy
`group vs. 1% in the exemestane-alone group), ane-
`mia (6% vs. <1%), dyspnea (4% vs. 1%), hypergly-
`cemia (4% vs. <1%), fatigue (4% vs. 1%), and
`pneumonitis (3% vs. 0%) (Table 2). The time to
`
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`525
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`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0006
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`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`[CI], 0.35 to 0.54; P<0.001) (Fig. 1 and Table 3).
`The median progression-free survivals on the ba-
`sis of central assessment were 10.6 months and
`4.1 months, respectively (hazard ratio, 0.36; 95%
`CI, 0.27 to 0.47; P<0.001) (Fig. 1 and Table 3).
`Both analyses crossed the prespecified thresholds
`for significance. The Kap lan–Meier estimates be-
`yond week 36 should be interpreted with caution
`because of the small number of patients at risk
`and lack of adequate follow-up. The results for
`progression-free survival were also consistent
`across all subgroups (Fig. 2).
`Response rates, on the basis of local assess-
`ment, were 9.5% and 0.4% in the combination-
`therapy and exemestane-alone groups, respec-
`tively (P<0.001), and central assessment showed
`consistent results (Table 3). Overall survival results
`were immature at the time of the interim analy-
`sis, with a total of 83 deaths: 10.7% of patients
`in the combination-therapy group and 13.0% of
`those in the exemestane-alone group died. Patients
`and investigators continue to be unaware of study
`assignments and will remain so until survival re-
`sults are mature for analysis.
`
`Discussion
`
`The BOLERO-2 study showed that the addition of
`everolimus to exemestane significantly improves
`progression-free survival, with observed medians
`of 6.9 and 2.8 months, corresponding to a 57%
`reduction in the hazard ratio. These results were
`confirmed with the use of an independent, blinded
`radiologic assessment and were consistent across
`all subgroups. Our positive results are consistent
`with the outcomes of two other studies of evero-
`limus and antiestrogen therapy in patients with
`HR-positive breast cancer.16,20 In one study in-
`volving patients with newly diagnosed breast can-
`cer, neoadjuvant everolimus combined with let-
`rozole improved the clinical response rate and
`decreased tumor-cell proliferation as compared
`with letrozole alone.16 More recently, in a random-
`ized, phase 2 study involving 111 postmenopausal
`women with ER-positive advanced breast cancer
`previously treated with an aromatase inhibitor,
`the combination of everolimus and tamoxifen
`was associated with significantly improved pro-
`gression-free survival relative to tamoxifen alone
`(8.6 months vs. 4.5 months, P = 0.002) and with
`significantly improved overall survival (median
`not reached vs. 24.4 months, P = 0.01).20 Taken
`
`A LocalAssessment
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Hazard ratio, 0.43 (95% CI, 0.35–0.54)
`P<0.001 by log-rank test
`
`Everolimus plus exemestane
`(median PFS, 6.9 mo)
`
`Placebo plus exemestane
`(median PFS, 2.8 mo)
`
`ProbabilityofEvent(%)
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`42
`Weeks
`
`48
`
`54
`
`60
`
`66
`
`72
`
`78
`
`00
`
`30
`
`31
`
`83
`
`485
`239
`
`398
`177
`
`294
`109
`
`212
`70
`
`144
`36
`
`108
`26
`
`75
`16
`
`51
`14
`
`34
`9
`
`18
`4
`
`No.atRisk
`Everolimus
`Placebo
`
`B CentralAssessment
`100
`90
`80
`70
`60
`50
`40
`30
`20
`10
`0
`
`Hazard ratio, 0.36 (95% CI, 0.27–0.47)
`P<0.001 by log-rank test
`
`Everolimus plus exemestane
`(median PFS, 10.6 mo)
`
`Placebo plus exemestane
`(median PFS, 4.1 mo)
`
`ProbabilityofEvent(%)
`
`0
`
`6
`
`12
`
`18
`
`24
`
`30
`
`36
`42
`Weeks
`
`48
`
`54
`
`60
`
`66
`
`72
`
`78
`
`00
`
`20
`
`31
`
`93
`
`485
`239
`
`385
`168
`
`281
`94
`
`201
`55
`
`132
`33
`
`102
`20
`
`67
`11
`
`43
`11
`
`28
`6
`
`18
`3
`
`No.atRisk
`Everolimus
`Placebo
`
`Figure 1. Kaplan–Meier Plot of Progression-free Survival.
`Panel A shows progression-free survival on the basis of local assessment
`Baselga (version for DE)
`AUTHOR:
`Revised
`of radiographic studies, and Panel B shows central assessment. PFS denotes
`progression-free survival.
`1 of 2
`FIGURE:
`
`SIZE
`ARTIST:
`ts
`4 col
`deterioration of ECOG performance status and
`TYPE:
`Line
`4-C
`Combo
`H/T
`22p3
`time to deterioration of quality of life (≥5%)
`AUTHOR,PLEASENOTE:
`Figurehasbeenredrawnandtypehasbeenreset.
`were not statistically different between the two
`Pleasecheckcarefully.
`treatment groups (data not shown).
`JOB: 36606
`ISSUE:
`02-09-12
`Efficacy
`The trial met its primary end point, progression-
`free survival; the median progression-free surviv-
`al, on the basis of radiographic studies assessed
`by the local investigators, was 6.9 months for
`everolimus plus exemestane versus 2.8 months for
`placebo plus exemestane (hazard ratio for pro-
`gression or death, 0.43; 95% confidence interval
`
`526
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0007
`
`

`
`everolimus in advanced breast cancer
`
`Table 3. Efficacy Analysis on the Basis of Local and Central Assessment.*
`
`Variable
`
`Local assessment
`
`Progression-free survival
`
`Events — no. (%)
`
`Duration — mo
`
`Median
`
`95% CI
`
`Best overall response — %
`
`Complete response
`
`Partial response
`
`Stable disease
`
`Progressive disease
`
`Unknown or too early
`
`Everolimus
`and Exemestane
`(N = 485)
`
`Placebo
`and Exemestane
`(N = 239)
`
`P Value
`
`Hazard Ratio
`(95% CI)
`
`202 (42)
`
`157 (66)
`
`<0.001
`
`0.43 (0.35–0.54)
`
` 6.9
`
`6.4–8.1
`
` 2.8
`
`2.8–4.1
`
` 0.4
`
` 9.1
`
`70.1
`
` 9.9
`
`10.5
`
` 0.0
`
` 0.4
`
`58.6
`
`31.4
`
` 9.6
`
`Objective response — % (95% CI)
`
`9.5 (7.0–12.4)
`
`0.4 (0.0–2.3)
`
`<0.001
`
`Central assessment
`
`Progression-free survival
`
`Events — no. (%)
`
`Duration — mo
`
`Median
`
`95% CI
`
`Best overall response — %
`
`Complete response
`
`Partial response
`
`Stable disease
`
`Progressive disease
`
`Unknown or too early
`
`114 (24)
`
`104 (44)
`
`<0.001
`
`0.36 (0.27–0.47)
`
`10.6
`
`9.5–NR
`
` 4.1
`
`2.8–5.8
`
` 0.0
`
` 7.0
`
`74.6
`
` 5.6
`
`12.8
`
` 0.0
`
` 0.4
`
`64.4
`
`21.8
`
`13.4
`
`Objective response — % (95% CI)
`
`7.0 (4.9–9.7)
`
`0.4 (0.0–2.3)
`
`<0.001
`
`* NR denotes not reached.
`
`together, these studies suggest that everolimus
`adds to the anticancer activity of antiestrogen ther-
`apy in a variety of clinical settings and with dif-
`ferent classes of endocrine agents.
`The magnitude of the observed benefit com-
`pares favorably with that of the limited options
`available to this group of patients with HR-pos-
`itive advanced breast cancer. The ER down-regu-
`lator fulvestrant (at a standard dose of 250 mg
`monthly) was associated with activity similar to
`that of exemestane, with a median progression-
`free survival of 3.7 months.6 High-dose fulvestrant
`(500 mg monthly), as compared with standard-
`dose fulvestrant, provided only a modest improve-
`
`ment in median progression-free survival, from
`5.5 to 6.5 months (hazard ratio, 0.80; P = 0.006).
`This improvement was less clear in patients whose
`most recent therapy was an aromatase inhibitor
`(hazard ratio, 0.85; P = 0.20) and in those who
`were considered to have had a response to the
`most recent endocrine therapy (hazard ratio, 0.85;
`P = 0.12).7 Our results also compare favorably to
`those shown with capecitabine and taxanes or
`anthracyclines, with a median progression-free
`survival duration of 6.2 months and 8.2 months,
`respectively, in patients with HR-positive disease.21
`Combination therapy was associated with a
`higher incidence of adverse events than exemes-
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`527
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0008
`
`

`
`T h e ne w e ngl a nd jou r na l o f m e dicine
`
`HazardRatio(95%CI)
`
`No.
`724
`
`449
`275
`
`137
`275
`274
`38
`
`435
`274
`
`610
`114
`
`406
`318
`
`500
`224
`
`118
`217
`389
`
`532
`122
`70
`
`586
`138
`
`119
`605
`
`306
`186
`
`232
`
`523
`184
`
`Subgroup
`All patients
`Age
`<65 yr
`≥65 yr
`Region
`Asia
`Europe
`North America
`Other
`Baseline ECOG performance status
`
`0 1
`
` or 2
`Sensitivity to previous hormonal therapy
`Yes
`No
`Visceral metastasis
`Yes
`No
`Measurable disease
`Yes
`No
`No. of previous therapies
`
`1 2 ≥
`
`3
`Most recent therapy
`Aromatase inhibitor
`Antiestrogen
`Other
`Purpose of most recent therapy
`Treatment of advanced or metastatic disease
`Adjuvant therapy
`Previous treatment with fulvestrant
`Yes
`No
`Previous chemotherapy
`Yes
`Neoadjuvant or adjuvant therapy only
`Treatment of metastatic disease (with or
`without neoadjuvant or adjuvant therapy)
`
`No
`Positive status for progesterone receptor
`Yes
`No
`
`0.1
`
`0.3
`
`0.5
`
`1.0
`
`10.0
`
`EverolimusBetter
`
`PlaceboBetter
`
`Figure 2. Consistency of Results for Progression-free Survival across the Various Subgroups.
`Scores for Eastern Cooperative Oncology Group (ECOG) performance status range from 0 to 5, with 0 indicating that
`the patient is fully active, 1 indicating that the patient is restricted in physically strenuous activity but is ambulatory and
`able to carry out work of a light or sedentary nature, and 2 indicating that the patient is ambulatory and capable of all
`self-care but unable to work. The number of patients may not add up to 724 owing to missing baseline data. The size of
`each square is proportional to the number of patients in the subgroup. The data are shown on a semi-logarithmic scale.
`
`tane alone. The adverse events observed with
`everolimus plus exemestane are consistent with
`those reported with everolimus and other rapa-
`
`mycin analogues and include stomatitis, fatigue
`and asthenia, diarrhea, cough, pyrexia, and hy-
`perglycemia.22,23 In the current study, a high per-
`
`528
`
`n engl j med 366;6 nejm.org february 9, 2012
`
`The New England Journal of Medicine
`
`Downloaded from nejm.org on November 26, 2016. For personal use only. No other uses without permission.
`
` Copyright © 2012 Massachusetts Medical Society. All rights reserved.
`
`Ex. 1079-0009
`
`

`
`everolimus in advanced breast cancer
`
`centage of patients discontinued everolimus be-
`cause of a lack of tolerability. The longer treatment
`duration in the combination-therapy group might
`have contributed to the high discontinuatio