IL..--l __ (_.\l-UG_INj-\l __ ,AI'_·-_nc:t~_~ _-------'II
`
`Everolimus for Advanced Pancreatic
`Neuroendocrine Tumors
`
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`.;~nd ~<jeH ()berg .. ~:'L[).) Ph,[), .. f():'~:he f{ . .:.\[)OOl in .Advanci~d Neuroendo(xine
`Tun·~o~·~;. T-hi:-d Tr~a_~ (Rl;[)~.ANT·-3) Study C;:"OUP
`
`ABSTRACT
`
`Everolimus, an oral inhibitor of mammalian target of rapamycin (mTOR), has shown
`antitumor activity in patients with advanced pancreatic neuroendocrine tumors, in two
`phase 2 studies. We evaluated the agent in a prospective, randomized, phase 3 study.
`
`We randomly assigned 410 patients who had advanced, low-grade or intermediate(cid:173)
`grade pancreatic neuroendocrine tumors with radiologic progression within the pre(cid:173)
`vious 12 months to receive everolimus, at a dose ofl0 mg once daily (207 patients),
`or placebo (203 patients), both in conjunction with best supportive care. The primary
`end point was progression-free survival in an intention-to-treat analysis. In the case
`of patients in whom radiologic progression occurred during the study, the treat(cid:173)
`ment assignments could be revealed, and patients who had been randomly assigned
`to placebo were offered open-label everolimus.
`
`The median progression-free survival was 11.0 months with everolimus as compared
`with 4.6 months with placebo (hazard ratio for disease progression or death from
`any cause with everolimus, 0.35; 95% confidence interval [CI], 0.27 to 0.45; P<O.OOl),
`representing a 65% reduction in the estimated risk of progression or death. Estimates
`of the proportion of patients who were alive and progression-free at 18 months were
`34% (95% CI, 26 to 43) with everolimus as compared with 9% (95% CI, 4 to 16) with
`placebo. Drug-related adverse events were mostly grade 1 or 2 and included stoma(cid:173)
`titis (in 64% of patients in the everolimus group vs. 17% in the placebo group), rash
`(49% vs. 10%), diarrhea (34% vs. 10%), fatigue (31% vs. 14%), and infections (23%
`vs. 6%), which were primarily upper respiratory. Grade 3 or 4 events that were more
`frequent with everolimus than with placebo included anemia (6% vs. 0%) and hyper(cid:173)
`glycemia (5% vs. 2%). The median exposure to everolimus was longer than exposure
`to placebo by a factor of 2.3 (38 weeks vs. 16 weeks).
`
`Everolimus, as compared with placebo, significantly prolonged progression-free sur(cid:173)
`vival among patients with progressive advanced pancreatic neuroendocrine tumors
`and was associated with a low rate of severe adverse events. (Funded by Novartis Oncol(cid:173)
`ogy; RADIANT-3 ClinicalTrials.gov number, NCT00510068.)
`
`From the University of Texas M.D. Ander(cid:173)
`son Cancer Center, Houston U.c.y.);
`Ohio State University Comprehensive
`Cancer Center, Columbus
`(M.H.S.);
`Graduate School of Medical Sciences, Ky(cid:173)
`ushu University, Fukuoka, Japan (T.L);
`Hopital Edouard Herriot, Hospices Civils
`de Lyon, Lyon, France (C.L.B.); Cedars(cid:173)
`Sinai Medical Center, Los Angeles
`(E.M.w.); University Hospital Gasthuis(cid:173)
`berg, Leuven, Belgium (E.V.C.); Mayo
`Clinic, Rochester, MN (T.J.H.); National
`Cancer Center Hospital, Tokyo (T.O.);
`Vall d'Hebron University Hospital, Barce(cid:173)
`lona U.c.); University Medical Center,
`Groningen, the Netherlands (E.G.E.Y.);
`University Hospital St. Orsola, Bologna,
`Italy (P.T.); Charite University Medicine,
`Berlin (M.E.P.); Novartis Oncology, Flor(cid:173)
`ham Park, NJ (S.H., T.H., J.L., D.L.); and
`University Hospital, Uppsala, Sweden
`(K.b.). Address reprint requests to Dr.
`Yao at the University of Texas M.D. An(cid:173)
`derson Cancer Center, 1515 Holcombe
`Blvd., Box 426, Houston, TX 77030, or at
`jyao@mdanderson.org.
`
`N EnglJ Med 2011;364:514-23.
`Copyright © 2011 Massachusetts Medical Society.
`
`514
`
`N ENGLJ MED 364;6 NEJM.ORG
`
`FEBRUARY 10, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org at EUROPEAN PATENT ORGANISATION on December 17. 2013. For personal use only. No other uses without permission.
`Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 1 of 10
`
`

`
`EVEROLIMUS FOR ADVANCED PANCREATIC NEUROENDOCRINE TUMORS
`
`?"y'''''':HE INCIDENCE AND PREVALENCE OF
`d '
`.
`®
`.
`® pancreatIc neuroen ocnne tumors are Ill-
`~ "ih. creasing1-3; these tumors represent approx-
`imately 1.3% of all cases of pancreatic cancer in
`incidence and 10% of cases in prevalence.1-3 Pan(cid:173)
`creatic neuroendocrine tumors are frequently
`diagnosed at a late stage, with approximately
`65% of patients presenting with unresectable or
`metastatic disease; as a result, these patients
`have a poor prognosis. The median survival time
`for patients with distant metastatic disease is
`24 months,2 and limited treatment options are
`available for this population.
`Streptozocin is the only approved therapy for
`pancreatic neuroendocrine tumors in the United
`States; however, the role of chemotherapy in ad(cid:173)
`vanced cases continues to be debated.3-12 The
`criteria that were used to determine the outcome
`measures in many earlier trials are considered
`unacceptable today, and a substantial number of
`adverse events were seen with regimens that
`showed improved response rates. 3,10,13,14 Large,
`prospective, randomized trials that use validated
`criteria are therefore required to show the value
`of promising new treatment regimens for ad(cid:173)
`vanced pancreatic neuroendocrine tumors. A re(cid:173)
`cent prospective study (reported by Raymond et al.
`elsewhere in this issue of the Journal) shows that
`sunitinib has antitumor activity.15
`Everolimus (Afinitor, Novartis Pharmaceuticals)
`has recently shown promising antitumor activity
`in two phase 2 studies involving patients with
`pancreatic neuroendocrine tumors. 3 ,16 Everolimus
`inhibits mammalian target of rapamycin (mTOR),
`a serine-threonine kinase that stimulates cell
`growth, proliferation, and angiogenesis.3,16,17 Au(cid:173)
`tocrine activation of the mTOR signaling path(cid:173)
`way, mediated through insulin-like growth fac(cid:173)
`tor 1, has been implicated in the proliferation of
`pancreatic neuroendocrine tumor cells.18 Consis(cid:173)
`tent with this observation is the finding that in(cid:173)
`hibition of mTOR has a significant antiprolifera(cid:173)
`tive effect on pancreatic neuroendocrine tumor cell
`lines.19,20
`The RADOOl in Advanced Neuroendocrine Tu(cid:173)
`mors, third trial (RADIANT-3) study was conduct(cid:173)
`ed to determine whether everolimus, at a dose of
`10 mg per day, as compared with placebo, would
`prolong progression-free survival among patients
`with advanced pancreatic neuroendocrine tumors.
`
`METHODS
`
`PATIENTS
`Patients were eligible to be included in the study
`if they were 18 years of age or older and had low(cid:173)
`grade or intermediate-grade advanced (unresect(cid:173)
`able or metastatic) pancreatic neuroendocrine tu(cid:173)
`mors and radiologic documentation of disease
`progression (an unequivocal increase in the size
`of tumors) in the 12 months preceding random(cid:173)
`ization. Prior antineoplastic therapy was not an
`exclusion criterion. Other key eligibility criteria in(cid:173)
`cluded the presence of measurable disease, as as(cid:173)
`sessed according to the Response Evaluation Cri(cid:173)
`teria in Solid Tumors (RECIST), version 1.0 (see the
`Supplementary Appendix, available with the full
`text of this article at NEJM.org)21; a World Health
`Organization (WHO) performance status of 2 or
`less (with 0 indicating that the patient is fully
`active and able to carryon all predisease activities
`without restriction; 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, such as light housework or
`office work; and 2 indicating that the patient is
`ambulatory and up and about more than 50% of
`waking hours and is capable of all self-care but
`unable to carry out any work activities)22; adequate
`bone marrow, renal, and hepatic function; and ad(cid:173)
`equately controlled lipid and glucose concentra(cid:173)
`tions. Patients were ineligible if they had under(cid:173)
`gone hepatic-artery embolization within 6 months
`before enrollment (within 1 month if there were
`other sites of measurable disease) or cryoablation
`or radiofrequency ablation of hepatic metastasis
`within 2 months before enrollment, had any se(cid:173)
`vere or uncontrolled medical conditions, had re(cid:173)
`ceived prior therapy with an mTOR inhibitor, or
`were receiving long-term treatment with gluco(cid:173)
`corticoids or other immunosuppressive agents.
`
`STUDY OVERSIGHT
`The protocol was approved by the institutional re(cid:173)
`view board or ethics committee at each participat(cid:173)
`ing center, and the study was conducted in ac(cid:173)
`cordance with Good Clinical Practice principles
`and applicable local regulations. All patients pro(cid:173)
`vided written informed consent.
`The study was designed by the academic inves(cid:173)
`tigators and by representatives of the sponsor,
`
`N ENGLJ MED 364;6 NEJM.ORG
`
`FEBRUARY 10, 2011
`
`515
`
`The New England Journal of Medicine
`Downloaded from nejm.org at EUROPEAN PATENT ORGANISATION on December 17, 2013. For personal use only. No other uses without permission.
`Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 2 of 10
`
`

`
`Novartis Oncology. The data were collected with
`the use of the sponsor's data management sys(cid:173)
`tems and were analyzed by the sponsor's statisti(cid:173)
`cal team. All the authors contributed to the in(cid:173)
`terpretation of data and the subsequent writing,
`reviewing, and amending of the manuscript; the
`first draft of the manuscript was prepared by the
`first author and by a medical writer employed by
`Novartis Oncology. The protocol, including the
`statistical analysis plan, is available at NEJM.org.
`All the authors vouch for the accuracy and com(cid:173)
`pleteness of the reported data and attest that the
`study conformed to the protocol and statistical
`analysis plan.
`
`STUDY DESIGN AND TREATMENT
`In this international, multicenter, double-blind,
`phase 3 study, patients were randomly assigned to
`treatment with oral everolimus, at a dose of 10 mg
`once daily, or matching placebo, both in conjunc(cid:173)
`tion with best supportive care. Patients were strat(cid:173)
`ified according to status with respect to prior
`chemotherapy (receipt vs. no receipt) and accord(cid:173)
`ing to WHO performance status (0 vs. 1 or 2) at
`baseline.
`Treatment continued until progression of the
`disease, development of an unacceptable toxic ef(cid:173)
`fect, drug interruption for 3 weeks or longer, or
`withdrawal of consent. The study-group assign(cid:173)
`ments were concealed from the investigators, but
`disclosure was permitted if an investigator de(cid:173)
`termined that the criteria for disease progression
`according to RECIST had been met and if there
`was an intention to switch the patient to open(cid:173)
`label therapy. Patients who had been assigned to
`placebo initially could then switch to open-label
`everolimus. This element of the study design was
`incorporated to address both ethical and recruit(cid:173)
`ment considerations, given that the trial involved
`patients with a rare disease. We recognized the
`potential influence of this aspect of the study de(cid:173)
`sign on the analysis of the end point of overall
`survival.
`Doses were delayed or reduced if patients had
`clinically significant adverse events that were con(cid:173)
`sidered to be related to the study treatment, ac(cid:173)
`cording to an algorithm described in the proto(cid:173)
`col. In such cases, two reductions in the dose of
`the study drug were permitted: an initial reduc(cid:173)
`tion to 5 mg daily and a subsequent reduction to
`5 mg every other day.
`
`EFFICACY AND SAFETY ASSESSMENTS
`The primary end point was progression-free sur(cid:173)
`vival, documented by the local investigator ac(cid:173)
`cording to RECIST and defined as the time from
`randomization to the first documentation of dis(cid:173)
`ease progression or death from any cause. If the
`disease had not progressed and the patient had
`not died as of the cutoff date for the analysis,
`data for progression-free survival were censored
`at the time of the last adequate tumor assessment
`- which was defined as the last assessment of
`overall lesion response that showed complete re(cid:173)
`sponse, partial response, or stable disease -
`be(cid:173)
`fore the cutoff date or the date of initiation of
`other anticancer therapy.23 In the primary analy(cid:173)
`sis, data for progression-free survival were cen(cid:173)
`sored at the time of the last adequate tumor as(cid:173)
`sessment if an event occurred after two or more
`missing tumor assessments. Data for patients
`without any valid post-baseline tumor assessment
`were censored on day 1 (the date of randomiza(cid:173)
`tion). Secondary end points included the confirmed
`objective response rate (according to RECIST, ver(cid:173)
`sion 1.0), the duration of response, overall surviv(cid:173)
`al, and safety.
`All randomly assigned patients were assessed
`for efficacy (intention-to-treat analysis). Tumor
`measurements (assessed by triphasic computed
`tomography or magnetic resonance imaging) were
`performed at baseline and were repeated every
`12 weeks. Scans were reviewed at the local site
`and centrally. In cases of a discrepancy between
`the local investigator's assessment and the radio(cid:173)
`logic assessment at the central location with re(cid:173)
`spect to the determination of progression-free
`survival, adjudication was performed by an inde(cid:173)
`pendent central adjudication committee compris(cid:173)
`ing a board-certified radiologist and an oncologist,
`both of whom had extensive experience with neu(cid:173)
`roendocrine tumors. The central adjudication com(cid:173)
`mittee, whose members were unaware of the pa(cid:173)
`tients' study-group assignments and of the source
`of the data (local or centra!), selected the assess(cid:173)
`ment that in their expert opinion reflected the
`more accurate evaluation.
`All patients who received at least one dose of
`the study drug and had at least one follow-up
`assessment were evaluated for safety. Safety as(cid:173)
`sessments consisted of the monitoring and record(cid:173)
`ing of all adverse events, regular monitoring of
`hematologic and clinical biochemical levels (lab-
`
`516
`
`N ENGLJ MED 364;6 NEJM.ORG
`
`FEBRUARY 10, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org at EUROPEAN PATENT ORGANISATION on December 17. 2013. For personal use only. No other uses without permission.
`Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 3 of 10
`
`

`
`EVEROLIMUS FOR ADVANCED PANCREATIC NEUROENDOCRINE TUMORS
`
`oratory evaluations) and vital signs, and physical
`examinations every 4 weeks. Adverse events were
`assessed according to the National Cancer In(cid:173)
`stitute Common Terminology Criteria for Ad(cid:173)
`verse Events, version 3.0 (http://ctep.info.nih.gov/
`protocolDevelopment/electronicapplications/docs/
`ctcaev3.pdf).
`
`Characteristic
`
`Age-yr
`
`Median
`
`Range
`
`Sex- no. (%)
`
`Male
`
`Female
`
`WHO performance status -
`o
`
`no. (%)
`
`2
`
`Histologic status of tumor -
`
`no. (%)
`
`Well differentiated
`
`Moderately differentiated
`
`Unknown
`
`Time from initial diagnosis -
`
`no. (%)
`
`,;6 mo
`
`>6 mo to ,;2 yr
`
`>2 yr to ,;5 yr
`
`Everolimus
`(N=207)
`
`Placebo
`(N=203)
`
`58
`
`23-87
`
`110 (53)
`
`97 (47)
`
`139 (67)
`
`62 (30)
`
`6 (3)
`
`170 (82)
`
`35 (17)
`
`2 (1)
`
`24 (12)
`
`65 (31)
`
`54 (26)
`
`64 (31)
`
`57
`
`20-82
`
`117 (58)
`
`86 (42)
`
`133 (66)
`
`64 (32)
`
`6 (3)
`
`171 (84)
`
`30 (15)
`
`2 (1)
`
`33 (16)
`
`43 (21)
`
`81 (40)
`
`46 (23)
`
`STATISTICAL ANALYSIS
`The estimation of the sample size was based on
`the ability to detect a clinically meaningful im(cid:173)
`provement in the primary end point, which was
`defined as a 33% reduction in the risk of disease
`progression or death (a hazard ratio for progres(cid:173)
`sion or death of 0.67), corresponding to a 50%
`prolongation in median progression-free surviv(cid:173)
`al, from 6 months with placebo to 9 months with
`everolimus. We estimated that with a total of 282
`progression-free survival events (i.e., disease pro(cid:173)
`gression or death), the study would have 92.6%
`power to detect a clinically meaningful improve(cid:173)
`ment, with the use of an unstratified log-rank test,
`at a one-sided significance level of 2.5%. Taking
`into account the estimated rate of patient accrual
`and a 10% loss of the study population to follow(cid:173)
`up, we estimated that we would have to enroll
`392 patients to observe the required number of
`events.
`Progression-free and overall survival were ana(cid:173)
`lyzed with the use of Kaplan-Meier methods; study
`groups were compared with the use of a log-rank
`test, stratified according to prior receipt or no
`prior receipt of chemotherapy and WHO perfor(cid:173)
`mance status, and the hazard ratio was estimated
`with the use of a stratified Cox proportional(cid:173)
`hazards model.
`
`RESULTS
`
`PATI ENTS AN D TREATM ENT
`Between July 2007 and May 2009, a total of 410
`patients from 82 centers in 18 countries world(cid:173)
`wide who had advanced pancreatic neuroendo(cid:173)
`crine tumors were randomly assigned to everoli(cid:173)
`mus (207 patients) or placebo (203 patients) (see
`the figure in the Supplementary Appendix). The
`baseline demographic and clinical characteristics
`of the patients were well balanced between the
`two groups (Table 1). More than 80% of the pa(cid:173)
`tients had well-differentiated disease, more than
`90% had metastases in the liver, and approxi(cid:173)
`mately 60% had received a diagnosis of pancreatic
`
`>5 yr
`
`Time from disease progression to random(cid:173)
`no. (%)
`ization -
`
`,;1 mo
`
`>1 mo to,;2 mo
`
`>2 mo to ,;3 mo
`
`>3 mo to ,;12 mo
`
`>12 mo
`
`No. of disease sites -
`
`no. of patients (%)
`
`2
`
`Organ involved -
`
`no. (%)
`
`Liver
`
`Pancreas
`
`Lymph nodes
`
`Lung
`
`Bone
`
`73 (35)
`
`43 (21)
`
`30 (14)
`
`58 (28)
`
`3 (1)
`
`51 (25)
`
`85 (41)
`
`70 (34)
`
`61 (30)
`
`53 (26)
`
`29 (14)
`
`54 (27)
`
`1 (<1)
`
`62 (31)
`
`64 (32)
`
`77 (38)
`
`190 (92)
`
`187 (92)
`
`92 (44)
`
`68 (33)
`
`28 (14)
`
`13 (6)
`
`84 (41)
`
`73 (36)
`
`30 (15)
`
`29 (14)
`
`neuroendocrine tumor more than 2 years before
`entering the study. A total of 24% of the patients
`had gastrinoma, glucagonoma, VIPoma, insulino(cid:173)
`rna, or somatostatinoma. The two groups were
`similar with respect to prior receipt of radiother-
`
`N ENGLJ MED 364;6 NEJM.ORG
`
`FEBRUARY 10, 2011
`
`517
`
`The New England Journal of Medicine
`Downloaded from nejm.org at EUROPEAN PATENT ORGANISATION on December 17. 2013. For personal use only. No other uses without permission.
`Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 4 of 10
`
`

`
`Variable
`
`Assessment by local investigator
`
`Everolimus
`(N=207)
`
`Placebo
`(N=203) Difference
`
`Hazard Ratio for Disease
`Progression or Death
`with Everolimus
`(95%CI)
`
`P Value
`
`Progression-free survival events -
`
`no. (%)i'
`
`109 (53)
`
`165 (81)
`
`Censored data -
`
`no. (%)
`
`98 (47)
`
`38 (19)
`
`Median progression-free survival- mo
`
`11.0
`
`4.6
`
`6.4
`
`0.35 (0.27-0.45)
`
`<0.001
`
`Review by central adj udication com mittee
`
`Progression-free survival events -
`
`no. (%)i'
`
`95 (46)
`
`142 (70)
`
`Censored data -
`
`no. (%)
`
`112 (54)
`
`61 (30)
`
`Median progression-free survival- mo
`
`11.4
`
`5.4
`
`6.0
`
`0.34 (0.26-0.44)
`
`<0.001
`
`i, Progression-free survival events include disease progression and death.
`
`apy (23% of patients in the everolimus group and
`20% in the placebo group), chemotherapy (50% in
`both groups), and somatostatin analogue therapy
`(49% in the everolimus group and 50% in the pla(cid:173)
`cebo group). Best supportive care included the use
`of somatostatin analogue therapy in approximate(cid:173)
`ly 40% of the patients.
`With a median follow-up period of17 months,
`the median duration of treatment with everolimus
`was 8.79 months (range, 0.25 to 27.47), as com(cid:173)
`pared with 3.74 months (range, 0.01 to 37.79) with
`placebo. A total of 31% of the patients in the
`everolimus group, as compared with 11% in the
`placebo group, were administered treatment for
`a minimum of 12 months. The mean relative
`dose intensity (the ratio of administered doses to
`planned doses) was 0.86 in the everolimus group
`and 0.97 in the placebo group. Dose adjustments
`(reductions or temporary interruptions) were re(cid:173)
`quired by 59% of the patients receiving everolimus
`and 28% of the patients receiving placebo.
`At the time the analysis was performed for this
`article, treatment was ongoing for 32% of the pa(cid:173)
`tients in the everolimus group and 13% of the
`patients in the placebo group; the primary reasons
`for discontinuation of treatment included disease
`progression (in 44% of patients in the everolimus
`group vs. 80% in the placebo group), adverse
`events (17% vs. 3%), withdrawal of consent (2% in
`both groups), and death (2% vs. 1%).
`
`EFFICACY
`The median progression-free survival (the primary
`end point), as assessed by the local investigators,
`
`was 11.0 months (95% confidence interval [CI],
`8.4 to 13.9) in the everolimus group, as compared
`with 4.6 months (95% Cl, 3.1 to 5.4) in the placebo
`group, representing a 65% reduction in the esti(cid:173)
`mated risk of progression (hazard ratio for dis(cid:173)
`ease progression or death with everolimus, 0.35;
`95% Cl, 0.27 to 0.45; P<O.OOl) (Table 2 and Fig. lA).
`The estimated proportion of patients who were
`alive and progression-free at 18 months was 34%
`(95% Cl, 26 to 43) with everolimus as compared
`with 9% (95% Cl, 4 to 16) with placebo, indicating
`that a sizable proportion of patients derived a
`prolonged benefit with everolimus.
`The findings of the independent adjudicated
`central assessment of median progression-free
`survival were consistent with those of the assess(cid:173)
`ment by local investigators. The median progres(cid:173)
`sion-free survival according to the central assess(cid:173)
`ment was 11.4 months (95% Cl, 10.8 to 14.8) with
`everolimus, as compared with 5.4 months (95% Cl,
`4.3 to 5.6) with placebo (hazard ratio for disease
`progression or death with everolimus, 0.34; 95%
`Cl, 0.26 to 0.44; P<O.OOl) (Table 2 and Fig. lB).
`Prespecified subgroup analyses indicated that
`the benefit was maintained across subgroups.
`A benefit with everolimus was evident irrespec(cid:173)
`tive of status with respect to prior chemotherapy
`(receipt or no receipt), WHO performance status,
`age, sex, race, geographic region, status with re(cid:173)
`spect to prior somatostatin analogue therapy (re(cid:173)
`ceipt or no receipt), and tumor grade (Fig. lC).
`Everolimus was associated with a superior re(cid:173)
`sponse profile, as assessed according to REClST
`(P<O.OOl with the use of a two-sided Mann-Whit-
`
`518
`
`N ENGLJ MED 364;6 NEJM.ORG
`
`FEBRUARY 10, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org at EUROPEAN PATENT ORGANISATION on December 17, 2013. For personal use only. No other uses without permission.
`Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 5 of 10
`
`

`
`u
`~ ::>
`5"
`~
`CD
`0..
`
`"cI
`
`z
`m
`Z
`Cl
`r
`
`;;:
`m
`o
`w
`'" c!':
`'"
`z
`"" ;;:
`o
`'" Cl
`
`~
`m
`
`A Progression-free Survival, Local Assessment
`
`C Progression-free Survival in Subgroups
`
`OJ
`OJ
`¢
`'= o
`'Vi "'-~~
`bJ)-
`0 -
`~ .~
`'0 i:
`>-,'"
`~V)
`J5
`
`jg e 0..
`
`100 "~i,
`I<aplan-Meier median
`\ft,...,
`Everolimus, 11.0 mo
`t
`'--"
`Everolimus
`Placebo, 4.6 mo
`·t ~-t~ Hazard ratio, 0.35 (95% CI, 0.27-0.45)
`P<O.OOl by one·sided log·rank test
`"
`"~"L'V
`/r
`.... ~ .. ~
`
`80-1
`
`60
`
`40
`
`20
`
`01
`o
`
`.~'::::,,::,::~~-:=C=--.
`
`2
`
`4
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`30
`
`Months
`
`B Progression-free Survival, Adjudicated Central Review
`
`~'"
`~~1'~
`.~
`" ~.
`
`100
`
`80
`
`60
`
`40
`
`20
`
`.
`~Everollmus
`
`Kaplan-Meier median
`Everolimus, 11.4 mo
`Placebo, 5.4 mo
`
`Hazard ratio, 0.34 (95% CI, 0.26-0.44)
`P<O.OOl by one·sided log·rank test
`..----...
`~ ... ~-c-
`
`.., .. ~
`
`••••••• -01
`
`Subgroups
`
`No.
`
`410
`410
`
`189
`221
`
`279
`131
`
`299
`111
`
`227
`183
`
`322
`74
`
`185
`156
`69
`
`Hazard Ratio (95% Cll
`
`P Value
`
`-+-
`--+-
`
`---+--
`---+--
`
`--
`-----
`
`---+--
`
`--+-
`
`- -0 -
`---+--
`
`--+-
`
`--
`
`---+--
`
`to
`<:
`to
`?:'
`0
`t:
`~
`c::
`en
`'"
`
`0
`?:'
`:to-
`t:I
`~
`Z
`()
`to
`t:I
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`0.35 (0.27-0.45)
`0.34 (0.26-0.44)
`
`0.34 (0.24-0.49)
`0.41 (0.29-0.58)
`
`0.39 (0.28-0.53)
`0.30 (0.20-0.47)
`
`0.39 (0.29-0.53)
`0.36 (0.22-0.58)
`
`0.41 (0.30-0.58)
`0.33 (0.23-0.48)
`
`0.41 (0.31-0.53)
`0.29 (0.15-0.56)
`
`0.36 (0.25-0.52)
`0.47 (0.32-0.69)
`0.29 (0.14-0.56)
`
`i:i' o
`8
`::>
`<2.
`8
`~
`;:;.
`gJ
`i:3 ;g
`n~ ,g
`'< >
`cfJ·
`t;l
`g-Z
`@>-3
`NO
`0:;0
`-0>-3
`->::0-
`~ Z CD
`"' ~ Z
`~ V1 CD
`~ > '"
`g.>-3m
`" ~::>
`~'(3..
`i'6
`"'
`~
`ti=i 0
`:::I
`~ ::>
`0..
`CD U ()
`0.. CD
`""'I
`"
`_. ("J
`::>
`CD
`('l
`e:.. 8 e:..
`V1 0- 0
`o ~ ~
`8. - ~
`Q-
`~-.J 8-
`. N - '
`> 0 8.
`~w~
`::J. ~
`0
`~~
`i!6 0
`'"
`::>
`'" "'
`CD ~
`P-~
`CD
`o
`::>
`0"
`~
`o
`5'(cid:173)
`~
`E;;
`~
`
`'"
`CD
`
`CD
`'"
`
`(JQ
`
`'0
`
`'" §:
`~
`i·
`
`o·
`P
`
`'" '" c
`" '" -<
`
`_0
`N
`
`S
`
`VI
`I-'
`'D
`
`Local investigator review
`Central adjudicated review
`Previous chemotherapy
`Yes
`No
`WHO performance status
`0
`1 or 2
`Age
`,,65 yr
`>65 yr
`Sex
`Male
`Female
`Race
`White
`Asian
`Region
`America
`Europe
`Asia
`Previous long·acting SSA
`Yes
`No
`Tumor grade
`Well differentiated
`Moderately d ifferenti ated
`
`26
`
`28
`
`30
`
`32
`
`OJ
`OJ
`¢
`'= o
`'Vi "'-~~
`bJ)-
`~ '"
`0 -
`c.. .~
`'0 i:
`>-,'"
`.~ V)
`J5
`jg
`e
`
`0..
`
`o 1
`o
`
`•• " .... ,<";"
`'.
`A~_.
`Placebo
`..... ~"".
`~
`··w .. ······, .. 'l".~ •••••• ?-/ ___ i
`;s-., Censoring times
`I ••••• ~?------------------------,
`:
`24
`
`2
`
`4
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`D Overall Survival
`
`Months
`
`100
`
`80
`
`60
`
`40
`
`20
`
`OJ
`
`'i!
`O~
`tooc;
`<= 'i!
`:0 ::::s
`"'VI
`.n e 0..
`
`>-,>
`
`'~-=x,..."
`
`r-._,.-.-;.~_.
`
`, ~~ ~V4.
`I<aplan-I~eier meAdian
`. 8'~~«>('.w""" ... ~~.~~:~.~,
`Evero Imus, N
`~[;!I6I ~[;!I6I li!l61
`Placebo, NA
`Everolimus
`
`'Z
`
`Hazard ratio, 1.05 (95% CI, 0.71-1.55)
`P~0.59 by one·sided log·rank test
`
`x"( Censoring times
`
`01
`o
`
`2
`
`4
`
`8
`
`10
`
`12
`
`14
`
`16
`
`18
`
`20
`
`22
`
`24
`
`26
`
`28
`
`30
`
`32
`
`Months
`
`<0.001
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`<0.001
`<0.001
`
`203
`207
`
`341
`65
`
`---+--
`---+--
`
`--+-
`
`0.40 (0.28-0.57)
`0.36 (0.25-0.51)
`
`0.41 (0.31-0.53)
`0.21 0.11-0.42)
`
`0.1
`•
`Everolimus Better
`
`1.0
`
`10.0
`•
`Placebo Better
`
`'"
`:to-
`Z
`()
`?:'
`to
`:to-
`>-l
`~
`()
`Z
`to
`c::
`?:'
`0
`to
`Z
`t:I
`0
`()
`?:'
`Z
`to
`>-l c::
`~
`0
`?:'
`en
`
`~
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 6 of 10
`
`

`
`.,
`
`<:
`Qj
`
`VI '" '" VI E g
`o 'Vi
`¢
`.,
`.,-'
`bJ)'Oj
`; e:o
`
`'" Ufo-..<:
`~to
`'" .,
`_ N
`~v;
`~ <:
`., .-
`c..
`~
`'"
`
`:=:=:: I ncrease in tumor size as best response M: Decrease in tumor size as best response
`
`Everolimus (N=191)
`
`Placebo (N =189)
`
`100
`
`:~ _~~_""7.' __ 777777
`
`25
`
`75
`
`50
`
`75
`
`Patients
`
`100~------------------------------------
`Patients
`
`Decrease in size of target lesions from baseline
`No change in size of target lesions from baseline
`I ncrease in size of large I lesions from baseline
`
`Everolimus
`no. COlO)
`
`Placebo
`
`123 (64.4)
`11 (5.8)
`43 (22.5)
`
`39 (20.6)
`10 (5.3)
`112 (59.3)
`
`ney U test). Confirmed objective tumor responses
`as assessed by local investigators (all partial re(cid:173)
`sponses) were observed in 10 patients receiving
`everolimus (5%) as compared with 4 patients re(cid:173)
`ceiving placebo (2%). Thus, the benefit from evero(cid:173)
`limus with respect to progression-free survival was
`seen primarily in the stabilization of disease or
`minor tumor shrinkage and in the lower incidence
`of progressive disease. Stable disease was evident
`in the case of 73% of the patients in the evero(cid:173)
`limus group as compared with 51% in the placebo
`group. Progressive disease as the best outcome
`occurred in 14% of the patients receiving evero(cid:173)
`limus and 42% of the patients receiving placebo.
`A total of 64% of the patients receiving evero(cid:173)
`limus, as compared with 21% receiving placebo,
`had some degree of tumor shrinkage (Fig. 2).
`Of the 203 patients initially assigned to receive
`placebo, 148 (73%) crossed over to open-label
`everolimus, thus confounding the detection of a
`treatment-related survival benefit. Median overall
`survival was not reached at the time of this analy(cid:173)
`sis, and no significant difference between the
`groups was observed (hazard ratio for death with
`
`everolimus, 1.05; 95% Cl, 0.71 to 1.55; P = 0.59)
`(Fig. 1D). The final analysis of overall survival
`will be performed once approximately 250 deaths
`have occurred.
`
`SAFETY
`Our findings with respect to safety were consis(cid:173)
`tent with the known safety profile of everolimus,
`and most adverse events were grade 1 or 2. The
`most common drug-related adverse events occur(cid:173)
`ring with a frequency of at least 10% are listed in
`Table 3. A total of 12 patients in the everolimus
`group (6%) and 4 in the placebo group (2%) died
`while receiving the study drug. Of these 16 deaths,
`8 (5 in the everolimus group and 3 in the placebo
`group) were attributed to the underlying cancer or
`disease progression. The remaining 8 cases (7 in
`the everolimus group and 1 in the placebo group)
`were attributed to adverse events; of these, 1 in the
`everolimus group was related to the study drug.
`The most common adverse events were stoma(cid:173)
`titis (in 64% of the patients in the everolimus
`group vs. 17% in the placebo group), rash (49% vs.
`10%), diarrhea (34% vs. 10%), fatigue (31% vs.
`
`520
`
`N ENGLJ MED 364;6 NEJM.ORG
`
`FEBRUARY 10, 2011
`
`The New England Journal of Medicine
`Downloaded from nejm.org at EUROPEAN PATENT ORGANISATION on December 17, 2013. For personal use only. No other uses without permission.
`Copyright © 2011 Massachusetts Medical Society. All rights reserved.
`
`NOVARTIS EXHIBIT 2061
`Par v Novartis, IPR 2016-00084
`Page 7 of 10
`
`

`
`EVEROLIMUS FOR ADVANCED PANCREATIC NEUROENDOCRINE TUMORS
`
`Adverse Event
`
`Everolimus (N=204)
`
`Placebo (N = 203)
`
`All Grades Grade 3 or 4
`
`All Grades Grade 3 or 4
`
`no. of patients (%)
`
`Stomatitis;'
`
`131 (64)
`
`14 (7)
`
`Rash
`
`Diarrhea
`
`Fatigue
`
`I nfections"j"
`
`Nausea
`
`Peripheral edema
`
`99 (49)
`
`69 (34)
`
`64 (31)
`
`46 (23)
`
`41 (20)
`
`41 (20)
`
`Decreased appetite
`
`40 (20)
`
`Headache
`
`Dysgeusia
`
`Anemia
`
`39 (19)
`
`35 (17)
`
`35 (17)
`
`35 (17)
`
`1 (<1)
`
`7 (3)
`
`5 (2)
`
`5 (2)
`
`5 (2)
`
`1 (<1)
`
`0
`
`0
`
`0
`
`12 (6)
`
`0
`
`34 (17)
`
`21 (10)
`
`20 (10)
`
`29 (14)
`
`12 (6)
`
`37 (18)
`
`7 (3)
`
`14 (7)
`
`13 (6)
`
`8 (4)
`
`6 (3)
`
`0
`
`0
`
`0
`
`0
`
`1 (<1)
`
`1 (<1)
`
`0
`
`0
`
`2 (1)
`
`0
`
`0
`
`0
`
`0
`
`14%), and infections (23% vs. 6%). Infections, as
`well as pneumonitis (which occurred in 12% of the
`patients in the everolimus group vs. 0% in the
`placebo group) and interstitial lung disease (2% vs.
`0%), represented some of the most important
`clinical concerns and were primarily grade 1 or 2.
`The most common grade 3 or 4 drug-related ad(cid:173)
`verse events were anemia, hyperglycemia, stoma(cid:173)
`titis, thrombocytopenia, diarrhea, hypophosphate(cid:173)
`mia, and neutropenia. Antibiotics were routinely
`prescribed for patients with infections. Glucocor(cid:173)
`ticoids were administered to six of the seven pa(cid:173)
`tients with grade 3 or 4 noninfectious pneumo(cid:173)
`nitis or interstitial lung disease; however, only
`5 (2%) of these events were considered to be drug(cid:173)
`related (Table 3). Atypical infections such as pul(cid:173)
`monary tuberculosis, bronchopulmonary asper(cid:173)
`gillosis, and reactivation of hepatitis B (each of
`which occurred in one patient) were also observed
`in association with everolimus therapy.
`The death from acute respiratory distress syn(cid:173)
`drome of one patient with insulinoma in the evero(cid:17