Articles
`
`Lancet 2008; 372: 449–56
`Published Online
`July 23, 2008
`DOI:10.1016/S0140-
`6736(08)61039-9
`See Comment page 427
`*Members listed at end of paper
`Memorial Sloan-Kettering
`Cancer Center, New York, NY,
`USA (Prof R J Motzer MD);
`Institut Gustave Roussy,
`Villejuif, France (B Escudier MD);
`Hôpital Européen Georges
`Pompidou, Paris, France
`(Prof S Oudard MD); US
`Oncology/Baylor-Sammons
`Cancer Center, Dallas, TX, USA
`(Prof T E Hutson DO); IRCCS
`San Matteo University Hospital
`Foundation, Pavia, Italy
`(C Porta MD); Azienda
`Ospedaliera, Perugia, Italy
`(S Bracarda MD); Medical School
`Hannover, Hannover, Germany
`(Prof V Grünwald MD); Cancer
`Care Alliance, Seattle, WA, USA
`(Prof J A Thompson MD); City of
`Hope National Medical Center,
`Duarte, CA, USA
`(Prof R A Figlin MD); Novartis
`Oncology, Florham Park, NJ,
`USA (N Hollaender PhD,
`G Urbanowitz BS, W J Berg MD,
`A Kay MD, D Lebwohl MD); and
`Hôpital Saint André CHU,
`Bordeaux, France
`(Prof A Ravaud MD)
`Correspondence to:
`Dr Robert J Motzer, Memorial
`Sloan-Kettering Cancer Center,
`1275 York Ave, New York,
`NY 10021, USA
`motzerr@mskcc.org
`
`Effi cacy of everolimus in advanced renal cell carcinoma:
`a double-blind, randomised, placebo-controlled phase III trial
`
`Robert J Motzer, Bernard Escudier, Stéphane Oudard, Thomas E Hutson, Camillo Porta, Sergio Bracarda, Viktor Grünwald, John A Thompson,
`Robert A Figlin, Norbert Hollaender, Gladys Urbanowitz, William J Berg, Andrea Kay, David Lebwohl, Alain Ravaud, for the RECORD-1 Study Group*
`
`Summary
`Background Everolimus (RAD001) is an orally administered inhibitor of the mammalian target of rapamycin (mTOR),
`a therapeutic target for metastatic renal cell carcinoma. We did a phase III, randomised, double-blind, placebo-controlled
`trial of everolimus in patients with metastatic renal cell carcinoma whose disease had progressed on vascular
`endothelial growth factor-targeted therapy.
`
`Methods Patients with metastatic renal cell carcinoma which had progressed on sunitinib, sorafenib, or both, were
`randomly assigned in a two to one ratio to receive everolimus 10 mg once daily (n=272) or placebo (n=138), in
`conjunction with best supportive care. Randomisation was done centrally via an interactive voice response system
`using a validated computer system, and was stratifi ed by Memorial Sloan-Kettering Cancer Center prognostic score
`and previous anticancer therapy, with a permuted block size of six. The primary endpoint was progression-free
`survival, assessed via a blinded, independent central review. The study was designed to be terminated after 290 events
`of progression. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number
`NCT00410124.
`
`Findings All randomised patients were included in effi cacy analyses. The results of the second interim analysis
`indicated a signifi cant diff erence in effi cacy between arms and the trial was thus halted early after 191 progression
`events had been observed (101 [37%] events in the everolimus group, 90 [65%] in the placebo group; hazard ratio 0·30,
`95% CI 0·22–0·40, p<0·0001; median progression-free survival 4·0 [95% CI 3·7–5·5] vs 1·9 [1·8–1·9] months).
`Stomatitis (107 [40%] patients in the everolimus group vs 11 [8%] in the placebo group), rash (66 [25%] vs six [4%]), and
`fatigue (53 [20%] vs 22 [16%]) were the most commonly reported adverse events, but were mostly mild or moderate in
`severity. Pneumonitis (any grade) was detected in 22 (8%) patients in the everolimus group, of whom eight had
`pneumonitis of grade 3 severity.
`
`Interpretation Treatment with everolimus prolongs progression-free survival relative to placebo in patients with
`metastatic renal cell carcinoma that had progressed on other targeted therapies.
`
`Funding Novartis Oncology.
`
`Introduction
`Everolimus (RAD001) is an orally administered inhibitor
`of the mammalian target of rapamycin (mTOR), a
`component of an intracellular signalling pathway that
`regulates cellular metabolism, growth, proliferation, and
`angio genesis. Everolimus, a derivative of rapamycin,
`binds to an intracellular protein, FKBP-12, forming a
`complex that inhibits the mTOR serine-threonine kinase.
`Abnormal functioning of signalling pathways
`is
`believed to contribute to the pathogenesis of many
`malignancies, and is particularly relevant to renal cancers.
`The pathogenesis of clear-cell renal cell carcinoma is
`linked to
`loss of the von Hippel-Lindau tumour
`suppressor
`gene,
`leading
`to
`accumulation
`of
`hypoxia-inducible factor 1 (HIF-1) and overexpression of
`HIF-1 target gene products, such as vascular endothelial
`growth factor (VEGF). VEGF and other factors induced
`by HIF-1 are thought to be the key drivers of tumour
`angiogenesis, permitting the growth and progression of
`renal cancers.1 Activation of mTOR also leads to increased
`expression of HIF-1,2 and several lines of evidence
`
`implicate mTOR as a valid target for treatment of renal
`cell carcinoma.3,4
`Until recently, metastatic renal cell carcinoma was
`considered a cancer with a poor outlook, with treatment
`options limited to cytokines (interferon, interleukin 2).5
`Median survival averaged 13 months.6 Two small
`molecules, sunitinib and sorafenib, which target the
`VEGF
`receptor
`(VEGF
`receptor
`tyrosine kinase
`inhibitors), temsirolimus, another mTOR inhibitor, and
`bevacizumab, a monoclonal antibody to VEGF, have
`shown clinical benefi t for patients with treatment-naive
`or cytokine-pretreated renal cell carcinoma by prolonging
`progression-free or overall survival.7–10 A systematic
`review of studies assessing targeted therapies for
`advanced renal cell carcinoma has recently been
`published.11
`Drugs targeting these pathways have produced robust
`clinical eff ects in patients with advanced renal cell
`carcinoma. However, there now exists a high unmet
`medical need for patients who have failed therapy with
`VEGF receptor tyrosine kinase inhibitors. At present, no
`
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`
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`approved therapeutic option exists for this recently
`established, pretreated population. An uncontrolled
`phase II trial of everolimus in pretreated patients showed
`a high proportion of durable disease stabilisation or
`tumour shrinkage in patients with metastatic renal cell
`carcinoma and progression of disease on cytokines.12
`Earlier studies had established a daily oral dosing
`schedule and the safety of everolimus in patients with
`various solid tumour malignancies.13–15
`In
`this
`international, multicentre, double-blind,
`randomised phase III trial, everolimus was compared
`with placebo for the treatment of metastatic renal cell
`carcinoma in patients whose disease had progressed on
`treatment with VEGF receptor tyrosine kinase inhibitors.
`
`Methods
`Patients
`This trial was done in 86 centres in Australia, Canada,
`Europe, Japan, and the USA. The study population
`consisted of adults (aged 18 years and above) with
`metastatic renal cell carcinoma that showed a clear-cell
`component, which had progressed on or within
`6 months of stopping treatment with sunitinib or
`sorafenib, or both drugs. Previous therapy with
`bevacizumab, interleukin 2, or interferon alfa was also
`permitted. Key eligibility criteria included the presence
`of measurable disease (as per the Response Evaluation
`
`554 patients screened
`
`410 patients randomly
`allocated to treatment
`December, 2006,
`to October, 2007
`
`272 patients assigned
`to everolimus
`10 mg/day
`
`138 patients assigned
`to placebo
`
`3 did not receive
`treatment
`
`2 did not receive
`treatment
`1 had no post-baseline
`safety assessment
`
`135 patients received
`treatment
`
`129 patients discontinued
`from study
`85 had disease
`progression
`26 had adverse events
`9 withdrew consent
`7 died
`2 lost to follow-up
`
`30 patients continue
`in ongoing study
`
`105 patients discontinued
`from study
`100 had disease
`progression
`3 died
`2 had adverse
`events
`
`269 patients received
`treatment
`
`140 patients continue
`in ongoing study
`
`Figure 1: Trial profi le
`
`450
`
`Criteria in Solid Tumours [RECIST]16), a Karnofsky
`performance status score of 70% or more (on a scale
`of 0 to 100, with higher scores indicating better
`performance), and adequate bone marrow, hepatic, and
`renal function. Patients were ineligible if they had
`previously
`received mTOR
`inhibitor
`therapy
`(temsirolimus), had untreated CNS metastases, or
`uncontrolled medical conditions (eg, unstable angina
`pectoris, symptomatic congestive heart failure, recent
`myocardial infarction, or diabetes).
`The protocol was approved by the institutional review
`boards of the participating institutions and the study was
`done in accordance with international standards of good
`clinical practice. All patients provided written informed
`consent.
`
`Procedures
`Patients were stratifi ed according to a Memorial
`Sloan-Kettering Cancer Center (MSKCC) prognostic
`score (favourable vs intermediate vs poor risk) and
`previous anticancer therapy (one vs two previous VEGF
`receptor tyrosine kinase inhibitors).17 Patients were
`randomly assigned in a two to one ratio to everolimus or
`placebo with the use of permuted blocks of six (four to
`everolimus, two to placebo) within each stratum.
`Patients received either continuous treatment with oral
`everolimus 10 mg once daily or placebo, both in
`conjunction with best supportive care. Study drugs
`(identical tablets of everolimus or placebo) were provided
`by the study sponsor, and were self-administered orally
`(two 5 mg tablets) daily in a fasting state or with a light
`fat-free meal. Each cycle was considered as 28 days of
`treatment; safety was assessed every 14 days for the fi rst
`three cycles and every 4 weeks thereafter.
`Doses were delayed or reduced if patients had clinically
`signifi cant haematological or other adverse events that
`were deemed to be related to everolimus, according to a
`nomogram described in the protocol. In such cases,
`doses were reduced to 5 mg once daily.
`Treatment in both groups was continued until disease
`progression, unacceptable toxicity, death, or dis continu-
`ation for any other reason. Investigators were unaware of
`the study group assignments, but disclosure was
`permitted after documented progression on the basis of
`investigator assessment. Patients who were initially
`randomised to placebo were then able to crossover to
`receive open-label everolimus. This element of the study
`design was incorporated to address both ethical and
`recruitment considerations.
`Progression-free survival, documented with RECIST
`and assessed via a blinded, independent central review,
`was the primary endpoint, defi ned as the time from
`randomisation to the fi rst documentation of disease
`progression or death (from any cause). Secondary
`endpoints included safety, objective tumour response
`rate, overall survival, disease-related symptoms, and
`quality-of-life.
`
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`Everolimus group
`(N=272)
`
`Placebo group
`(N=138)
`
`61 (27–85)
`
`60 (29–79)
`
`212 (78%)
`60 (22%)
`
`105 (76%)
`33 (24%)
`
`Age (years)
`Sex
`Male
`Female
`Karnofsky performance status
`75 (28%)
`100
`98 (36%)
`90
`70 (26%)
`80
`28 (10%)
`70
`1 (<1%)
`Missing
`MSKCC risk factors for second-line therapy*
`39 (28%)
`Favourable
`79 (29%)
`78 (57%)
`Intermediate
`153 (56%)
`21 (15%)
`Poor
`40 (15%)
`Previous treatment with VEGF receptor tyrosine kinase inhibitors
`Sunitinib only
`124 (46%)
`60 (43%)
`Sorafenib only
`77 (28%)
`42 (30%)
`Both sunitinib and sorafenib
`71 (26%)
`36 (26%)
`Other previous systemic therapy
`Interferon
`Interleukin 2
`Chemotherapy
`Bevacizumab
`Previous surgery (nephrectomy)
`Previous radiotherapy
`Common sites of metastases
`Lymph nodes
`Lung
`Bone
`Liver
`Number of disease sites†
`1
`2
`3
`≥4
`
`40 (29%)
`53 (38%)
`30 (22%)
`15 (11%)
`0
`
`72 (52%)
`33 (24%)
`22 (16%)
`14 (10%)
`131 (95%)
`38 (28%)
`
`98 (71%)
`112 (81%)
`43 (31%)
`49 (36%)
`
`14 (10%)
`35 (25%)
`41 (30%)
`45 (33%)
`
`138 (51%)
`60 (22%)
`36 (13%)
`24 (9%)
`262 (96%)
`83 (31%)
`
`203 (75%)
`199 (73%)
`100 (37%)
`94 (35%)
`
`26 (10%)
`67 (25%)
`87 (32%)
`88 (32%)
`
`All randomly assigned patients were assessable for
`effi cacy (intention-to-treat analysis). Tumour measure-
`ments (assessed by CT or MRI scans) were done at
`screening and were subsequently repeated every 8 weeks
`for
`the remainder of
`the study, as well as on
`discontinuation of study drug. Additional scans were
`done as warranted to confi rm response (no sooner than
`4 weeks and no later than 6 weeks after its initial
`observation), or whenever disease progression was
`suspected. Selection of target lesions and tumour
`assessments by the blinded central review were done
`independently of investigator evaluations.
`All patients who received at least one dose of study
`drug and had follow-up were assessed for safety. Safety
`assessments consisted of monitoring and recording of all
`adverse events, regular monitoring of haematology and
`clinical chemistry measurements (laboratory evaluations),
`regular measurement of vital signs, performance of
`physical examinations, and recording of all concomitant
`medications and therapies. Adverse events and laboratory
`abnormalities were graded according to the National
`Cancer Institute’s Common Terminology Criteria for
`Adverse Events, version 3.0.
`Health-related quality-of-life was assessed with the
`European Organization for the Research and Treat ment
`of Cancer (EORTC) QLQ-3018 and Functional Assess-
`ment
`of Cancer Therapy Kidney
`Symptom
`Index—Disease-Related Symptoms (FKSI-DRS) question-
`naires.19 These question naires were administered before
`random isation, on day one of each cycle, and on dis con-
`tinuation from the study.
`
`Statistical analysis
`The sample size was calculated on the basis of the
`primary endpoint. A clinically meaningful improvement
`was defi ned as a 33% risk reduction (hazard ratio 0·67),
`corre sponding
`to a 50% prolongation
`in median
`progression-free survival, from 3·0 months for the
`placebo arm to 4·5 months for patients receiving
`everolimus. With the two to one randomisation and
`assuming a one-sided cumulative α of 0·025, we
`calculated that a total of 290 events as per central radiology
`review were required to achieve 90% power for the
`three-look group sequential plan. With a scheduled
`recruitment period of 16 months and additional follow-up
`of 5 months, we estimated that we would need to enrol
`about 362 patients (assuming that around 10% of patients
`would be lost to follow-up) to observe the required
`number of events.
`The fi rst and second interim analyses were planned
`after observing about 30% and 60%, respectively, of the
`targeted 290 events required for the fi nal statistical
`analysis. These interim analyses allowed the study to be
`stopped on the basis of safety, or futility or effi cacy
`(second analysis only). The fi nal analysis was to be done
`when 290 progression events had been observed, if the
`stopping rule had not been met at an interim analysis.
`
`Data are median (range) or n (%). *Risk factors associated with shorter survival in
`second-line therapy were low serum haemoglobin, raised corrected serum calcium,
`and poor performance status; favourable=no risk factors, intermediate=one risk
`factor, poor=two or more risk factors.14 †As per baseline assessment for
`independent central radiology review; seven patients did not have centrally
`reviewed tumour assessments.
`
`Table 1: Patient demographics and disease characteristics
`
`After the second interim analysis, the study steering
`committee, on the recommendation of the independent
`data monitoring committee, decided to terminate the
`trial early because the pre-specifi ed effi cacy stopping
`boundary (p≤0·0057, determined according to the
`method of Lan and DeMets with O’Brien-Fleming-type
`stopping rules20,21) was crossed, the null hypothesis
`rejected, and the criteria for a positive study met. This
`second
`interim analysis was designed
`to have
`45% probability of detecting an eff ective treatment under
`protocol assumptions on the treatment eff ect. As per
`
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`Everolimus group
`(N=272)
`
`Placebo group
`(N=138)
`
`101 (37%)
`
`90 (65%)
`
`Progression-free survival
`Number of progression events
`(independent central review)
`82 (59%)
`85 (31%)
`Progression
`8 (6%)
`16 (6%)
`Death
`48 (35%)
`171 (63%)
`Censored
`Best objective response (independent central review)
`Partial response rate
`3 (1%)
`Disease stabilisation*
`171 (63%)
`Progressive disease
`53 (19%)
`Disease could not be assessed
`45 (17%)
`Overall survival
`Number of deaths
`
`0
`44 (32%)
`63 (46%)
`31 (22%)
`
`42 (15%)
`
`26 (19%)
`
`adjusting for strata defi ned by MSKCC prognostic score
`and the hazard ratio estimated by use of a stratifi ed Cox
`proportional hazards model.
`East version 3.1 was used to calculate the sample size
`and stopping boundaries; all other statistical analyses
`were done with SAS version 8.2. This trial is registered
`with ClinicalTrials.gov with the identifi er NCT00410124.
`
`Role of the funding source
`The study sponsor contributed to the design, conduct,
`data collection, and data analysis. The corresponding
`author had access to all data and takes responsibility for
`the accuracy and completeness of the data reported. The
`corresponding author had fi nal responsibility for the
`decision to submit for publication.
`
`Results
`The trial profi le is shown in fi gure 1. Baseline demographic
`and disease characteristics were much the same in the two
`groups (table 1). Details of previous treatment for renal cell
`carcinoma are shown in table 1. 193 (71%) patients in the
`everolimus group and 109 (79%) in the placebo group had
`progressed while receiving previous therapy.
`The median duration of treatment was 95 (range 12–315)
`days in the everolimus group and 57 (21–237) days in the
`placebo group. Treatment was ongoing for 140 (51%)
`patients in the everolimus group and 30 (22%) patients
`in the placebo group at the time of data cutoff for this
`analysis. The main reasons for treatment discontinuation
`included disease progression, adverse events, death, and
`withdrawal of consent (fi gure 1).
`At the time of data cutoff , progression-free survival, as
`assessed by independent central review, was signifi cantly
`prolonged in the everolimus group compared with the
`placebo group (hazard ratio 0·30, 95% CI 0·22–0·40;
`p<0·0001; table 2 and fi gure 2). Median progression-free
`survival was 4·0 (95% CI 3·7–5·5) months in the
`everolimus group and 1·9 (1·8–1·9) months for placebo.
`The probability of being progression-free at 6 months was
`26% (95% CI 14–37) for patients receiving everolimus
`compared with 2% (0–6) for patients in the placebo
`group.
`Analyses of progression-free survival using investigator
`assessments of disease status, rather than central review,
`were consistent with those of the primary effi cacy analysis
`(median progression-free survival 4·6 months, 95% CI
`3·9–5·5 in the everolimus group vs 1·8 months, 1·8–1·9;
`hazard ratio 0·31, 95% CI 0·24–0·41; p<0·0001).
`Sensitivity analyses of potential confounding factors
`(including stratifi cation factors at baseline and missing
`data or loss to follow-up) confi rmed the robustness of the
`results for the primary effi cacy analysis. Predefi ned
`subset analyses (MSKCC risk classifi cation) plus a series
`of exploratory analyses designed to investigate the
`homogeneity of the treatment eff ect across relevant
`patient subgroups (number of previous VEGF receptor
`tyrosine kinase inhibitors, age, sex, and geographic
`
`*Stable disease was defi ned as disease that remained unchanged for at least 56 days.
`
`Table 2: Summary of effi cacy measures
`
`protocol, this second interim analysis was planned after
`observing about 60% of the targeted 290 progression-free
`survival events (per central radiology); however, because
`this central assessment was not done in real time and
`the number of events needed was unknown, the cutoff
`date (Oct 15, 2007) was determined using a statistical
`prediction model based on events per the investigator.
`The actual number of centrally assessed progression-free
`survival events observed as of the cutoff date and
`included in the analysis was 191 (or 66% of the targeted
`290 events).
`Patients without tumour progression or death at the
`time of the data cutoff for the analysis or at the time of
`receiving an additional anticancer therapy were censored
`at their last date of adequate tumour evaluation.
`Progression-free and overall survival curves were
`estimated with Kaplan-Meier methodology; treatment
`arms were compared with a stratifi ed log-rank test
`
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`Time (months)
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`Everolimus
`Placebo
`
`
`2
`
`
`132
`32
`
`
`0
`
`
`272
`138
`
`
`100
`
`
`80
`
`
`60
`
`
`40
`
`
`20
`
`
`0
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`Probability (%)
`
`
`
`Number at risk
`Everolimus
`Placebo
`
`Figure 2: Kaplan-Meier estimates of progression-free survival
`
`452
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`HR
`0·30
`0·31
`
`0·35
`0·25
`0·39
`
`0·29
`0·30
`0·28
`
`0·32
`0·29
`
`0·29
`0·36
`
`0·24
`0·37
`0·10
`
`p value
`<0·0001
`<0·0001
`
`<0·0001
`<0·0001
` 0·009
`
`<0·0001
`<0·0001
`<0·0001
`
`<0·0001
`<0·0001
`
`<0·0001
` 0·002
`
`<0·0001
`<0·0001
` 0·001
`
`N
`410
`410
`
`118
`231
`61
`
`119
`184
`107
`
`259
`151
`
`317
`93
`
`130
`251
`29
`
`Central review
`Investigator review
`MSKCC risk
`Favourable
`Intermediate
`Poor
`Previous treatment
`Sorafenib only
`Sunitib only
`Both
`Age
`<65 years
`≥65 years
`Sex
`Male
`Female
`Region
`USA and Canada
`Europe
`Japan and Australia
`
`0
`
`0·2
`0·4
`0·6
`0·8
`In favour of everolimus
`
`1
`
`1·4
`1·2
`In favour of placebo
`
`Figure 3: Progression-free survival in sensitivity analyses and predefi ned subgroups (independent
`central review)
`p values for subgroup analyses based on unstratifi ed log-rank test. HR=hazard ratio.
`
`group and 20 (15%) in the placebo group required a dose
`interruption, whereas 14 (5%) in the everolimus group
`and one (<1%) in the placebo group had a dose reduction
`with no previous interruption.
`14 (5%) patients receiving everolimus therapy and
`six (4%) in the placebo group died within 28 days of their
`last dose (all causes). One patient in the everolimus
`group died
`from overwhelming candidal sepsis,
`complicated by acute respiratory failure, and which might
`have been attributable to study drug, and one patient
`receiving placebo died from myocardial infarction; all of
`the remaining deaths were attributed to the underlying
`malignancy.
`
`
`100
`
`
`80
`
`
`60
`
`
`40
`
`
`20
`
`
`0
`
`Probability (%)
`
`
`
`Number at risk
`Everolimus
`Placebo
`
`region) indicated that benefi t was maintained across
`subgroups (fi gure 3).
`Confi rmed objective tumour responses (all partial
`responses) assessed by independent central review were
`seen in three (1%) patients receiving everolimus and
`none in the placebo group. The eff ect of everolimus on
`progression-free survival is thus probably the result of
`disease stabilisation (table 2).
`At the time of the analysis, median overall survival had
`not been reached for the everolimus group and
`was 8·8 (95% CI 7·9–not available) months for the
`placebo group. There was no signifi cant diff erence
`between groups in terms of overall survival (hazard
`ratio 0·83, 95% CI 0·50–1·37; p=0·23; fi gure 4), probably
`due to confounding by crossover: of the 98 patients in the
`placebo group who progressed as per investigator
`assessment, 79 crossed over to open-label everolimus
`after disease progression. 60 of these 79 patients had
`progressed within 8 weeks of enrolment.
`No signifi cant diff erences were evident between the
`two
`treatment groups
`in
`the
`time
`to defi nitive
`deterioration of patient-reported outcomes, as determined
`by pre-established criteria for clinically meaningful
`changes (EORTC QLQ-C30: physical functioning scale
`hazard ratio 0·94, 95% CI 0·64–1·39; global health
`status/quality-of-life score 1·02, 0·70–1·50; FKSI-DRS
`risk score: 0·82, 0·57–1·18). Longitudinal mean scores
`for the FKSI-DRS and the physical functioning, global
`health status/quality-of-life, role functioning, emotional
`functioning, cognitive functioning, social functioning,
`and symptoms scales of
`the EORTC QLQ-C30
`questionnaire indicated that quality of life was sustained
`during treatment with everolimus relative to placebo,
`irrespective of the adverse eff ects that might be expected
`from the toxicities associated with an active treatment
`(data not shown).
`As anticipated, adverse events were more frequently
`reported within the everolimus treatment group than in
`the placebo group (table 3); these events were mostly
`grade 1 or 2. The most common events were stomatitis,
`rash, fatigue or asthenia, and diarrhoea. The proportion of
`grade 3 or 4 events was low for both groups. Patients
`receiving everolimus had higher rates of grade 3 or 4
`stomatitis, infections, and non-infectious pneumonitis
`than did those in the placebo group (table 3). Of the eight
`patients with grade 3 pneumonitis, six discontinued
`everolimus therapy. Four showed complete clinical
`resolution, and three improvement to grade 2 or less.
`Grade 3 or 4 lymphopenia, grade 3 hyperglycaemia, grade 3
`hypophosphataemia, and grade 3 hypercholesterolaemia
`occurred more often in patients receiving everolimus than
`in those administered placebo (table 3).
`Study drug toxicity led to treatment discontinuation
`for 28 (10%) patients receiving everolimus (with
`pneumonitis, dyspnoea, lung disorder, and fatigue the
`most common reasons) and for fi ve (4%) patients in the
`placebo group. 92 (34%) patients in the everolimus
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`10
`
`
`1
`1
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`
`12
`
`
`0
`0
`
`453
`
`
`Everolimus
`Placebo
`
`
`2
`
`
`229
`111
`
`
`0
`
`
`272
`138
`
`
`4
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`
`126
`62
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`6
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`Time (months)
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`61
`25
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`8
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`9
`9
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`Figure 4: Kaplan-Meier estimates of overall survival
`
`NOVARTIS EXHIBIT 2059
`Par v Novartis, IPR 2016-00084
`Page 5 of 8
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`

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`Articles
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`Everolimus group (N=269)
`
`Placebo group (N=135)
`
`All grades
`
`Grade 3
`
`Grade 4
`
`All grades
`
`Grade 3
`
`Grade 4
`
`Adverse event
`Stomatitis*†
`Rash
`Fatigue
`Asthenia
`Diarrhoea
`Anorexia
`Nausea
`Mucosal infl ammation
`Vomiting
`Cough
`Dry skin
`Infections*‡
`Pneumonitis§
`Dyspnoea
`Laboratory abnormality
`Anaemia
`Hypercholesterolaemia*
`Hypertriglyceridaemia
`Hyperglycaemia*
`Raised creatinine
`Lymphopenia*
`Raised alkaline phosphatase
`Hypophosphataemia*
`Leukopenia
`Raised aspartate
`aminotransferase
`Thrombocytopenia
`Raised alanine
`aminotransferase
`Hypocalcaemia
`Neutropenia
`
`107 (40%)
`66 (25%)
`53 (20%)
`48 (18%)
`46 (17%)
`44 (16%)
`41 (15%)
`39 (14%)
`32 (12%)
`32 (12%)
`29 (11%)
`27 (10%)
`22 (8%)
`22 (8%)
`
`244 (91%)
`205 (76%)
`191 (71%)
`135 (50%)
`125 (46%)
`114 (42%)
`101 (37%)
`87 (32%)
`70 (26%)
`56 (21%)
`
`55 (20%)
`48 (18%)
`
`46 (17%)
`29 (11%)
`
`9 (3%)
`2 (<1%)
`8 (3%)
`4 (1%)
`4 (1%)
`1 (<1%)
`0
`3 (1%)
`0
`0
`1 (<1%)
`6 (2%)
`8 (3%)
`4 (1%)
`
`24 (9%)
`9 (3%)
`2 (<1%)
`31 (12%)
`1 (<1%)
`38 (14%)
`2 (<1%)
`12 (4%)
`0
`1 (<1%)
`
`2 (<1%)
`1 (<1%)
`
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`3 (1%)
`0
`0
`
`1 (<1%)
`0
`0
`0
`0
`4 (1%)
`0
`0
`0
`0
`
`0
`0
`
`0
`0
`
`11 (8%)
`6 (4%)
`22 (16%)
`11 (8%)
`4 (3%)
`8 (6%)
`11 (8%)
`3 (2%)
`5 (4%)
`5 (4%)
`5 (4%)
`3 (2%)
`0
`3 (2%)
`
`103 (76%)
`43 (32%)
`41 (30%)
`31 (23%)
`44 (33%)
`39 (29%)
`40 (30%)
`9 (7%)
`11 (8%)
`9 (7%)
`
`0
`0
`1 (<1%)
`1 (<1%)
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`7 (5%)
`0
`0
`2 (1%)
`0
`7 (5%)
`2 (1%)
`0
`0
`0
`
`3 (2%)
`5 (4%)
`
`8 (6%)
`4 (3%)
`
`0
`0
`
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`0
`
`0
`0
`0
`0
`0
`0
`0
`0
`1 (<1%)
`0
`
`1 (<1%)
`0
`
`0
`0
`
`*Sum of grade 3 and 4 events signifi cantly diff erent between everolimus group and placebo group (two-sided Fisher’s
`exact test): stomatitis, p=0·03; infections, p=0·03; hypercholesterolaemia, p=0·03; hyperglycaemia, p<0·0001;
`lymphopenia, p=0·002; hypophosphataemia, p=0·01. No adaption for multiple testing was done. †Includes aphthous
`stomatitis, mouth ulceration, and stomatitis. ‡Includes all infections. §Includes interstitial lung disease, lung
`infi ltration, pneumonitis, pulmonary alveolar haemorrhage, and pulmonary toxicity.
`
`Table 3: Treatment-related adverse events of interest and those that occurred in at least 10% of patients
`in the everolimus group and laboratory abnormalities
`
`Discussion
`In this randomised, phase III study, everolimus was
`associated with a reduction in the risk of progression or
`death compared with placebo in patients with metastatic
`renal cell carcinoma whose disease had progressed after
`treatment with VEGF-targeted
`therapies. mTOR
`inhibitors such as everolimus have a distinct mechanism
`of action from the recently established standard-of-care
`VEGF pathway inhibitors such as VEGF receptor tyrosine
`kinase inhibitors (sunitinib and sorafenib) and VEGF
`ligand antibodies (bevacizumab).4 The results of our trial
`suggest that clinical resistance to VEGF inhibitors does
`not imply clinical resistance to mTOR inhibitor treatment
`with everolimus.
`
`Assessment of the primary endpoint of progression-free
`survival was determined by independent review under
`blinded conditions. The prolongation in progression-free
`survival seen here was greater than the expected
`improvement that was used to calculate the sample size
`for the study; the trial was thus halted at the second
`interim analysis. Progression-free survival is a recognised,
`credible endpoint for oncology trials,22 and prolongation
`of progression-free survival has been shown to correlate
`with improved overall survival in renal cell carcinoma.8
`While designing our trial, we had advised the study
`sponsor that all patients experiencing disease progression
`on placebo should be off ered the option of receiving
`open-label everolimus because there were no agents with
`demonstrated effi cacy available in this setting. This ethical
`requirement to switch patients receiving placebo at the
`time of disease progression to what was considered to be
`an active treatment23 meant that we were unable to
`adequately address the eff ect of everolimus on overall
`survival, since crossover would probably confound the
`detection of any treatment-related benefi t. We believe that
`the improvement in progression-free survival seen in this
`trial is an appropriate indicator of everolimus’ anti-tumour
`eff ect in metastatic renal cell carcinoma. Our rationale
`was to rely mainly on unbiased progression-free survival
`data as opposed to confounded overall survival results. In
`general, with the advent of ever more eff ective second and
`third-line therapies as cancer treatments, and the growing
`use of crossover designs, it is becoming increasingly
`diffi cult to detect improvements in overall survival in
`confi rmatory phase III studies.
`The administration of everolimus in conjunction with
`best supportive care in this trial was associated with more
`toxic eff ects than was placebo plus best supportive care.
`Stomatitis, rash, and diarrhoea occurred with a higher
`frequency among patients receiving everolimus, but were
`deemed to be severe in nine (3%) patients or fewer.
`Hyperglycaemia, hypercholesterolaemia, and hyper-
`lipidaemia were more common in the everolimus group
`than in the placebo group, probably as a result of inhibition
`of mTOR-regulated glucose and lipid metabolism.
`Non-infectious pneumonitis, a potentially serious
`adverse event associated with rapamycin and rapamycin
`derivative treatment,24 is also seen with everolimus. It
`comprises one of a number of typical radiographic
`appearances with or without signs and symptoms (pleural
`eff usion, hypoxia, cough, dyspnoea, malaise) in the
`absence of a non-drug cause. Clinical evidence of grade 3
`pneumonitis was reported for eight (3%) patients
`receiving everolimus in the current trial. A detailed
`analysis is planned of the radiological and clinical fi ndings
`associated with lung symptoms and pneumonitis. This
`will provide guidance
`for
`improved diagnosis,
`management and, if possible, prevent