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`JUN 2 9 2rma
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`EXHIBIT LJ
`~b4'<Mt l
`"3 17 //j-
`
`MARK RICHMAN. RPR
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`JOURNAL OF CLINICAL ONCOLOGY
`The Official Journal of the American Society of Clinical Oncology
`
`Journal <if CliJ1ica/ Oncology (ISSN 0732-l 83X) is published monthly by Lippincott Williams & Wilkins, 351
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`I ···- ···---··-· ···-· - - · ·-·---- -· . ......... _ ........ -· - -· ----· I
`
`Multinational Study of the Efficacy and Safety of Humanized.
`Anti-HER2 Monoclonal Antibody in Women Who Have
`HER2-0verexpressing Metastatic Breast Cancer That Has
`Progressed After Chemotherapy for Metastatic Disease
`
`By Melody A Cobleigh, Charles L Vogel, Debu Tripathy, Nicholas J. Robert, Suw Scholl, Louis Fehrenbocher;
`Janet M. Wolter, Virginia Paton, Steven Shak, Gracie Lieberman, and Dennis J. Siemon
`
`Purpose: Overexpression of the HERZ protein occurs
`in 25% to 30% of humon breast cancers and leads to a
`particularly aggressive form of the disease. Efficacy ond
`safety of ~ombinant humanized anti·HER2 monoclo(cid:173)
`nal antibody as a sin·gle agent was evaluated in women
`with HER2·overexpreHing metastatic breast cancer that
`had progressed a(ter chemotherapy for metastatic dis·
`ease.
`P~tients and Methods: Two hundred twenty-two
`women, with. HER2•.overexpressing metastatic breast
`cancer that had progressed after one or two chemother(cid:173)
`apy regimens, were enrolled. Patients r'eceived a load·
`ing dose of 4 mg/ kg intravenously, foltowed by o
`2-mg/ kg maintenance doH at weekly intervals.
`Results: Study patients had advanced metastatic dis(cid:173)
`ease and had r~eived extensive prior therapy. A
`blinded, independent response evaluation committee
`identified eight complete and 26 partial responses, for
`an objective response rate of 15% in the intenMo·treot
`population (95% confidence interval, l 1 % to 21 %). The
`median duration of responsa was 9 .1 months; the
`
`median duration of survival was 13 months. The most
`common adverse events, which occunred in approxi·
`motely 40% of patients-, were infusion-associated fevl)r
`and/or chills that usually occur.red only during the first
`infusion, and were of mild to moderate severity. These
`symptoms were treated suc.cessfully w ith ocatamino(cid:173)
`phen and/ or diphenhydromine. The most clinically sig•
`nificant adverse even~ was cardi.ac dysfunction, which
`occurred in 4.7% of patients. Only 1.% of patients discon·
`tinued the study because of treatment.,elated adverse
`events.
`Conclusion:. Recombinant humanixed anti·HER2 mono·
`clonal antibody, administered as a single·agan.t,. produces
`durable objective responses and is well tole.rated by
`women with HER2-overexpressing metastatic breast
`cancei: that has progressed after chemotherapy for
`metastatic disease. Side effects that are commonly ob(cid:173)
`served with chemotherapy, .such as alopecia, muc.ositis,
`and neutrope nia, are rarely seen.
`J Clin Onco/ 17:2639-2648. c 1999 by American
`Society of Clinical Oncology.
`
`PROTO-ONCOGENES THAT encode growth factors
`
`and their Teceptors contriblttC to the pathogenesis of
`human malignanci'.es, including breast cancer.1 The human
`epidermal growth factor receptor 2 (HER2) gene, also
`known as 11eu and c-erbB-2, encodes a 185-kd transmem(cid:173)
`brane glycoprotein receptor (pl8Sllli'R2). pl8SHER2 has par(cid:173)
`tial homology with the epidermal growth factor receptor and
`shares intrinsic tyrosine kinase activity with that receptor. 2·4
`HER2 is overexpressed by at least one fourth of htunan
`breast cancers,5·6 and correlates with poor clinical outcome
`in women with node-positive and node-negative disease.6.S
`Additional fi.ndings from HER2-trnnsfected cells, as well as
`transgenic animals, support the bypotbesis that this proto(cid:173)
`oncogen.e is not just a marker but direetly contributes to the
`pathogenesis and clinical ag;gressi veoess of tumors that
`overexpress HER2.9-ll To target this specific growth factor
`receptor, monoclonal antibodies directed against pl85HER2
`were developed.12 In preelinical studies, these antibodies
`inhibited the growth ofHER2--0verexpressing tumor cells.12-15
`Recombinant humanized anti-HER2 monoclonal anti(cid:173)
`body (rhuMAb HER2 [ttastuzumab]) was engineered from a
`cloned human IgG, framework and the antigen-binding
`residues of Uie murine monoclonal antibody 4D5.16 The
`
`antibody was humanized to minimize. the immunogenitity
`associated with murioe monoclonal anttbodies and to en(cid:173)
`hance the potential for enlisting endogenous irnmw1e antiru(cid:173)
`mor effects. Resril!S of small phase II trials provided
`p(eliminary evidence that rhuMAb HER2 is safo and
`clinically active iJ1 women with HER:Z...overexpressing meta(cid:173)
`static breast cancer.17•18
`Based on these observatibns, two large clinical trials of
`rhuMAb HER2 were conduct.ed in patient~ with HER2-
`overexpressing metastatic breast ca11cer. One tdal 'compared
`
`Fro1111he Rush·.Pres/>yreria11-SI l.Ad~e's Medical Cente1; ChiC4go, IL;
`Col11mbil); {[lCA) Cancer Research Network of Florida, Ave11f/Jm, t 'L;
`U11ivertity of Califomia, San Fra)!cisco Cancer Ce111~r, San Francisco.
`Kaiser Pe1111c1.11ente, No11hem Ci1lifotni11, Va/l,jo, Gciemech, Jue.
`South San Francisco, ond UCLA School of Medicine, los AJ1geles, CA;
`Ftlirfax Prince William Hospital, Amiandale, VA; and Jn.rtifut Curie,
`Paris, France.
`Sabmitted Ja1111ary 19. 1999: accepred Ma.v 11, 1999.
`S1t11parted i11 part by a grant /mm Genentech, Inc.
`Address reprilll rr11111e~ts to Melody A. Cobleigli, MD, Ru.th(cid:173)
`Presbyferfon-St Luh's Mdiwl Cetuer, Professio11al Building. 1725
`West llartiso11, S11iur82J, Chicago, IL606/1.
`o 1999 by Am.otica" Societ)i of Clinical 011cology.
`0732-l 83Xf')9/J 709-2639
`
`Jovmal of Clinical Oncology, Vol 17, No 9 (September), 1999: pp 2639-2648
`
`2639
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`2640
`
`' !he. safety and efficacy of rbuMAb HER2 plus chc111otberapy
`versus chemotherapy alone in first-line treatment.19 A sec(cid:173)
`ond trial, reported here, investigated the safety and efficaey
`of rlmMAb HER2 in patients with metastatic breast cancer
`that had progressed after one or two chemotherapy regimens
`for merast'8.tic disease. The primary objectives of this trial
`were to detenni:ne the overall objective response rate to
`rhuMAb HER2 treatment as a single agent and to further
`characterize the safety proJUe of rhuMAb HER2.
`
`PATIENTS AND METHODS
`
`Palients
`Eligible pai.ieuts wue women w.itb lff>R2-ove.rexpi:essiog. metastatic
`brenst cancer. All patients had progressive dise3se after OM or two
`cytotoxic cbcmolbet!lpy regimens for metastatic dlscn~e Md bidimen(cid:173)
`siooully meai.'Urable disease. Patients were excluded if th.ey had
`umreated bnri11 metastases, bune :metastas~s as the only disease site,
`~oacomk.ml malignancy nor curatively !teated. or a Kamof&l>y perfor(cid:173)
`mrui.ce s.tatus of Jess than 60%. Paticllls were also excluded if they were
`pi:egnant. aursil1g, or if they hall used lnvestigatioaal or unlicensed
`agepts wilhla 30 days. Informed oonseni w~ obtained and documented
`in writin-g before .si:udyeotry. 1bis study was perfonne,d afte( ap1irnval
`by local human investiga.tl'ons coomuttees.
`El\pressfon of HBR2 wai1 d_etei:!nined by immunobistocllemical
`analysis ot' tumor tlssue, coUected either at the time of primury
`dia-gnQsis or nt recurrence, aml U,ied rbe 405 and CBl'J moriae
`monoclooaI ami-.HER2 m\tibodie,~. B~pression was scored by a core
`research pntholoi;y luboratory as 0, I+. 2+, or 3+ ushig ~tandarclized
`cri.teria.All enrolled patients had 2 + or 3+ ovetexpression using cilhei'
`antibody (weak lo stroog complete memhr:.ne ~1runing observed in >
`10% ofthe.tunwrc.-e!ls).
`
`A111;body Ad111inistra1io11
`chuMAb HBR2 (trastuzumnb {Herceptin]) was produced by Geneu(cid:173)
`tcCb, lqc (South Sau Francisco, CA) and WM admi11istered i11m1vc-
`11ously in the out11atiem setrillg 1u, u dose.selected to mainraiu a minimal
`serum JroUS"b concentration of LO µg/J'OL to 20 µglmL. Pntients received
`n loading dQSe of 4 mg/kg, followc.'tl by weekly a~miaisln(rion of 2
`mg/kg. The infusion was initially administei:ed over 90 mlautcs. If the
`infusion was well tolerated, st1bscquem infu~'i<>n periods. were shortened
`to 30 min;ites.
`The 2-mg/kg weekly maintenance dose was continned wi.iliout
`dosage modification. If n patient developed disease progrcssio;i, rile
`Investigator could continue the 2-mg/kg dosage, increase the dose to 4
`m~g weekly, or dL~continuc treatmem. Additio11al antitumor therapy
`was :Jso permitted upon diseq~e. pro~ion.
`
`Tumor Response
`The primary end point of objective tumor response was assessed at
`specified time points; before treau11e11t, at weeks. 8, I 6, aud 24, and
`every 12 weeks thereafter. Resp<mses were detenniued by an indepen(cid:173)
`dent respon.<1e evaluacion commirtee (REC). Reading 'teams were
`comj,osed of an oncologist 1111d a radiologist, ""ho were blinded to
`treatln!!nt Responses (complete or pnrriat responses) were confirmed 4
`weeks-after the initial response detemtination. Complere =ix:mse was
`defined as the dis:ippeamnce of r<idiographicnlly, pa!p:ible, 3J)d/or
`visually appurenr iumor. Purt.ial response was defined as a 'a: 50%
`<lecrease in !he snm of.the products of the perpendicular diameters of ull
`
`COSLEIGH ET Al
`
`measurable lesions. Disease progression w.as defined as a :2: 25%
`incre:ise in any measurable lesion or rbc appear!l(lce of a new lesion.
`The prespccified secoodm:y end poinlS wcie durntion of response,
`time to disease progression, tlln6 to trc:umertt failure. and survival.
`Duration llf response wa.~ defined as the rime fro1J1 (ir.;t response to
`disease progressfoo. Time to disea$e pmgrcssip11 was defined as the
`time from en(Ol!ment to disease ptogress~on or dtath (whichever
`occurred first) nnd was censored.at the la.~t date of comact for patienrs
`whose disea.~e did not progress. 1i me t0 treatment failure was defined as
`tbe thne. from enrollment to disease progression, death, treatment
`discomirmation, or inltil\tipn o.f ft uew antitumor therapy. Survival was
`defined as the titnc from cnr'ollmcnt to denth .and wns censored nt the
`date of las1 contnct for parients who were alive,
`
`Ot~r Asse.s.sme111s
`A complete physical examination; a cUnical asse~ent~ a vital sign
`analy$is, chest )(·r~ys, and lnboratol'}' tests were p"erfonne.cJ' at pr:ec:Jete:r(cid:173)
`mined intervals and at srudy termination. Adverse event') were cl'ISsified
`ill: mild, mt'>derate, or severe. A mi.Id adverse event wus defille'd as
`anooying but not affecting baseline s.tatus or binderlag the patiem's
`normru functioning level. A. moderate" adverse event was uncomfortable
`and impaired nom1al (unction but was not ba"znroous ID he;ilth. A s1>vere
`advet'lie event caused severe·discomfort, severely limited or prevented
`oom\al foncHon, and was a definite· hazard lo health. 11ie N:1fional
`Cuncer Institute Common Toxicity Criteria were .nol ased to classify
`clinical ~dvew events. LJiboralory abnortn!\lities were clnssiticd by the
`W'orld Health organization g;.1dlng system.
`A blinded -independent ·cardtnc review 11nd evaluation <.'Ommittee was
`t:Stablisbcd retrospectively to a.o;sess cardi~c dysfunction in all rhuMAb
`HER~ clinical trials-2n Clinicnl data fm.m all patients enrolled l;1 tb1s
`~tudy wete thoro11gbly rcVie,ved by !he cofl)piittee to identify all
`potent.i"nr ca..<;CS of cardiac dysfunction. The severity of cardiac dysfunc(cid:173)
`r1on was classified ushlg the New York Heart Associruiort crltcri'n.
`The Quality of Life Questionnai~I). a ques1jonnaire developed
`by the European Organizarion f.or Researoh and Treatment of Cancer;JJ
`was uS!ld to assess CJ.llali!Y oflifo initiatly :it weeks I, i2, 24,J6,·and48,
`rl;en every 12 weeks, and finally at study terminn1fon.
`Blbod samples wt.'11! colleetcd at predetermined inturvals for the
`pbarmacokinetic analysis of serum rhuMAb HEIU concentmtions,
`determination Qf s~m concentrations of the cx1n1001lular domain. o.f
`the HER2 protein1(shed anitgetl), arid measuremel1L5 of antibody ro
`muMAb HER2. Serum rhuMAb HER2 co11~1trations wcre'dete.tmined
`by no enzyme-linked i1.11mu110so.rbent ass.ay (BLlSA) with a lower liJnit
`of sensitivity of 156 ng/mL nt a nlinimum dilution of l/HJ0.17-18 Serum
`baseLine shed. a11tige11 couceiltrot.ions were determined by an BUSA
`with a }ower limit ofiieteclioJi ot3.4 ng/mL. Antibodles lo the Fnb a.ad
`Fe ·regions of rhuMAb BER2 were measured by EUSAs.
`
`Statistical Methods
`TI1e finlll analysis of efficacy and safely was performed 15 months
`afierenrc!J.ment of thela$t patient.The median follow-up for all (llltie,ntS
`was 12.S months. Demographic and baseline characteristics were
`summari7.ed by de.~criplive.statistics.
`Response rnte wa.~ evaluated in all enrolled patients (intent-to-treat
`analysis) imd in treated patient~ (ie, all patients who received at least
`one .dmMAb Ell;.R2 dose). Response duration was evaluated in patient$
`with p:utial or complete responses. Time to disease progression, ti100 to
`tteatmentfailm:e, and sun~vul were evaluated by intcnt-lo-tn.-al lllllilysis
`of ull patients. Time to event end points we£e t'$tUntitod by Kaplan(cid:173)
`Mcier survival methodology. The dfec! of ba.~eliae cbatacteristics on
`respon5e rnte~ wa~ evaluated by the x1 test and logistic regression
`
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`ANTI-HER2 MONOCLONAi- ANTIBODY AS A SlNGlE AGENT
`
`model. 'TI1e risk; facto.rs for time to progres.'iion were determined by the
`Cox jiroportiooal hllZatds regrcss.ion.1no<leJ.
`TI1e onnlysis of safety was petformed on nil patientl who received at
`least one dose of rhuM:Ab 1 l'ER2. Adverse eveors and labo_ramry
`nbuonnalities were snrnmal'.ized by descriptive statistics. lnfusion(cid:173)
`associat<->d adverse events were evahrnred by compioring the rares of
`cvenrs ufle.r lhe loading dose with tbc rat~s ot' the same evcnt.s after
`subsequent.infusions.
`Quality-of-life dara were evaluated in paticnlli with baseline and at
`lens.t one foll.ow-up os5essment. The primary analysis was a repeated(cid:173)
`measures analysis of variance on the ~obal quality-of-life score and
`four funct.ioning scale.~ (ie, fatigue, [ihysical, einmlonal. nod social
`functions).
`The phannacoki·neticprofile of ibol\:!Ab l;IER2 was detennined i1150
`randomly selected pa(icnts. Pharmacokinetic parameters were. es1im1tted
`by nonlinear ~gression using Profes:.ional WinNonlin {v. LS; Soientific
`Coosulti11g. Jnc- Cary. NC), a software progr.1.m for pbannacokinctlc
`analysis . .Baseline-shed antigen data were sumniarized.: an analysis of
`variance on logaritluuic ll'lllL'lformation at base l 0 of the absolute value
`of tJ1e. baseline shed anfigen was performed to evaluate the interaction
`with patient baseline characteristics.
`
`RESULTS
`A total o.f222 patients were enrolled. by investigators from
`54 centers in the United St.ates, Cana,da, Belgiup1, France,
`Germany, the United Kingdom, and Australia between April
`1995 and September l996~Atotal of213 patients received at
`l~t one dose of dmMAb HER2. Nine pati.ents were not
`treated for the following reiisons: brain metastases (n = 3),
`laboratory abnonnality (n = 2)., adverse event (n = 1 ), re(cid:173)
`fusal to p11nic:,i]lllte (n = I), clinical instability (n = l ). and
`death (n = l). As of the Clttoff date of December 31, 1997,
`179 patients (&1%) bad discontinued the study, 14 palients
`(6%) remained on the study without disease progressio11,
`and 29 patients (13%) were continulug treatni.ent after
`disease progression.
`Patient baseline characteristic..5 are listed in Table 1. Less
`Chan half had estrogen receptor-positive tumors. 1Weo.ty(cid:173)
`seven percef:lt had<:: 10 positive lymph nodes at the time of
`p:dmary diagnosis. Thirty-seven percent had a disease-free
`iurervnl of less than 12 months. Most patients (78%) had
`metastatic disease at multiple sites, and 72% had liver or
`lung involvement. All patients had received extensive previ(cid:173)
`ous treatment. Sixty-eight percent had !?fior adjuvant cbemo(cid:173)
`therapy, and all had recci ved prlor chemotherapy for meta(cid:173)
`static disease; 32% had one prior and 68% had two pdor
`chem<>therapy regimens for metastatic disease. Most had
`received both prior antlu:acyclilie and taxane therapy; 26%
`had undergone bigh-dose chemotherapy with bone marrow
`or stem-cell rescue before enrollment
`
`1l.111wr Response
`The lndepe11deot REC determined eight complete (4%)
`and 26 partial ( 11 % ) responses, for an objective response
`t·ate of 15% in the inteot-fo-treat population of 222 patients
`
`Table 1. Patient Chotocterisfics
`
`50 :t 11.6
`28-81
`
`dlOl'Odert.li<
`
`Age,yeors
`Mean :!:: SD
`Range
`Kornofsky >c:ore
`90%Jo 100%
`80%
`:S 7o%
`Re<:eptor •lotus
`Eslrogen receplor positive
`Progesterone receplor positive
`HE~-2 averexpres.ion
`2+
`3+
`No. of lymph nodes ot primary dia9nosl•
`Nono
`i'-9.
`-.10·
`Dise1u..-free interval, mooths
`<12
`12-24
`>24
`No. of metastolic sites
`l
`2
`:.:3
`Metastatic site
`Skin or soft !Usoe
`lM>rorlung
`Pri<ir therapy
`Adiuvant Chemotherapy
`Cnemotherapy-metostatfc dioeose, no.
`of regimens
`1
`:.: 2
`Prior anlhro<ydi1ies
`Prior loxones
`Rodro1heropy
`Hormoool therapy
`Bone marfoW ot stem-cell tronsplontotfon
`
`2641
`
`No.of
`Pot."'11>/No.
`Anai}":ed
`
`152/211
`36/211
`23/211
`
`85/190
`77/188
`
`50/222
`172/222
`
`42/176
`87/176
`47/176
`
`80/214
`.d8/2!4
`86/214
`
`.d7/214
`91/214
`76/214
`
`14/214
`155)214
`
`"
`
`72
`17
`11
`
`45
`41
`
`22
`78
`
`24
`49
`27
`
`37
`22
`40
`
`22
`42
`36
`
`6
`72
`
`1.d6/21.d
`
`68
`
`214/214
`69/214
`145/214
`201/214
`143/214
`151/214
`122/214
`53)7.05
`
`100
`32
`68
`94
`67
`71
`57
`26
`
`(Table 2). 'I11e investigators identified nine complete re(cid:173)
`sponses (4%) and 37 partial responses (17%), for an
`ohjecti\le response rate of 22% in the treated population of
`213 patients. In addition, there were L2 minor responses
`(6%), 62 patient~ (29%) wicb stable disease, and 93 patients
`(44%) with progressive disease. Twenty-two percent of
`patienti; were f,ree of disease progression at 6 tnonths.
`The median duration of response to rbuMAb HER2. in the
`patients ide11tifi.ed as complete or partial responses by the
`REC, was 9.1 months (range, 1.6 to > 26 months) (Fig 1).
`Eight (24%) of 34 patients with a response were free of
`disease progression at the cutoff date. Among all treated
`patient~, the median time to disease progressiori was 3.1
`
`
`
`5 of 12
`
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`

`

`2642
`
`Population
`
`REC assessment
`All enrolled, inlenHo-lrect
`Alltrecled
`Investigators' assessment
`All enrolled, intenf·to·lrl!Ot
`All treated
`
`No.of
`Palienb.
`
`222
`213
`
`222
`213
`
`No. of
`Pa1il!ol>
`
`8
`8
`
`9
`9
`
`Tobie 2. Tumor Response
`
`Potticl R.,;pOtlden
`No.of
`PaN.tlb
`
`4
`4
`
`4
`4
`
`26
`26
`
`37
`37
`
`COBlEIGH ET AL
`
`"
`
`12
`12
`
`17
`17
`
`objeaive
`Ro<pqn ..
`RCl!e 00
`
`15
`16
`
`21
`22
`
`9.51:0
`
`11-21
`11·22
`
`16·27
`16-28
`
`months (range, 0 to > 28 months); the median time to
`treatment failure was 2.4 monchs (range, 0 to > 28 months).
`The median time to treatment failure among the 34
`patients with a response was 11 months (range, Z to > 28
`months). 1n contrast, for th.e prior regj.men of cytotoxic
`chemotherapy in these patients, the median time to treatment
`failure was 5.4 months (range, 0 to 27.4 months). The
`
`median duration of survival in all patients was 13 months
`(range, 0.5 to> 30 months) (Fig 1).
`In general, the efficacy of rhuMAb HER2 was observed
`.consistently across patient subgroups, with a few excep(cid:173)
`tions. Patients whose tumors overexpressed HER2 at the 3 +
`level tended to have higher :re-~nse rates than those with a
`2+ kyel of overe;icpression (18% '\t 6%; P = .06). Patients
`wbQse time to first relapse was more than 6 months tencled to
`have higher response rates than those who relapsed earlier
`(20% 11 9ro; P = .03). Of note, tuinor responses were
`observed in 12 (11 % ) of 109 patients with liver metastases,
`and in 14 (26%) of 53 patients with prior trans.plants. 1n a
`multivariate logistic regression analysis, none of the patient
`baseline -characteristics were independently predictive of
`tumor response.
`Signiii.cant correlations were detected between time to
`disease progression and patient baselin.e characteristics. Jn a
`univariate analysis, the median time to disease progresstoIJ
`was longer among· patients whose tumors overexpressed
`HER2 at the 3+ level (3.3 v 1,9 months; P = .0034), who
`had relapsed 1norc than 6 months after treatment (3.4 v 2.1
`months; P = .0045), who had a Karnofsky score of 100% or
`90% v_ersus Jess than 90% (3..2 or 3.5 v 2.0 months;
`P = .0068), or who had one or two versus :<::: three metastatic
`sites (3.5 or 3.2 v 2.3 months; P = .001). In a multivariate
`proportfonaJ hazards model, three factors (number of meta(cid:173)
`static sites at study entry, level ofHER2 overexp(essioJJ, and
`months .to first relapse) significantly (P < .05) affected time
`to .diseas.e progressioi1.
`A number of patients were treated after disease progres(cid:173)
`sion with 4 mg/kg rhuMAb HER2 as a single agent. Of the
`34 patients treated with 4 mg/kg as a single. agent, three
`patients, each of whom hao an initial partial response or
`minor response to the 2cmg/k.g dose, had n subsequent
`partial response to 4 mg/kg.
`
`100
`
`80
`
`A
`15
`Q)
`~
`u.. c
`le .Q
`(/) 60
`Q)
`-0 (/)
`c~
`0 C)
`a. 0 40
`.....
`(/)
`OJ a...
`
`er: -0
`
`~ 0
`
`median = 9 .1 months
`
`20
`
`0
`
`0
`
`10
`25
`20
`15
`5
`Months from Initial Response
`
`100
`
`80
`
`60
`
`median== 13.0 months
`
`B
`
`(/)
`
`Q)
`
`"O
`
`'E
`~ a...
`Q) Q) => o= c <( 40
`-0
`
`w
`~ 20
`
`~ a
`
`0
`
`0
`
`10 15 20 25 30
`5
`Months From Enrollment
`
`(A) KQplan-Meier plots of the duration of response In potients with
`fig 1.
`tumor mponse (complete or partial response) and (B) survival in oil enrolled
`patients.
`
`Quality-of-Life Assessment
`One hundred fifty-four patients completed the EORTC
`Qu.ality of Life Questionnnire-C30 at baseline and at week
`12 . .Before disease progression, treatment with rhuMAb
`
`
`
`6 of 12
`
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`IPR2017-01122
`
`

`

`ANTI·HER-2 MONOQONAL ANTIBODY AS A SINGLE AGENT
`
`HBR2 was associated with maintenance of health-related
`quality of life, as measured by the physical function, role
`function, social function, global quality-of-life.. and fatigue
`scales. However, after disease progression, overall health(cid:173)
`rclated quality of life declined. The subset of 34 patients
`1\ith a respO'nse had clinically meaningful improvements in
`the evaluated parameters. A detailed analysis of quality of
`life will be published separately.
`
`Phannac:okinetics and Shed Antigen
`The mean volume of disnibution (38.0 mUkg) approxi(cid:173)
`mated the scrum volume. The mean steady-state concentra(cid:173)
`tion was 59.7 µg/mL. The mean elJ1uination J1alf-life. was 6.2
`days. Among the 195 patients with pl1nnnacokinetic data,
`the mean pe·ak r111d rrough serum concentrations of rhuMAb
`HER2 after the first dose were 100.3 µg/mL aod 25.0 pg/mL,
`respectively. The trough semm concentrations tended LO
`increase through week 20 and, thereafter, tended to plateau
`(Pig 2). To minimize the potential <>:onfouhding effect of the
`declining number of asses.sable patients over time. trough
`concentrations were evaJu11ted in a ~'llbs.et of 37 patie1\l:S who
`had data through week 36. Similar findings were observed in
`this subset, except that the trough coucentmtions tended to
`plat.eau after week 12 (data not shown). .Me.an trot1gh
`concentration~ at weeks 7 and 8 were higher in complete
`(70.3 µg/mL) and partial (58.4 µg/nlL) responders than in
`nonresponders (44.3 µg/m.L; P < .001 ).
`
`2643
`
`Se.rum concentrations of baseline shed antigen were
`below the detectable level in 73 (38%) of 191 patients,
`between 3.4 ng/mL and 100 ng/mL in 78 patients (41 %),
`between 100 ng/mL and 500 ng/mL in 28 patients (15%),
`!Ind above 500 n.glml.. in 12 patients (6%). Patients whose
`tumors overex.pressed HER2 at the 3+ level had higher
`median shed antigen concentrations (16.2 nglmL) than
`patients whose tumors overexpressed HER2. at the 2+ level
`(3.4 ng/mL; P < .0001). No significant correlations were
`demonstrable: between shed antigen concentrations and
`response st~tus.
`
`Safety
`Patients who received at least one close of rhuMAb HER2
`we1~ evaluated fur safety. 01emotherupy was added to
`rllllMAb HER2 in 36 patients after disease progression. This.
`safety analysis included adverse events occurring before
`disease progressjon upless oth.erwise noted. The media.n
`number of iJJfusions was 12 (tange, I to 96). A total of 2J.O
`patients (99%) experienced. :~t leost one advers.e event; 88
`patients ( 41 % ) bad severe adverse events. Wheu events were
`limited ro. those that Lhe investigator considered to be
`possibly or probably n::lated to treatme111 (hereafter, treatm~t­
`related events), 179 patient,.~ (84%) experienced at lea,st one
`adverse evenr; only 29 patients ( 14%) had severe events.
`Seve,e tt-eatmeut-related adyerse C-\'ents that occurred in
`
`j -.- Mean Trough Serum Cone. (ug/ml) I
`
`I --e· ·n I
`
`Fig 2. Meon trough (±SOI serum
`concenlrarioru of thuMAb HER2 for
`all potients for whom doto we.re
`avoiloble In =- number of patients).
`
`...-.
`~ 0)
`2-
`0
`c:
`0
`(.)
`E;
`:::>
`.....
`Q)
`(/)
`.c
`Ol
`:::>
`0
`'-I-
`c: m
`Q)
`:?
`
`80
`
`70
`
`60
`
`50
`
`40
`
`30
`
`20
`
`10
`
`0
`
`200
`
`150
`
`100
`
`................................ .._.._-'-'....._ ............................................................................................ .._. .............................. '-' 0
`25
`20
`40
`5
`30
`35
`0
`15
`10
`Week
`
`
`
`7 of 12
`
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`
`

`

`2644
`
`• more than one patient were pain (n = 9). chills (n = 5),
`dyspnea (n = 2), and abdominal pain (n = 2).
`Six patients (3%) discontinued the study because of
`adverse events, four before disease prngressioll and two
`after disease progression. One patient developed an annphy(cid:173)
`lactoid reaction during the first dose. One patient withdrew
`from treatment after developing tuberculosis,, and one pa(cid:173)
`tient withdrew from treatment .because of atherosclerotic
`heart disease. The other tbree patients discontinued the ·study
`because of adverse events experienced before initiati.on of
`rhuMAb HER2 treatment.
`The most common adverse events seemed to be related co
`the initial infusion, particularly fever, chills, pain, asthet\ia,
`nausea, vomiting, and headache (Table 3). These adverse
`events .were mild to moderate in intensity and were rarely
`severe. Often, the infusion was temporarily irtterrup:te.d. Th<:
`symptoms were usually successfully treated with acetamino(cid:173)
`phen, diphenhydrrunine, and/or n:ieperidine and Qsually did
`not recur with subsequent infusions, For example, 40% of
`patients experienced fever and/or chills \Juring or shortly
`after the first infusion, but less than 3% of these pa