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`Keywords:
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`crlotinils
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`FCLEPD: wephdvanal growth
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`uture
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`Me
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`FO2P TEL ASROOC4 14.649.208
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` Radure
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`Mecicine ict (SSN 147¢-d894
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`Puig@ Oneci, (2008) 1A) 449-460
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`449
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`OSI 2019
`OSI 2019
`APOTEX V. OSI
`APOTEX V. OSI
`IPR2016-01284
`
`IPR2016-01284 EXHIBIT
`
`2 6f9
`
`

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`F erlotinihbeefs
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`Was appannesn all patient sudyrougys
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`‘Fine twdeseriovarios. of pariens seported simp.
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`was wel. rlersted and, asexprcted,
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`padenes fro(IS centers ts4:
`Patienss_ received
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`ith she *
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`to-proatediion, biden pasienesof1 eilotinipas
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`were sitnilay In.
`Incidedios
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`ebo, apart fronr a grater Incidence of
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`Exploring new inernpedfic options
`Trai
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`role’ of ugenis such as
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`
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`The reason fer the
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`The
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`
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`
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`might
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`fhe effect of fstfine crefuncar wich enlannsb in
`
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`
`advanced
`could minimize such effects. However, the face
`fens {oFGvx
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`a Phase U
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`a
`substantial
`
`ROLES is abo being inveingared &
`
`Improvement
`in- survival
`in partests who had
`study, Prehodinary resules jndkcace thar erlorinity js
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`
`never srooked, Indicates cha auch.
`inveraccions
`
`well alerared as
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`shaw
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`enoouraging therapeutic activin, Among che 34
`pation cvaluated,
`there were
`four
`partial
`
`resptatses and T4 with stable disease
`
` ID SOME CHCRTESEE OSs,
`
`wwwfivemedicine.com
`
`453
`
`

`

`
`
`rnodes af
`with difcrern:
`Combining
`acoosaval 3 Hottied overlay of safety profiles coudd
`
`Combina-
`lead eo bmproved therapeutic strategie.
`Hen simatemes that use two.or mots targeted agenes
`leach, wach apacitic effece as a diferae aspece af
`
`tumor Molaay) are parents
`efng and. are acreach
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`and:
`othe
`and
`ciuprising edo
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`grosesh eros monoclonal andbady.
`berg
`stumiab, has been examined in a Phase HY
`Daas Rad
`
`invedving patients sei: NSC
` ast one previous chemocherpy segi-
`dar]
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` ae
`rea. Scotal oF 50 (80%) df thepatients had
`PY
`Beeast, and ror chan half had seceived nwer or
`more
`previous
`cherrorkerapy
`repimens
`for
`NSCLS.
`tn the Phase T steady co dose-limiting
`
`
`rooiedties were bse
`do andeddatinih 13¢ mgfday
`
`orally plus ineravenous bevaazumeat
`15 mgrke
`
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`
`every 2) days was conblishedas che dase &
`i
`iacthe Phase 3 sandy. Among the 4fh purienss
`
`
`areas
`ir Of
`Pinake Bhase dT] seuds che can
`
`
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`famab was well.
`tole:
`efotinis and besac:
`dd.
`Aid -scemodevant rash, liaehes and proteinuris
`were the csosr aimemion evens, All pe casts bad-at
`
`least two cycles oftherapy, and. 13 remained inshe
`
`
`study for moi than Gmoriths. recciving ar feu
`Ae patients (25%) had.
`
`nite cydles, A taal afeng
`
` pa
`hadstable disease
`RESPONSES. and 26 GS85)
`as their best respon. The aondian overall survival
`for the $4 patients treated vsith che Phase UD close
`was 12.6 sionths, while the median progrestian-
` ival was G2 npinths. Thon was no evi- frees
`
`deace of a pharmacokinene asters
`an benweer
`exlotingds and bevacizumab (6.
`
`ewoocladon hereon scaaity of
`
`
`ysake wen Phase TH otalof
`leaden whibe addi
`
`senafeelotiash vest-nde as
`red with impeded
` pared
`surviodl bn all PAHETIS, subatalyzes demonse
`that parenwho developed ash survived longer
`
`phan. those vedio did nor flaca fram (351 Phares
`j
`rash and sur
`
` hed
`
`5
`mm padeng wishMonet
`monotherapy
`
`
`being|invessiggiod. A hetrer understanding af the
`joaship between the occurrence and. severiny
`
`
`
`
`of meh add clinical qurcore
`will be cequited
`
`
`before the presence ofcech cab be used as 2 pred.
`tor ofresponse in individtsal paaienss. drawl alos
`4 fo understand the cooley ot
`
`therash is a consequena ofiee
`
`this mireors
`Hos
`in the skin, and shecher
`
`HERIJEGER inhibirion in the rumor
`ther suresgatex of reeaponmeto HEUEGPR
`THIs are a
`i
`igation.. Recearly,.
`s¢. wax
`
`fund thanx
`ing rautatians th
`
`the gene encoding he¢ HER VEGER PR domain
`
`are present
`in approxinarely. 106. of NSCLC
`gutiente in the USA, and more than 40%uy Ease
`
`Asi
`5
`The enaloey of those mauations is
`
`unknown, bur they are mor
`fresyLENT. in SELRTHOTS
`frome pacienex whachave never smoked, I WwOnnes:
`
`and ie adencmycisomas is: Aliost 2096 of che
`guurtions orien ae either ambldrsicleatide tn-
`wepEO, ive
`frase defevignts
`;
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`offouy amine:
` ds, or ea singde ruicleonde:sab-
`
`stininen, of urinine for lencine at gos’
`
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`(LESSRY ia exon
`21
`Accarenary ofpub
`
`
`reperts of
`magations. Ga pahienss
`
`meectsd NSCUCte shown ir Table
`r has been guggested thas che pr
`oF
`
`Tordare, no clear associationnnasx been idennfed
`seoweer bevelg oF HERVE
` Pig agents
`MERVEGPE avuetions may deling a specilic
`CRPTESSH ad xl
`Le Fe,
`MORPOGSe FF
`that tease be
`metecnber suht
`eof CATCH
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`sid GOSE
`pardewasly scnsicive co pelicinib ise.
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`rhs).
`An onivef the fire
`
`be affected be faceors
`
`biv also to erlor
`oh HEBUEGER,
`inchediag.
`receceptor PUIAdans,
`
`the: Five
`munations were ddendfied in each of
`
`hereradimerizadian wih sehr }EER anearbers.
`Pacants whe bad tesponded ta eefesiih, text in
`
`
`
`deur doersponders
`fn. a secand
`PR, altered exphession af hmands dred
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`sendy cight. of che nine parent: wink gefiinis-
`levels. of intra
`liskar
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`cEEE Sig
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`aierapping ah
`
`Tydee43
`respes
`NSCLC. had
`
`
` IRENTE
`
`Another consideration ie the emerging Buk
`SATOHS 5the “EX regddin, Pix iissi. Pe and cak
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`
`bebwsen
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`prawn, rashceabe
`AUEGEE-T
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`dona’ain fti saeBersFeat“ve@
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`iy. providinga tal co ssaximizeclinical omen.
`SER TM Kens who
`as well as seven of ton
`responded 09 erlomuth,
`
`A pooled analysis of data feons chize Place 1 cals
`
`
`geftinid texpotiders
`sho (Table2.
`ib 730 meyday monuhstagy jaadvanced
`
`
`A dod Grher ty
`demonsteaed 3 crend
`The presema: of mutarion’
`
`
`watighed wail reponse i. testing!
`beewenn higher grades of rash and: response, afd 4
`
`Predictive morkers of resmanse io
`HER 1 JEGER IRs in AECLC
`
` Bre
`
`Future Oncol 20N5) 4a
`
`

`

`
`
`
`Author
`
`Muang. ef al
`
`Kosaks
`
`N of
`patients
`FGI
`
`Mutations
`
`Martations in
`adenorarchionas
`
`Comments
`
`No differance in smoking history
`
`sein feinaies,
`
`
`fdas ahd never
`
`tecprocsl exciusiod
`
`
`fats
`
`$37
`
`sa]
`
`
`
`
`
`
`
`bo
`
`
`
`Steokens ot af,
`
`Shinerrwat
`
`136 24%)
`
`BSI (AD
`1 P4289 140%)
`
`
`
`
`
`
` inal growth fovtor recents:
`nat growth factor rategtas; HER Humian ep,
`
`Aounntaions in sduamods and
`:
`reciorocal
`
`BS
`
`
`
`:
`ssmiokers aan
`East Asens, choral axcusioy:
`
`
`LO Non-smadlcel vag carcino,
`mye:
`73) ax these
`bar dees “aon appear ro bean exclusive require
`coespaced with onby 144% {ten of
`mene as paticuns without musacions alsespan.
`without munadors: Overalisarvical was prolonged
`Atotal oF sis of BE parenrs whe weermpomed co
`im those with. mastations: (0:5 +s G6 months:
`
`have:
`partial
`responses
`os mmerked
` chaical
`p< 0.007). Goweversix patenn seh muriions
`fea bad seable
`i
`
`‘
`mopraverieat while on.
`therapy with TKis had
`ware nearespanders {
`ase and
`
`
`
`eeas thebestt
`& susie: Fy a
`wild-tage sequenoe: Incexons 18-0)
`
`nowy had progre
`
` © presence. of a seuna
`resent review, Pao.and colleagnes nowd char all che
`tréatraens}
`
`25 maations that bad been found in parienss
`vs
`confer susceptibility to 4
`may Bot
`
`geared swith THs were in patients who. were
`although the predictive value of muzaicions: for
`ig murvationg: had
`fespomders gO reatment
`tespanse-ny TKI therapyappears to he high, and
`
`tigar
` ecnmens from
`<
`been found among 29 tumor sf
`pethaps higher
`nan asy other velewany px
`patigets who woe reagunent refractory, Ins recent
`chameterisnes, Ho
`vever, dis needs to. be con-
`
`study from Korea, Parrand colleagues identified
`firmed in a prospective cual, Table 2 guiterarizes
`mutations in [7 of 90 consecutive patients weated
`the findings puldished co dare.
`
`betes
` Among the
`fents witht rau:
`with getuimb ¢
`Amalyses che—relationshipof
`
`
`
`sons, 65% (1) of 23) had! eespamses to treatments,
`HERMECER TR mnuasions and survival in farge
`
` Anthor
`
`EGER
`
`No
`
`Series
`
`inbibiter
`
`padients
`
`EGER.
`mutants/
`responders
`6/9
`iia)
`WIZ
`RIO
`CASK
`33
`
`EGFR mutante/ Race
`
`Refs
`
`nocresporsdoers
`
`ar
`
`
`
`%
`
`Glaccone et-ah
`66
`Caucasian
`Ghee
`O4
`Consecutive
`26
`Fatal
`
`
`
`
`
`WWWRELSODOICIIa 2 OETE
`
`Selected
`Selected
`
`a
`bLyach ef af
`wmAer Otel,
`“
`Pag ef at
`
`Paco al
`
`Lys
`AMMNOT AL
`
`Huanef af,
`Han et at
`Mésudemief af
`
`Getitimb
`
`Edotinite
`Cetuxined
`Getitnib
`
`Sefkteits
`
`
`
`16
`3
`24
`38
`ta
`3
`
`1G
`30
`58
`
`
`
`‘
`COmsscatie
`Codkecuive
`
`749
`VUet
`PALE
`
`Ve
`8/59
`534
`
`hinese
`Korean
`Japanese
`
`
`
`

`

`
`
`Phase UP tabooevlotinity, including the BR23
`
`
`stidy, are ongoing. However, die Rigetsdon that
`
`8 Nid decount jor
`HiERIE
`with che HERVEGER
`
`a made: based onthe data
`| BR,2"date tflat
`“The analysis
`Gam the
`in
`
`wed thacthe survival benatir
`(42.596 waprove-
` aHvs placebo},
`ment in miedian susvival wich &
`
`assimaing 3 10-15% rmurmsion mte among the
`paricnss it the coal, and chat all pariercs with
` s
`
`mons would have at least partial.
`resposis
`could wor be aecounsed for by the presence
`
`
`
`tons alone. However:
`in the ISEL study,
`
`
`
`
`vival conipared with gefitinib, which failed to dem:
`onstrate a survival benefic, Edaditib and gefiinib
`Be SenilerHf ooeciies, both belonging 1 the quina-
`
`
`
`si, butrhels bidlopic activiey ix differ.
`
`
`exatiaib bax beendound ro bese
`
`
`
`¢ than gefitinib in indiibit-
`least
`art times
`1
`
`ing purified TK GCs, 2 os 23-79 aM). ai
`
`discussed, big expose zethesedrugs
`
`and alasosy complere}
`
`
`
`
`appears ‘oo be necessaty f
`
`dovinentearn dtnaling, and ac thelr
`appiaved clind-
`cal
`doses
`ferlodcih, and gefiinih
`150 and
`250 ma/dey, respecrively), exposure tocedosinib x
`Moaxeo-
`
`several cies higher chanto pelinib ou:
`
`elylowdlases of bath offs
`
`ven while relac
`ib and
`gehiaib may be effecdve againsr cinioe with
`
`
`mangins HERMEGER, aigher doses snag bec
`sary te inhtbie the wiHe
`Dreceptarn, Dae a the
`
`relative cariy of HERE GER munsgious ip Cases:
`
`
`nang dose-asay be 2 4, ar bust ae Eurane'artd
`
`the USA. The siniarion naay be very difference in
`
`
`
`Asian oowicries, where MERLEGRE maurstions
`have heen teponud init pach higher praperdon of
`
`tos,
`and here geartnear with
`pation G4
`
`geluinib has heen eeported us improve survival
`SHUTSTHOTE
` cently, the presence of secondary
`hasbeen linked wish chs ulevelapenenr of resier
`Je YKis bx NSCLO. One
`
`rept
`
`paugat whe
`
`fa
`adh,
`
`i
`reapended 1 ge
`&
`RILEGEP yrntarepy
`plerenimsion on gefel
`and
`Of ag
`
`
`ence afa second point curation ak gositians790
`fT700M} of HERIVEGER, Anockey group slen-
`
`
`dhed the same maration da revo of five
`patients
`with acquired venistance to gehdail or erlotinib
`
`heme WHO
`piivand in a exch pat
`mer’ propeagsest
`on, adjuvant pefitinih after conmiplese resecdon.
`The meatatianceradd noe be deceered ze mereatesd
`
`hanor sumes.. Biochemie) analyses of reans-
`
`fecred Cells and’ prowily inhihinion sradiés with
`
`inag cancer céll Hisex, sageested. thar the T?90M
`
`
`mination confers
`redletance:
`to ALTER IMEGER
`
`
`
`moran that are usually
`sensitive co gefitinib or
`
`the gectnd tata
`etloritah
`
`
`waz, Ingercsnely
`at
`ROTinhilizas of a
`seis sensitive w anather
`
`‘
`
`
`class
`» whist
`diGercue chen
`2 Suppests thar sec-
`
`
`SER Tks may have « role
`ond generation EG
`
`the treatment of
`is disease,
`
`Enlotinid Insoanereatic cancer & other
`hurnox types & setings
`sg
`ctert Phase TH eal involving
`OD patients
`canter. etlodinib corabined: with,
`geincitabine was reported 4© dignificandy prc ong
`overall sumdvd Gb = 0.095) and ptogtessiondme
`tf
`BANS} catspowed with genicne
`surviveal fp
`Lae wit
`
`17% for
`
`
`GUaNE, WE
` 9 that ersiosinib cate be combined suce
`demonstra
`cessfully with chemodierspy.
`fatefescingly ous
`
`comewas sulf tiyproved with ox
`&
`
`
`Kome muiatians Gvbich ab
`naponse 1 HERIEGCER TRIS are presentip
`
`spare than 20%ofpancreatic cane
`
`The effect oferisdinib camabiitnan
`
` vapy haa
`
`alen by
`sined in Phase (hese
`
`
`& in a variety
`ofechr fuenor types verre
`Foresand nobSPU,
`
`
`FOLYL BOXS)1) be ww
`letieOva
`
`jenes with sold aumore ral
`
`tolerated ig ps
`
`
`
`
`Amosg 27 parients, Ove
`ul response
`
`and 1S bad stable disease as th
`best reapsSt,
`widence
`
`‘Trigo-and colleaguas: fond preliminary
`of antnumosacnelty foc she combinauonofeda-
`tint play capeciablas and docerael in
`
`j
`with merasraric breasr cancer
`
`Phase dial of 18 pationwith mecsninc
`
`erlotinib was found. ta. be generally
`ecral cancer,
`
`ation wih
`well volexared vehets teed ial nombre
`
`capecitabine
`and oxalghin (XYLO
`ava
`
`
`swith proven-aciiviny in chic
`wee.
` Phere. was.
`no plunbacekisetic.
`datersecion
`between theuhsee deugs, und aind-nanor actives
`was observed foverall, four panenis
`had a
`
`
`
`response anid LI had sable disease} oa.
`Erlotinid 150 mpfday has been exainined aS
`mocotherapy for a variety of advurwed velinctoyy
`ected Hf
`eancers, Phase TT snedies have been re:
`
`and
`head and neck ¢
`wasions cell cascar
`
`He wanas cancer
`RERIEGE Reape
`The
`rome: were promisinggiven the heavily prerecated
`narues of reastafthe path
`
`
`
`

`

`PadUe Peayspuustive
`y
`reported
`
`che
`are Mnnpartake poorer for
`deveiopinens ofertotineb ia
`
`
`afdisease:
`warligy sta
`than ia panedss vdeo hove dled’ hemotherapy
`
`
`so usually There is. stl ator co dearn swith segardao che bess
`mid ov modente in inemsiqn These resuls were
`approach ia the lategzeations pfagents: such ayule:
`
`
`dariBed ie the Fume I soul
`cintibs
`samdard cherpochenipe opines,
`
`particuduris in she rearrnenc of hung cagces,
`need ay second: or chi
` 2f
`
`
`patios oth sclapsed NSCLC.SQ afd
`Identifications of the clindesl: and meade
`and clashes were she most commen adverse
`prackers that predicerespouse 10 che TKis nayald
`
`
`eae sdecdon for clinical ataly and/or theen-
`eats. Wher adveise overs did ocas, they were
`pati
`mney nid os modemre le wevedty and were Oflcurton of pasenes likey abevelirdenen. shes:
`metg
`
`oan
`Ths: ache
`
`vasily -enanaged |
`se arent coon with
`apy Acthe geesene chun, thers dose nor appeaste
`
`combinadion eath chemhcrpy
`edunih in
`be a
`single acoutaie predictor of vespense,
`although: HA
`
`tegardiess of the mginion) wer seadar to those
`BREGEE mutations certainly debae
`
`with chemotherapy alone wich the exception of
`a specific grovp ofparients with NSCLCwho w
`muildicomoderate rash and chasthe:
`
`
`hencfle most afes, Further srucies are neem
`Among
`Hin mast beeell
`
`
`
`
`
`partuncs she received erionmb 159 ine/daveither
`to berter define rhe2.padenewhey,
` i
`tions af
`(n= 856) ot with chetsotherapy.
`from rreataient, his aay allow: pop
`a monorhyRFSRS
`
`
`fy
`~ L228), prade 3/4 rash and
`yameris co be dented for whom Sagdeagene
`
`is Dand O%of parents, x
`:
`erlotinih may be the roost appropriate trestmenr
`
`of pacicnesuequined adese reduction duc ta rash,
`for Hastdine systemic. chempy, either alae ot in
`ow. fe i most Hicombination with chemorhers
`
`
`and 16% due ts dianhea (erlotinih (tae
`
`nowever that combinarions with ¢sther agentswil
`ibing information, Genenieebs Seu
`
`*harmaceuricals
`and
`OX!
`be used. and this will-enlame che selection of
` JEMES QE larger EGGS.
`
`
`thong
`
` i deny cancer.
`
`
`
`rat eccomis for more than J
`
`
`
`
`
`tae
`
`pasients wish glioblastoma muddinnine is ongoing. ©GOnefasion
`
`
`and based on an interior analysis. vingle-azent
`ratemale for the use of HER VEGHER tar.
`
`trlosieib
`appeats 2G have acdviey in this mimor
`gered agents in NSCLC andarher nemar oypes 8
`wpe
`
`
`. WAner and colleagnes found chat sing
`vapelling. Ia madosized coareolled tial
`
`ages: ecotiih had minimal acusiy.in. pasenss.
`rats has heen demunarrared ce pravide +i
`
`
`
`wh advanced 3
`i
`
`
`
`with lacully adva:
`PO HISHAGRE
`PASE CAL
`IMIpPHRAVOTAEME INbs
`
`
`
`
`although high levels of HERI/EGE
`aad pancreas
`Rexprasian
`
`
`
`chemotherapy,
`have ner be
`fi reported mn brease rani
`L
`wieratality and converionee, and posible Cot
`
`Safehy & tolerdbility profife of x
`
`
`Rashwt ichis* aseally wuld at ax
`
`ie MbdianSuivival for patignts with advar:
`is Be
`pinents in chemozherasy have delivered: only modest
`
`Moalecudar- targeted therapies
`o Homan egidedn
`af Qrowth facter recep
`
`
`
`ry R
`continof cel
` ERV/EGEE are grapethe
`i growth and 3s in
`
`* Therapies that targ
`Eviotinits
`
`
`
`i
`
`
`
`
`tat plays e cent
`stget for news therapeutic seated:
`
`
`
`vated gravth of the tumor cell.
`of the new generation of agents.
`
` Kivrosine kinase:
`¥ Erlotiai is & potert, s@lactivenand raversibie inhiten af HE
`
`
`
`& Erlotisib Has semonstrased and
`“Tumor acthity a7 wire and avive in tumor xenagralt modeis.
`
`
`NAS demonst
`ain fenciorhlzed Controle
`
`in Survival, &s ¢ sige aged inna
`
`
`
`cell RING cancer and it comuination therapy in petle
`
`efeconiraendend ch
`
`
`WiATEMIACHOINeCoa
`
`457
`
`

`

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