Adv Ther (2013) 30:870–884
`DOI 10.1007/s12325-013-0060-1
`
`ORIGINAL RESEARCH
`
`Everolimus Plus Exemestane in Postmenopausal
`Patients with HR+ Breast Cancer: BOLERO-2 Final
`Progression-Free Survival Analysis
`
`Denise A. Yardley • Shinzaburo Noguchi • Kathleen I. Pritchard • Howard A. Burris III • Jose´ Baselga •
`
`Michael Gnant • Gabriel N. Hortobagyi • Mario Campone • Barbara Pistilli • Martine Piccart •
`
`Bohuslav Melichar • Katarina Petrakova • Francis P. Arena • Frans Erdkamp • Wael A. Harb •
`
`Wentao Feng • Ayelet Cahana • Tetiana Taran • David Lebwohl • Hope S. Rugo
`
`To view enhanced content go to www.advancesintherapy.com
`Received: September 18, 2013 / Published online: October 25, 2013
`Ó The Author(s) 2013. This article is published with open access at Springerlink.com
`
`ABSTRACT
`
`Introduction: Effective
`for
`treatments
`hormone-receptor-positive (HR?) breast cancer
`(BC)
`following
`relapse/progression
`on
`nonsteroidal
`aromatase
`inhibitor
`(NSAI)
`therapy are needed. Initial Breast Cancer Trials
`of OraL EveROlimus-2 (BOLERO-2) trial data
`demonstrated that everolimus and exemestane
`
`Portions of the data have been presented previously:
`Piccart-Gebhart MJ, Noguchi S, Pritchard KI, Burris HA,
`Rugo HS, Gnant M, et al. Everolimus for postmenopausal
`women with advanced breast cancer: Updated results of
`the BOLERO-2 phase III trial [abstract]. Presented at the
`48th Annual Meeting of the American Society of Clinical
`Oncology; June 1–5, 2012; Chicago, IL. Abstract 559.
`
`Electronic supplementary material The online
`version of this article (doi:10.1007/s12325-013-0060-1)
`contains supplementary material, which is available to
`authorized users.
`
`D. A. Yardley (&) H. A. Burris III
`Sarah Cannon Research Institute and Tennessee
`Oncology, PLLC, Nashville, TN 37203, USA
`e-mail: dyardley@tnonc.com
`
`Enhanced content for Advances in Therapy
`articles is available on the journal web site:
`www.advancesintherapy.com
`
`123
`
`progression-free
`prolonged
`significantly
`survival (PFS) versus placebo plus exemestane
`alone in this patient population.
`Methods: BOLERO-2 is a phase 3, double-blind,
`randomized,
`international
`trial
`comparing
`everolimus
`(10 mg/day)
`plus
`exemestane
`(25 mg/day) versus placebo plus exemestane in
`postmenopausal women with HR? advanced BC
`with recurrence/progression during or after
`
`S. Noguchi
`Department of Breast and Endocrine Surgery, Osaka
`University, Suita, Osaka 565-0871, Japan
`
`K. I. Pritchard
`Sunnybrook Odette Cancer Centre and the
`University of Toronto, Toronto, ON M4N 3M5,
`Canada
`
`J. Baselga
`Memorial Sloan-Kettering Cancer Center, New York,
`NY 10065, USA
`
`M. Gnant
`Department of Surgery, Comprehensive Cancer
`Center, Medical University of Vienna, 1090 Vienna,
`Austria
`
`G. N. Hortobagyi
`The University of Texas MD Anderson Cancer
`Center, Houston, TX 77030, USA
`
`M. Campone
`Institut de Cance´rologie de l’Ouest, Rene´
`Gauducheau, Centre de Recherche en Cance´rologie,
`44805 Nantes Saint Herblain, France
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`871
`
`NSAIs. The primary endpoint was PFS by local
`investigator
`review, and was confirmed by
`independent central radiology review. Overall
`survival, response rate, and clinical benefit rate
`were secondary endpoints.
`Results: Final
`study
`results with median
`18-month follow-up show that median PFS
`remained significantly longer with everolimus
`plus
`exemestane
`versus
`placebo
`plus
`exemestane [investigator
`review: 7.8 versus
`3.2 months, respectively; hazard ratio = 0.45
`(95% confidence interval 0.38–0.54); log-rank
`P\0.0001;
`central
`review:
`11.0
`versus
`4.1 months, respectively; hazard ratio = 0.38
`(95% confidence interval 0.31–0.48); log-rank
`P\0.0001] in the overall population and in all
`prospectively defined subgroups,
`including
`patients with visceral metastases, patients with
`recurrence during or within 12 months of
`completion
`of
`adjuvant
`therapy,
`and
`irrespective of age. The incidence and severity
`of adverse events were consistent with those
`reported at the interim analysis and in other
`everolimus trials.
`Conclusion: The addition of everolimus
`to
`in
`exemestane markedly
`prolonged
`PFS
`patients with HR? advanced BC with disease
`
`recurrence/progression following prior NSAIs.
`These results
`further
`support
`the use of
`everolimus plus exemestane in this patient
`population. ClinicalTrials.gov #NCT00863655.
`
`Keywords: Advanced
`cancer;
`breast
`Everolimus; Exemestane; Hormone receptor
`positive; Nonsteroidal aromatase inhibitors;
`Oncology; Postmenopausal; Progression-free
`survival
`
`INTRODUCTION
`
`The majority of women with breast cancer (BC;
`approximately 70% worldwide) have hormone-
`receptor-positive (HR?) tumors [1]. Almost all of
`these women will receive endocrine therapy as a
`standard part of their treatment for early and/or
`advanced-stage disease [2–4]. Currently, third-
`generation nonsteroidal aromatase inhibitors
`(NSAIs:
`anastrozole
`and
`letrozole)
`and
`steroidal
`exemestane
`(EXE)
`represent
`the
`preferred
`front-line
`therapy
`for
`postmenopausal women with HR? advanced
`BC [4]. However, progressive disease ultimately
`develops in virtually all patients, either as early
`failure to respond to endocrine therapy (de
`
`B. Pistilli
`Department of Medical Oncology, Ospedale di
`Macerata, 62100 Macerata, Italy
`
`F. Erdkamp
`Department of Medical Oncology, Orbis Medical
`Center, 6162 BG Sittard-Geleen, The Netherlands
`
`M. Piccart
`Institut Jules Bordet, Universite´ Libre de Bruxelles,
`1000 Brussels, Belgium
`
`B. Melichar
`Department of Oncology, Palacky University
`Medical School and Teaching Hospital, 775 20
`Olomouc, Czech Republic
`
`K. Petrakova
`Masaryk Memorial Cancer Institute, 656 53 Brno,
`Czech Republic
`
`F. P. Arena
`NYU Langone Arena Oncology, P.C., Lake Success,
`NY 11042, USA
`
`W. A. Harb
`Horizon Oncology, Lafayette, IN 47905, USA
`W. Feng A. Cahana T. Taran D. Lebwohl
`Novartis Pharmaceuticals Corporation, East
`Hanover, NJ 07936, USA
`
`H. S. Rugo
`UCSF Helen Diller Family Comprehensive Cancer
`Center, San Francisco, CA 94115, USA
`
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`
`novo resistance) or as relapse/progression after
`initial response (acquired resistance) [5].
`A significant proportion of tumors in BC
`patients retain their sensitivity to endocrine-
`directed
`approaches
`even
`after
`disease
`progression on prior endocrine therapy, and
`may respond to another endocrine agent [6, 7].
`In view of
`the favorable safety profile of
`endocrine-directed
`agents,
`extending
`the
`benefit of
`endocrine
`therapy at
`relapse/
`progression
`is
`an
`important
`clinical
`consideration. In particular, the low toxicity of
`endocrine agents compared with chemotherapy
`represents a major advantage in a population of
`patients with a high incidence of comorbidities.
`However,
`sequential
`lines of
`single-agent
`endocrine therapy are associated with modest
`clinical benefit [6, 7]. Accordingly, combination
`endocrine therapies [8–10] and co-targeting of
`downstream elements
`of
`the molecular
`pathways associated with BC progression and
`the development of endocrine resistance [e.g.,
`histone deacetylase or mammalian target of
`rapamycin (mTOR)] have been investigated [11,
`12].
`Preclinical and clinical evidence shows that
`everolimus (EVE), a rapamycin derivative, has
`direct anticancer effects, and that mTOR
`inhibition can enhance
`the
`efficacy
`of
`endocrine therapy in breast tumors [13–15].
`The strategy of dual inhibition with endocrine
`therapy
`and
`an mTOR
`inhibitor was
`investigated in the Breast Cancer Trials of
`OraL EveROlimus-2 (BOLERO-2)
`trial
`[16].
`Data
`from the
`protocol-defined
`interim
`analysis at 7.6-month median follow-up of this
`randomized, placebo-controlled, phase 3 trial
`demonstrated that
`EVE?EXE
`significantly
`improved
`progression-free
`survival
`(PFS)
`compared with placebo (PBO) ? EXE [hazard
`ratio (HR) 0.43; P\0.001 based on local
`investigator assessment; HR 0.36; P\0.001
`
`123
`
`based on the independent central radiology
`assessment]
`[16]. This
`led to the recent
`regulatory approval in the United States and
`Europe of EVE in combination with EXE for the
`treatment of postmenopausal women with
`HR?, human epidermal growth factor receptor
`2-negative (HER2-) advanced BC recurring or
`progressing after prior NSAIs [9]. The final
`analysis of PFS, other efficacy endpoints, and
`updated safety are reported here.
`
`METHODS
`
`Details of patient selection criteria and the
`clinical protocol of
`this
`study have been
`previously reported [16].
`
`Patients
`
`Enrolled patients were adult postmenopausal
`women with HR? metastatic/locally advanced
`BC not amenable to surgery or radiotherapy and
`progressing
`after
`anastrozole or
`letrozole
`(defined as disease recurrence during or within
`12 months of end of adjuvant treatment or
`progression during or within 1 month of end of
`treatment for advanced disease). Patients whose
`tumors
`showed
`HER2
`overexpression
`3?)
`(immunohistochemistry
`or
`gene
`amplification (in situ hybridization positive) or
`who had received prior therapy with EXE or
`mTOR inhibitors were excluded.
`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 of 1975, as revised in
`2000 and 2008, and other applicable local
`regulations. A steering committee supervised
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`873
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`study conduct. An independent data and safety
`monitoring committee performed semiannual
`safety reviews and reviewed the interim efficacy
`results.
`
`Study Design
`
`BOLERO-2 was a multicenter, double-blind,
`randomized, placebo-controlled, international
`phase 3 study. Patients were randomly allocated
`in a 2:1 ratio to receive EVE 10 mg/day or
`matching PBO in a blinded manner; all patients
`received open-label EXE 25 mg/day (N = 724).
`Patients were
`stratified according to the
`presence of visceral metastasis (yes vs no) and
`sensitivity to previous hormonal therapy (yes vs
`no), as previously described [16]. The primary
`endpoint for this study was PFS as assessed by
`local
`investigator
`[based
`on
`Response
`Evaluation Criteria In Solid Tumors (RECIST)
`1.0] and confirmed by central review. Secondary
`endpoints
`included overall
`response
`rate
`(complete
`response
`or
`partial
`response);
`clinical benefit rate (CBR; defined as complete
`response ? partial response ? stable disease for
`at least 24 weeks); overall survival (OS); quality
`of life (QOL), changes in bone marker levels,
`and patient safety.
`
`Study Assessments
`
`Tumor assessments were based on computed
`tomography (CT) scans or magnetic resonance
`imaging (MRI) of the chest, abdomen, and
`pelvis at baseline and every 6 weeks until
`disease progression. Patients who discontinued
`one or both study treatments for any reason
`other than progression were followed with the
`same assessment schedule until progression. A
`bone scan or skeletal survey using radiography,
`CT scanning, or MRI was required within
`6 weeks before randomization. Abnormalities
`
`observed on bone scans were assessed using
`the
`same method every 6 weeks. After
`discontinuation of
`treatment, patients who
`progressed were followed every 3 months for
`survival.
`biochemical
`parameters,
`Hematologic
`measures, and vital signs were assessed at
`baseline and at each visit, and the lipid profile
`was assessed every 6 weeks. Adverse events (AEs)
`were monitored continuously throughout the
`study and graded according to Common
`Terminology Criteria
`for Adverse Events,
`version 3.0 [17].
`
`Statistical Analysis
`
`The primary efficacy analysis of PFS by local
`investigator assessment required 528 PFS events
`to achieve 90% power to detect an HR of 0.74
`(26% risk reduction) using a log-rank test and
`2-look Lan-DeMets group [18] sequential design
`with O’Brien–Fleming-type boundary at a one-
`sided cumulative 2.5% significance level; one
`interim analysis was conducted after observing
`60% of events (previously reported) [16]. Based
`on the magnitude and stability of the EVE
`treatment effect over time, as well as lower-
`than-expected event rates, final analysis after
`slightly fewer events than planned (i.e., 510
`events) was considered appropriate.
`
`RESULTS
`
`A total of 724 patients were randomized
`between June 2009 and January 2011 to
`(n = 485) or
`receive
`EVE?EXE
`PBO?EXE
`(n = 239). Baseline characteristics were similar
`between treatment groups (Table 1) [16]. At
`baseline, 77% of patients had bone lesions
`(21% had bone-only lesions), and of
`the
`approximately 59% with visceral disease, 84%
`had
`involvement
`at
`2
`or more
`sites.
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`
`Table 1 Patient demographic,
`treatment characteristics
`
`baseline disease,
`
`and
`
`Table 1 continued
`
`Characteristic
`
`Characteristic
`
`Median age, years
`(range)
`
`EVE1EXE
`(n 5 485), %
`
`PBO1EXE
`(n 5 239), %
`
`62 (34–93)
`
`61 (28–90)
`
`78
`
`19
`
`1
`
`2
`
`59
`
`59
`
`68
`
`33
`
`30
`
`77
`
`16
`
`84
`
`75
`
`50
`
`16
`
`65
`
`26
`
`69
`
`47
`
`Race
`
`White
`
`Asian
`
`Black
`
`Other
`
`ECOG performance
`status 0
`
`Visceral disease
`Measurable diseasea
`
`Metastatic site
`
`Lung
`
`Liver
`
`Bone
`
`Prior therapy
`
`74
`
`20
`
`3
`
`3
`
`60
`
`58
`
`70
`
`30
`
`33
`
`77
`
`Setting of most recent treatment
`
`Adjuvant
`
`Advanced/
`metastatic disease
`
`LET or ANA as most
`recent treatment
`
`Tamoxifen
`
`Fulvestrant
`
`Chemotherapy (any
`setting)
`
`Chemotherapy for
`metastatic BC
`
`21
`
`79
`
`74
`
`47
`
`17
`
`69
`
`26
`
`70
`Radiotherapy
`Number of prior therapiesb
`
`1 or 2
`
`46
`
`123
`
`EVE1EXE
`(n 5 485), %
`
`PBO1EXE
`(n 5 239), %
`
`C3
`54
`53
`From Baselga et al. [16]. Copyright Ó 2012 Massachusetts
`Medical
`Society. Reprinted with permission from
`Massachusetts Medical Society. Any minor differences
`between this table and the original report by Baselga et al.
`[16] are a consequence of the investigator’s data correction
`at the subsequent analysis
`ANA anastrozole, BC breast cancer, ECOG Eastern
`Cooperative Oncology Group, EVE everolimus, EXE
`exemestane, LET letrozole, PBO placebo
`a All other patients had C1 mainly lytic bone lesion
`b Prior therapies include those used in the adjuvant setting
`or to treat advanced disease
`
`Approximately 48% of patients had been
`previously treated with tamoxifen (TAM), and
`approximately 17% had previously received
`fulvestrant
`(both in addition to the NSAI
`required per inclusion criteria). Approximately
`80% of patients received prior therapy for
`metastatic disease,
`including chemotherapy
`(26%), whereas 20% of patients received study
`treatment as their first therapy for metastatic
`disease.
`At the cutoff date for the final PFS analysis,
`December 15, 2011, 510 PFS events had accrued
`based on local assessment and 320 per central
`radiology review. The median duration of
`follow-up at data cutoff was 17.7 months
`(range 10.9–28.6 months). Eighty-one patients
`(16.7%) in the EVE?EXE arm and 10 patients
`(4.2%)
`in the PBO?EXE arm continued to
`receive study treatment.
`In the EVE?EXE arm, median duration of
`exposure
`to EVE was 23.9 weeks
`(range
`1.0–123.3 weeks) and median exposure to EXE
`was 29.5 weeks (range 1.0–123.3 weeks). In the
`PBO?EXE arm, median exposure to EXE was
`1.0–101.0 weeks).
`14.07 weeks
`(range
`The
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`
`median relative dose intensities for EVE and
`EXE were 86% and 100%, respectively, in the
`EVE?EXE arm. The median relative dose
`intensity for EXE was 100% in the PBO?EXE
`arm. This
`represents an increase in drug
`exposure of 117.5 patient-years (60%) in the
`EVE?EXE arm and 23.7 patient-years (32%) in
`the PBO?EXE arm compared with the protocol-
`specified interim analysis [16].
`treatment
`for
`The
`main
`reason
`discontinuation in both study arms was
`disease progression (61.9% for EVE?EXE vs
`88.7% for PBO?EXE). Among the patients
`who
`discontinued
`from treatment,
`the
`proportion receiving new anticancer therapy
`was numerically smaller in the EVE?EXE arm
`compared with PBO?EXE
`(81% in the
`EVE?EXE arm vs 91% in the PBO?EXE arm).
`The most
`common post-study
`systemic
`treatments in the EVE?EXE and PBO?EXE
`arms included cytotoxic chemotherapy (42%
`and 59% of patients,
`respectively),
`and
`hormonal therapy (35% and 40% of patients,
`respectively).
`
`Efficacy
`
`The addition of EVE to EXE significantly
`prolonged median PFS versus EXE alone per
`assessment by local
`investigators
`[7.8 vs
`3.2 months,
`respectively;
`HR 0.45
`(95%
`confidence interval (CI) 0.38–0.54);
`log-rank
`P\0.0001]
`(Fig. 1a). Analysis
`by
`central
`assessment
`confirmed
`the
`PFS
`benefit
`[11.0 months for EVE?EXE vs 4.1 months for
`PBO?EXE; HR 0.38 (95% CI 0.31–0.48); log-
`rank P\0.0001]
`(Fig. 1b). The
`effect of
`EVE?EXE
`treatment
`(assessed
`by
`local
`investigators) was consistent across patient
`subgroups defined by patient characteristics
`and prior
`therapy, with an estimated HR
`ranging between 0.25 and 0.62 (Fig. 2a).
`
`These analyses were concordant with similar
`subgroup analyses from data based on central
`review (Fig. 2b).
`In particular,
`EVE?EXE
`treatment substantially extended PFS benefits
`compared with PBO?EXE regardless of baseline
`disease or prior therapy characteristics (e.g.,
`only
`prior
`adjuvant
`therapy,
`prior
`chemotherapy,
`and
`presence
`of
`visceral
`metastases or bone lesions).
`At the time of analysis, fewer deaths were
`reported with EVE?EXE
`(25.4%)
`versus
`PBO?EXE (32.2%; Table 2). A final analysis of
`OS is planned after 398 events. Improvements
`were also observed with EVE?EXE versus
`PBO?EXE
`in overall
`response,
`objective
`response rate, and CBR according to both local
`and central assessments (Table 3).
`
`Safety
`
`The most commonly reported AEs (affecting
`[25% of patients)
`in the EVE?EXE arm
`included stomatitis,
`rash,
`fatigue, diarrhea,
`nausea, decreased appetite, weight loss, and
`cough, versus nausea and fatigue in the
`PBO?EXE arm. The maximum grade of
`toxicity was 1/2 for approximately half the
`patients
`in the EVE?EXE arm. The most
`common grade 3/4 AEs with EVE?EXE
`included
`stomatitis,
`fatigue,
`dyspnea,
`anemia,
`hyperglycemia,
`and
`gamma-
`glutamyltransferase increase (Table 4). Gamma-
`glutamyltransferase increase was
`the most
`common grade 3/4 toxicity with PBO?EXE.
`Despite the increased toxicity observed with
`EVE?EXE versus PBO?EXE, health-related QOL
`was not worse with EVE?EXE [19].
`In the EVE?EXE arm, 66.8% of patients
`required dose interruptions or reductions for
`EVE and 23.9% of patients
`required dose
`interruptions or reductions for EXE. In the
`PBO?EXE arm, 11.8% of patients required
`
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`Fig. 1 Kaplan–Meier estimates of progression-free survival
`of patients treated with everolimus plus exemestane versus
`a
`exemestane
`alone based on assessment by
`local
`
`investigator or b central review. CI confidence interval,
`HR hazard ratio, EVE everolimus, EXE exemestane, PBO
`placebo
`
`dose modifications for EXE. The most common
`reasons for dose modification in both study
`arms were AEs (62.4% for EVE in the EVE?EXE
`arm vs 5.5% for EXE in the PBO?EXE arm).
`Stomatitis (23.7%), pneumonitis (7.5%), and
`thrombocytopenia
`(5.4%) were
`the most
`common AEs leading to dose modifications in
`the EVE?EXE arm (versus no single AE as a
`predominant cause in the PBO?EXE arm).
`Overall, the safety profile of EVE?EXE was
`consistent with that reported at the interim
`analysis [16].
`
`Adverse events leading to discontinuation of
`at least 1 study drug were reported in 26.3% of
`patients in the EVE?EXE arm versus 5% of
`patients in the PBO?EXE arm. Rates of AEs
`leading to discontinuation that were suspected
`to be related to at least 1 study drug were 21.4%
`(EVE?EXE) versus 3.4% (PBO?EXE). The 2 most
`common
`AEs
`leading
`to
`treatment
`discontinuation in the EVE?EXE arm were
`pneumonitis (5.6%) and stomatitis (2.7%). The
`most
`common AEs
`leading to treatment
`discontinuation in the PBO?EXE arm were
`
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`b
`
`Fig. 2 Subgroup analysis of progression-free survival by
`a local investigator review and b central review. ECOG
`Eastern Cooperative Oncology Group, EVE everolimus,
`EXE exemestane, HR hazard ratio, NSAI nonsteroidal
`aromatase inhibitor, PBO placebo, PFS progression-free
`survival, PgR progesterone receptor
`
`[increased gamma-
`laboratory abnormalities
`glutamyltransferase
`(1.7%)
`and
`increased
`aspartate
`aminotransferase
`(1.3%)]. Higher
`incidences of AEs, dose modifications, and
`treatment discontinuation among EVE-treated
`patients may, in part, be attributed to the longer
`
`treatment duration in the EVE?EXE arm.
`Details on dose modifications will be discussed
`in another manuscript.
`The incidence of death because of AEs was
`1.4% among patients receiving EVE?EXE versus
`0.4% among patients receiving PBO?EXE. In
`the EVE?EXE arm, one death each was
`attributed
`to
`pneumonia,
`sepsis,
`staphylococcal
`sepsis,
`tumor hemorrhage,
`ischemic stroke, suicide, and renal failure. In
`the PBO?EXE arm, one death was attributed to
`pneumonia.
`
`Table 2 Between-arm differences in overall survival over time
`
`PFS interim
`(7-month follow-up)
`
`PFS update
`(12-month follow-up)
`
`PFS final
`(18-month follow-up)
`
`Cutoff date
`
`OS events, n
`
`Feb 11, 2011
`
`83
`
`EVE vs PBO, % of events
`
`10.6 vs 13.0
`
`D OS events, % of events
`
`2.4
`
`Jul 8, 2011
`
`137
`
`17.3 vs 22.7
`
`5.4
`
`Dec 15, 2011
`
`200
`
`25.4 vs 32.2
`
`6.8
`
`EVE everolimus, OS overall survival, PBO placebo, PFS progression-free survival, D change
`
`Table 3 Summary of tumor response
`
`Response
`
`Local assessment
`
`Central assessment
`
`EVE1EXE
`(n 5 485)
`
`PBO1EXE
`(n 5 239)
`
`EVE1EXE
`(n 5 485)
`
`PBO1EXE
`(n 5 239)
`
`Best overall response (%)
`
`Complete response (CR)
`
`Partial response (PR)
`
`Stable disease (SD)
`
`Progressive disease
`
`Unknown
`
`ORR (CR or PR), %
`
`95% CI for ORR
`
`0.6
`
`12.0
`
`71.3
`
`10.1
`
`6.0
`
`12.6*
`
`9.8–15.9
`
`CBR (CR?PR?SD C 24 weeks), %
`
`51.3*
`
`0
`
`1.7
`
`59.0
`
`32.6
`
`6.7
`
`1.7
`
`0.5–4.2
`
`26.4
`
`95% CI for CBR
`
`46.8–55.9
`
`20.9–32.4
`
`0
`
`12.6
`
`73.4
`
`5.8
`
`8.2
`
`12.6
`
`0
`
`2.1
`
`62.8
`
`23.4
`
`11.7
`
`2.1
`
`9.8–15.9
`
`49.9
`
`45.4–54.4
`
`0.7–4.8
`
`22.2
`
`17.1–28.0
`
`CI confidence interval, CBR clinical benefit rate, EVE everolimus, EXE exemestane, ORR objective response rate, PBO
`placebo
`* Statistically significant difference, P\0.0001
`
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`
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`
`Table 4 Most common adverse events (reported in C10% of patients)
`
`AE (preferred term)
`
`EVE1EXE (n 5 482), %
`
`PBO1EXE (n 5 238), %
`
`Stomatitis
`
`Rash
`
`Fatigue
`
`Diarrhea
`
`Nausea
`
`Decreased appetite
`
`Grade
`
`All
`
`59
`
`39
`
`37
`
`34
`
`31
`
`31
`
`1
`
`29
`
`29
`
`18
`
`26
`
`21
`
`19
`
`2
`
`22
`
`9
`
`14
`
`6
`
`9
`
`10
`
`3
`
`8
`
`1
`
`4
`
`2
`\1
`1
`
`4
`
`0
`
`0
`\1
`\1
`\1
`0
`
`3
`\1
`0
`
`Grade
`
`All
`
`12
`
`7
`
`27
`
`19
`
`29
`
`13
`
`1
`
`9
`
`5
`
`16
`
`14
`
`21
`
`8
`
`3
`
`2
`
`2
`
`2
`
`10
`
`4
`
`7
`
`4
`
`5
`
`879
`
`4
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`Weight decreased
`
`Cough
`
`Dysgeusia
`
`Dyspnea
`
`Headache
`
`Arthralgia
`
`Peripheral edema
`
`Anemia
`
`Epistaxis
`
`28
`
`26
`
`22
`
`22
`
`23
`
`21
`
`21
`
`21
`
`17
`
`10
`
`21
`
`18
`
`10
`
`17
`
`15
`
`14
`
`4
`
`16
`
`16
`
`4
`
`4
`
`6
`
`6
`
`5
`
`6
`
`10
`
`2
`
`0
`
`0
`
`0
`\1
`0
`
`0
`
`1
`\1
`0
`
`5
`\1
`\1
`1
`
`7
`
`7
`
`12
`
`6
`
`11
`
`15
`
`17
`
`6
`
`5
`
`1
`
`1
`\1
`1
`\1
`0
`
`0
`
`0
`
`0
`\1
`0
`
`0
`
`0
`\1
`0
`
`0
`
`3
`
`0
`
`2
`
`2
`
`5
`\1
`2
`
`0
`
`8
`
`6
`
`8
`
`13
`
`11
`
`5
`
`2
`
`1
`
`9
`
`Vomiting
`
`Pyrexia
`
`Pneumonitis
`
`Constipation
`
`Back pain
`
`Pruritus
`
`Insomnia
`
`Asthenia
`
`AST increased
`
`17
`
`16
`
`16
`
`15
`
`15
`
`13
`
`14
`
`14
`
`14
`
`11
`
`13
`
`7
`
`11
`
`10
`
`11
`
`10
`
`7
`
`6
`
`0
`\1
`\1
`3
`\1
`\1
`\1
`\1
`2
`
`3
`
`6
`
`3
`
`6
`
`2
`
`5
`
`2
`
`4
`
`5
`
`5
`
`0
`\1
`0
`\1
`\1
`\1
`0
`\1
`\1
`0
`\1
`2
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`\1
`0
`\1
`0
`
`0
`
`0
`
`0
`
`0
`
`13
`
`7
`
`0
`
`13
`
`11
`
`5
`
`8
`
`4
`
`5
`
`2
`
`3
`\1
`0
`
`5
`
`3
`
`2
`
`5
`
`0
`
`8
`
`5
`
`3
`
`6
`
`3
`
`Hyperglycemia
`
`ALT increased
`
`Dry mouth
`
`Alopecia
`
`Nasopharyngitis
`
`Pain in extremity
`
`Urinary tract infection
`
`GGT increase
`
`14
`
`12
`
`11
`
`10
`
`10
`
`10
`
`10
`
`10
`
`4
`
`5
`
`10
`
`9
`
`9
`
`6
`
`3
`
`2
`
`5
`
`4
`
`1
`
`1
`
`1
`
`3
`
`7
`
`2
`
`5
`
`3
`
`0
`
`0
`
`0
`\1
`\1
`5
`
`0
`\1
`\1
`\1
`\1
`0
`
`0
`
`0
`
`0
`
`0
`
`2
`
`3
`\1
`2
`\1
`2
`\1
`0
`
`2
`
`5
`
`2
`\1
`
`0
`\1
`1
`\1
`2
`
`0
`
`0
`
`0
`
`2
`
`0
`
`5
`
`2
`\1
`\1
`7
`
`5
`
`7
`
`5
`\1
`\1
`
`5
`
`7
`
`5
`
`9
`
`12
`
`2
`
`9
`
`0
`
`0
`
`0
`
`0
`
`0
`
`0
`
`2
`
`AE adverse event, ALT alanine aminotransferase, AST aspartate aminotransferase, EVE everolimus, EXE exemestane, GGT
`gamma-glutamyltransferase, PBO placebo
`
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`880
`
`DISCUSSION
`
`The current protocol-defined final analysis of
`PFS from BOLERO-2 confirms the benefits of
`EVE?EXE on PFS, the primary endpoint of the
`trial, first reported at the interim analysis [16].
`At 18-month median follow-up, EVE?EXE more
`than doubled median PFS (as assessed by the
`local investigator) versus PBO?EXE (an absolute
`in median PFS [4 months)
`difference
`in
`patients with HR?, HER2- advanced BC
`recurring/progressing on/after
`initial NSAI
`therapy. Moreover, subgroup analyses indicate
`that EVE?EXE is an effective therapeutic option
`in all patients,
`regardless of
`age, prior
`chemotherapy in the advanced setting, visceral
`disease, skeletal involvement, or setting of last
`prior therapy [adjuvant/neoadjuvant (i.e., those
`who recurred during or within 12 months of
`completion of adjuvant treatment and received
`study therapy as first-line
`treatment
`for
`metastatic disease) or therapy for advanced/
`metastatic disease]. No limitations of procedure
`or protocol were observed during the conduct of
`this study.
`The central role of the mTOR pathway in BC
`progression and integrating proliferative signals
`provides a strong molecular
`rationale for
`combining endocrine therapy with mTOR
`inhibition. The results of the BOLERO-2 study
`are
`remarkably similar
`to those of
`the
`randomized phase 2 Tamoxifen Plus RAD-001
`(TAMRAD)
`trial
`that compared EVE?TAM
`versus TAM alone
`in a population of
`metastatic BC patients who had progressed
`after prior aromatase inhibitor (AI) therapy
`[13].
`In the TAMRAD study, EVE?TAM
`prolonged median PFS to 8.6 months (versus
`4.5 months with
`TAM; HR 0.54),
`and
`demonstrated survival benefit (HR 0.45) [13].
`Enhanced response in the neoadjuvant setting
`has also been reported with the combination of
`
`123
`
`Adv Ther (2013) 30:870–884
`
`EVE with NSAI letrozole versus letrozole alone
`[14].
`for HR?
`treatment goal
`The principal
`In this
`advanced BC is disease
`control.
`context,
`the benefit of prolonging PFS is
`clinically relevant provided patient QOL is
`maintained.
`Analysis
`of
`patient-reported
`outcomes from BOLERO-2 demonstrated that,
`despite the higher
`incidence of AEs with
`EVE?EXE
`versus
`EXE
`alone, QOL was
`maintained [20]. These rates are slightly higher
`than the rates reported at the interim analysis
`[16], presumably because of
`increased drug
`exposure with longer follow-up. This suggests
`that the significantly improved clinical efficacy
`outcomes achieved by adding EVE to EXE may
`have outweighed the impact of toxicity [20].
`Current guidelines recommend sequential
`administration of another line of endocrine
`therapy at relapse/progression after previous
`endocrine therapy, whereas chemotherapy is
`recommended for patients
`requiring rapid
`symptom control or who have exhausted three
`prior
`lines of endocrine treatment
`[2, 4].
`Although endocrine therapy has a favorable
`toxicity profile, second- or third-line endocrine-
`directed approach has so far demonstrated
`modest efficacy, with CBR ranging from 25%
`to
`35% [6,
`8]. Randomized
`controlled
`comparisons of experimental single [6, 7] or
`combination endocrine agents [8, 10] showed
`minimal to no improvement in median PFS or
`time to progression versus EXE (3.7 months
`post-NSAI) [6] or fulvestrant (from 4.4 months
`post-NSAI to 6.5 months post-AI/antiestrogen)
`[7].
`In contrast,
`the BOLERO-2 study data
`demonstrate
`that
`EVE?EXE
`significantly
`improved median PFS by more than twofold
`versus EXE alone.
`Current guidelines also acknowledge that
`cytotoxic chemotherapy regimens
`(whether
`single agents or combinations) are generally
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`
`881
`
`effective in controlling rapidly progressing
`disease, but are associated with considerable
`toxicity [8, 21]. Moreover, the clinical benefits
`from sequential chemotherapy in patients
`previously exposed to cytotoxic agents in the
`adjuvant and/or metastatic setting may be
`limited because of treatment resistance, as well
`as the potential risk of cumulative toxicities
`such as cardiac, gastrointestinal, hematologic,
`and neurologic toxicities
`[21]. Given the
`palliative intent of treatment in the second or
`higher
`line of
`therapy and the toxicities
`associated with chemotherapy, postponing the
`initiation of cytotoxic therapy can be an
`important
`consideration for patients
`and
`physicians [22]. In this respect it is important
`to note that all patient subsets [including those
`with disease characteristics that might support
`the use of
`chemotherapy
`(e.g.,
`visceral
`metastases and/or multiple metastatic sites)] in
`the BOLERO-2 study experienced clinical
`benefit
`similar
`to
`that
`of
`the
`overall
`population treated with EVE?EXE.
`The AE profile of EVE?EXE in this analysis
`from BOLERO-2 after 18-month median follow-
`up is consistent with the established safety
`profile of EVE in other
`settings
`[23, 24].
`Notably,
`these updated analyses
`show no
`substantial risk of cumulative toxicities or new
`safety signals despite a 60% increase in
`cumulative
`treatment
`exposure
`in
`the
`EVE?EXE arm. Adverse events of clinical
`interest
`associated with
`EVE
`treatment
`included
`stomatitis,
`rash,
`noninfectious
`pneumonitis,
`infections,
`and metabolic
`abnormalities, with the majority being grade
`1/2. The majority of
`these
`events were
`effectively
`resolved using protocol-defined
`management
`strategies based on extensive
`prior
`experience
`and
`resulting
`clinical
`recommendations for the management of EVE-
`related AEs in medical oncology (e.g., renal cell
`
`[25–27]. Overall, vigilance and
`carcinoma)
`proactive monitoring for signs and symptoms
`of key AEs are key to facilitate prolonged
`treatment with EVE [26].
`
`CONCLUSION
`
`The BOLERO-2 trial is the first phase 3 study to
`demonstrate
`that dual
`blockade of
`the
`endocrine and mTOR pathways is a feasible
`and adequately tolerated strategy that provides
`significant clinical benefit. The final analysis of
`the primary endpoint from the BOLERO-2 study
`demonstrates that EVE?EXE is well tolerated
`and provides clinically meaningful PFS benefit
`versus EXE alone in the overall population of
`patients with HR? advanced BC progressing
`during/after NSAI therapy, irrespective of age,
`and among clinically relevant
`subsets of
`patients
`including those receiving first-line
`treatment for advanced disease, and patients
`with visceral involvement. Overall, these data
`support the use of combination therapy with
`EVE?EXE to substantially improve PFS without
`compromising QOL,
`thereby achieving an
`important
`goal
`in the management
`of
`advanced BC.
`
`ACKNOWLEDGMENTS
`
`Sponsorship and article processing charges for
`this study were funded by Novartis. We thank
`the patients who participated in the BOLERO-2
`trial and the investigators, study nurses, and
`clinical research associates from the individual
`trial centers who provided ongoing support.
`Financial
`support
`for medical
`editorial
`assistance
`was
`provided
`by
`Novartis
`Pharmaceuticals. We thank Jerome F Sah, PhD,
`ProEd Communications, Inc., for his medical
`editorial assistance with this manuscript. Dr.
`
`123
`
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`
`882
`
`Adv Ther (2013) 30:870–884
`
`Denise A. Yardley is the guarantor for this
`article,
`and takes
`responsibility
`for
`the
`integrity of the work as a whole.
`
`Conflict of
`
`interest. Wentao Feng is an
`employee of Novartis.
`Ayelet Cahana is an employee of Novartis.
`Tetiana Taran is an employee of Novartis.
`David Lebwohl is an employee of Novartis.
`Francis P. Arena has been a consultant/advisor
`for Novartis and has received research funding
`from Novartis.
`Jose´ Baselga has been a consultant/advisor for
`Novartis.
`Mario Campone has been a consultant/advisor
`for Novartis, has received honoraria from Nov-
`artis, and has received research funding from
`Novartis.
`Frans Erdkamp has been a consultant/advisor
`for Amgen, Roche, Novartis, and Sanofi-Aven-
`tis.
`Michael Gnant has been a consultant/advisor
`for Novartis and Herrion, has received hono-
`raria from Amgen, Pfizer, Novartis, Glaxo-
`SmithKline, Bayer, Sandoz, AstraZeneca, and
`Genomic Health, and has received research
`funding from GlaxoSmithKline, Sanofi-Aventis,
`and Roche.
`Gabriel N. Hortobagyi has been a consultant/
`advisor for Allergan, Amgen, Antigen Express,
`AstraZeneca, Galena, Genentech, Novartis,
`Rockpointe, and Taivex, and has received
`research funding from Novartis.
`Bohuslav Melichar has been a consultant/
`advisor for Roche and Novartis, has received
`honoraria from Amgen, Pfizer, GlaxoSmith-
`Kline, and has received other forms of remu-
`neration from Novartis and Roche.
`Shinzaburo Noguchi has been a consultant/
`advisor for Novartis, has rece