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`Current Opinion
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`Phosphodiesterasc Inhibitors ‘.'_' CPI}
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`Leading Article
`Checkpoint Inhibitors as Nova;- '-< ncer Therapies
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`_ Review Articles
`Oral Anticoagulams
`. nsion Guidelines
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`Drugs
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`Vmume74- Nundwrl7-
`
`2014
`
`CURRENT OPINION
`
`l 983
`
`i993
`
`2015
`
`2033
`
`Phosphodiesterase Inhibitors l'or (‘hronie Obstructive Pulmonary Disease:
`What Does the Future Hold?
`
`MI}. Malera - I’. Rogliani . L. (‘alxella - M. Canola
`
`LEADING ARTICLE
`
`Clinical lmpael oi'Checkpoint Inhibitors as Novel (.‘aneer 'I'herapies
`K. Shih - H.-T. Arkenau - .l.R, Inl‘anle
`
`REVIEW ARTICLES
`
`New Ural Antieoagulants for the ‘l'reatment ol' Venous 'l‘hromboembolism:
`Understanding Differences and Similarities
`HP. Dohesh - .l. I‘anikos
`
`Updated National and International I-Iyperlension Guidelines: A Review
`of Current Reeormnendations
`
`S. Kjeldsen - RD. Feltiman . L. Lisheng - .i.-J. Mlllll'llli v(‘.—L-'. ('Iiiang . W. Xhang -
`7,. Wu - W. Li - B. Williams
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`ADIS DRUG [iVALl iA'I‘lONS
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`205Eu
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`Extended-Release 'l‘aeroliinus: A Review of Its Use in De Noyo Kidney
`
`'l‘ransplanlation
`I’.l.. McCormack
`
`2065
`
`2079
`
`Rioeiguat: A Review of Its Use in Patients with Chronic 'l‘hromlmembolir
`Pulmonary Hypertension or Pulmonary Arterial Hypertension
`KJ’. (ial'nuek—Jones
`
`l-ZmtrieitabinefRilpivirinef'l‘enol‘ovir Disoproxil Fumarate Single-'l‘ablet Regimen:
`A Review of Its lise in HIV Infection
`ILD. I.)eeks
`
`R&IJ lNSi(.iIlT RI‘ZI’UR'I‘
`
`20‘)?
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`Dulaglulide: First (:lobal Approval
`M. Sanford
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`Drugs Gill—it 7'11: luvs Etllfl
`l)t]|
`|li.|iill7ls4lilffi I'll-l-tlfiiifiufi
`
`LEADING ARTICLE
`
`Clinical Impact of Checkpoint Inhibitors as Novel Cancer
`Therapies
`
`Kent Shih - Hendrik—'I‘ohins Arkenau -
`
`.leti‘rey R. Infante
`
`Published onlinc: 25 (ictobcr 20H
`
`“1- The Authorts} Jill-l. This article is published nith open access at Springerlinkcom
`
`lmmttne responses are tightly regulated via
`Abstract
`signaling through nttmerous co-stintnlalm'y and co-inhibi-
`tory molecules.
`lisploitation ot‘ these immune checkpoint
`pathways is one ol the mechanisms by which tumors evade
`anth’or escape the immune system. A growing under-
`standing of the biology ol‘ immune checkpoints anti tumor
`immunology has led to the development of monoclonal
`antibodies designed to target co—stimulatory and co—inhib—
`itory molecules in order to rc-engage the immune system
`and restore antitumor immune responses. Anti-cytotoxic
`'l'—|yInphoeyte—associated antigen 4 t("l‘l.A—4) antibodies
`were among the lirst
`to be tested in the clinic. and ipi—
`limumab was
`the
`first
`immune checkpoint
`inhibitor
`
`approved l'or an anticancer indication. Agents targeting the
`programmed death I tPl)—l)pathway. either PD—l orone of
`its
`ligands. programmed death ligand I. are in active
`clinical development
`For numerous cancers.
`including
`advanced melanoma and lung cancer. Understanding the
`dil'l'erent mechanisms
`ol‘ action.
`safety profiles.
`and
`
`response patterns associated with inhibition of the ("FLA-4
`and PD—l pathways may improve patient management as
`these therapies are moved in to the clinical practice setting
`and may also provide a rationale for combination therapy
`with different
`inhibitors. Additional
`immune checkpoint
`
`molecules with therapeutic potential. including lymphocyte
`activation
`gene-3
`and
`glucocorticoid-indttced
`tumor
`necrosis factor receptor-related gene. also have inhibitors
`in early stages ol‘ clinical development. Clinical responses
`and sal‘ety data reported to date on immune checkpoint
`
`This article is part ol' the topical collection on |mtnun:i—(lncology.
`—___#__—_
`
`.l, R. Inl'antc
`K. Sliili ti".‘t - l|.-'l'. Arkcnau -
`Sarah t’annou Research Institute and 'l'ennessec {Jncology H .l.( I
`Nashville. TN .ii‘lllfi. l’SA
`e mail: ksliilt(“'IItottc.coitt
`
`inhibitors suggest these agents may have the potential
`markedly improve outcomes lor patients with cancer.
`
`to
`
`Key Points
`
`Immune checkpoint inhibitors are designed to
`interrupt inhibitory immune signals and restore
`immune responses against tumors.
`
`Numerous immune checkpoint inhibitors are in
`advanced stages of development and show activity
`across multiple tumor types. including advanced
`melanoma and advanced non—small-cell lung cancer.
`
`Understanding the mechanistn-associated adverse
`events and response patterns is important to the
`management of patients as these drugs are moved
`into the clinical practice setting.
`
`I
`
`Introduction
`
`Rudolph Vircltow may have been one ol‘ the first physi—
`cians in modern times to observe the link between the
`
`imtnunc systetn and malignancy in what he termed “lyin—
`phoreticular intiltrates". 'l'hesc intiltrates were leukocytes
`surrounding malignant
`tumors. and he hypothesized that
`proinllannnatory states might
`induce normal
`tissues to
`
`become malignant [I I. Since then. we have learned a great
`deal about how the immune system responds and reacts to
`tumors. which tumor—specific antigens are recognized as
`foreign. and how immtlne responses can be manipulated
`and harnessed to enhance tumor cell killing.
`
`A Adis
`
`

`

`K. Shill el al.
`| 904
`
`
`Recently. it has been recognized that. on its own. tumor
`peptide presentation by major histocompatibility complex
`tMl-K‘)
`to 'l‘—ccll
`receptors is
`inadequate for successful
`'l‘-cell activation and immune destruction ot‘ cancer cells.
`
`(To-regulatory signals. eitlter inhibitory or stimulatory. are
`also required 12. 3t. T cells play a critical role in cell—
`mediated tutnor itntnunity. and do so through an intricate
`counterbalance ot‘ co—stintulatory and co—inltihitory cell—to-
`celi signals between various components of the immune
`systettt.
`'l‘his systetn of checks and balances is necessary
`ttot only to allow a powerl’ul destructive response against
`both pathogens attd tnalignancies.
`l'ItIl also to prevent
`immune responses from heittg generated against normal
`tissues.
`(.‘t'itical
`‘chcckpoints' control and line-tune the
`immune system through regulation ol' this complex net-
`work ol‘ co—stimulatory and ctr-inhibitory signaling 13}.
`in
`this paper. we review some. of the important
`immune
`checkpoint molecules elucidated to date. as well as el'l'orls
`to block these molecules in order to shift
`the balance
`
`towards antitumor immunity. We also describe some of the
`
`and challenges encountered using these
`complexities
`checkpoint inhibitors in the clinic.
`
`2 Cytotoxic 'I‘-Ivymphoeyte-Associated Antigen
`(C’l‘LAl-4
`
`ll Background
`
`More than 40 years of research has led to the development
`ot‘ a two—signal
`theory ol'
`'l‘—cell activation: antigenic
`stimulation of the 'l'—cell receptor t'l'(‘R) [signal I) together
`with eo-slimulation by other molecules on the cell surl‘ace
`(signal 2) f2. KI. One of the key co~sti|tttllatory mechanisms
`involves tlte interaction ol‘ (1)28 on the surl'ace ol‘ tire T
`
`cell with B? molecules (‘on or €on on antigen—pre—
`senting cells. ("FLA—4. a transmemln'ane glycoprotein with
`considerable homology to CUES. binds to the same l5?
`ligands. as such (Fig.
`it. Upon 'l‘f‘R stimulation by anti-
`gens. T cells express ("FLA—4. which can hittd B7 mole—
`cules: however, unlike (”028.
`(TIA—4 inhibits 'l‘—cc|!
`
`l'or ntaintenance of immune
`important
`responses artd is
`tolerance. Expression ol'
`("FLA—'4 raises the activation
`
`threshold and attenuates clonal expansion: thus. a produc-
`tive. T—cell response ensues only upon a net co—stintttlatory
`signal.
`
`2.2 Hl‘tieacy ol‘ ("FLA—4 inhibitors
`
`2.2.! i‘pit't'initnmb
`
`tpilimumab. one ot‘ the. best—studied monoclonal antibodies
`targeting (."['l.A—4 [table 1
`I4-- top. has been evaluated in
`
`A Adis
`
`Antigen presenting cellt'Tumor
`
`T cell
`
`MHC class I or ll-
`
`GAL9
`
`enso orcnae --q—o'
`\
`
`CD80 or CDSB
`
`F‘D-L‘l or PD-L2
`
`'l‘-ccll activation and immune checkpoint pathways. ‘l'-ce|l
`l
`Fig.
`activation requires tvro signals: tl} presentation ol‘ antigenic peptides
`by MlIC to the TCR and IE: co-stimttlalion. typically via (‘DZKzt'Ufiti
`or ('ozsi‘nse ligation.
`Immune checkpoint pathways comprising
`receptors on T cells and ligands on antigen-presenting cells andi’or
`tumors line—lune immune responses via 'l'—cell activation or inhibition.
`("Fiat-4 cytotoxic 'l‘-lymphocyle—associaletl antigen 4. (MM) galec—
`tin-9. (EH'R glueocorticoid-induccd 'I‘Nl" receptor—related gene. (HT-
`Rl’. gILlcoc:irlicoid—induced 'I‘Nl" receptor-related gene ligand. L-lU-J’
`lymphocyte activation gene-3. MHE.‘ major histoeompatihilily cont—
`ples. PD-i programmed death— I. Pill—{.1 programmed death ligand |.
`{JD-LE programmed death ligand 3. KW 'l‘-cell receptor. 'f'iMa'
`'I'-eell
`immtmoglobulin and ntucin domain 3. TN!" tttlnor necrosis lactor
`
`a clinical trial program of more than 2,000 patients with a
`variety ot‘ solid tumors I4. 5.
`li—l‘Jl.
`lpilimumab (Yer-
`voym J. administered every 3 weeks for four doses. gained
`US FDA approval in 20! | for the treatment ot‘ unreseclable
`or ittetastatic melanoma. based on data from two phase [I]
`randomized trials showing improvement on ntcdian overall
`survival (03) over control arms in patients with melanoma
`
`triais evaluated
`E4. 5. 2(}|. One of the pivotal phase [ll
`ipilitnumab with or without gpitlt] vaccine in previously
`treated patients with advanced melanotna. Although the
`best overall response rates were modest.
`lt).9 '95
`in the i—
`pilittttunab—alone group and 5.? ‘3'?- in the ipilimumah plus
`gplttt) vaccine group. some patients in both groups main—
`tained an objective response For at least ’2 years I4I. In this
`trial. the 3-year OS rate for ipilimumab tnonotherapy was
`20 "it.
`l4]. which cotnpares t‘avorahly with the 3—year ()3
`rate of 13'
`‘Zr. for historical control patients receiving stati—
`dard of care chemotherapy in a separate clinical trial |2t|
`['l'able 2 I4. 5. 7.
`l8.
`l9. 2 | —33l}. The other pivotal phase.
`[ll
`trial was conducted in treatment-naive patients with
`metastatic melanoma
`and compared ipilintuntah pltts
`dacarbazine versus dacarbazine plus placebo [5|. Although
`the dose and schedule Were slightly different.
`the rate ol‘
`best overall
`response was 15 ‘ii
`in the ipilintuntah plus
`dacarhaxinc group versus It) ‘J’r- for the dacarhazine plus
`
`

`

`Immune (‘heckpoinl Inhibitors in Cancer
`
`I‘mfi
`
`Table l
`
`
`Immune checkpoinl inhilnlors in clinical decelopnwnt l-l—lhl
`
`
`
` Name (‘umpany Description of agent
`
`
`
`lpil'nnumah I4. 5|
`‘l'retnelil‘mlnmh |o|
`Peml‘nmtizumah (M K3415} I'll
`Ni\-'olumah {EMS—(136658] |H|
`l‘itlilimmah [CT-{ll I: I‘ll]
`AMP-224 |l[ll
`I'VII’IMJZBUA lll. l3]
`BMS-‘BnSSU llfil
`MliDHT-lo II-ll
`lMl’32] ||5|
`TRXSIX ||6|
`
`lluman lgUl mAh against ("ILA-4
`Bristol-Myers Squibb
`l-lunlan lg(i3 mAh againsl ("HA-4
`Med]mnumelAslraZencca
`Ilnnlanixed lg(i—l tnAh against I’D-l
`Merek
`Human IgCE-l mA‘n againsl I’D—l
`Bristol-Myers Squibb
`l-lunlanired lgUl mAh againsl PD-l
`(‘ure'l'eelt
`|’I)-l.3-lg(i I‘UCtll'Ill'lll'lillll
`l'usion prolcin
`Amplimmune'. (llamSmilhKlinc
`lluman lg(i mAlu agaiusl I’D-H
`(ienenleeln’Roclte
`Human lgG-J nmh aga'tnsl I’ll—Ll
`BrisIoI-Myers Squibb
`Human nmh againsl l’l)—l.|
`MedlmmanefAsIraZeneca
`Soluble LAG-3 lg I'usion protein and MIIC' elass‘ || agonisl
`lmmulep
`
`GITR. Inc llumanized mAh against (il‘l‘R
`
`immu—
`.u'gt’;
`(‘HAA-J cytotoxic ‘[‘-l5mphoeyte-assnc'talcd anligen 4. (EUR gluesJeorlicoid-indueed Imnur necrosis factor receplolwrelaled gene.
`noglohulin (F. Uta-fl lymphocyle aelivalion gene-3. mx‘th momelonal antibody, MHC major hisloconunuihilit)‘ complex. I’D-I programmed
`death I. I’D-H programmed death ligand l. Hit-L3 programmed death ligand 2
`
`Table 2 Preliminary el'licacy data will] immune checkpoint
`El 33]
`
`l‘nead—lo-ltead: Irials" l4. 5. 7. 17.
`inhihilors or controls from individual tnut
`
`
`IX.
`
`Median 08
`Survival rale
`Rel'erencetst
`Athaneed tumor setting
`Agent or cnnlrnl
`Median l’l-‘S
`__—_.————-—-—-——-—-—————
`
`Melanoma
`
`(‘TX (("l‘X-mn‘ve pls}
`
`ND
`
`l).l—lt).? months
`
`lpilinnunah
`'I'remelimumah
`
`Pemhrolizulnah
`Nivolunlal‘n
`
`l’itlilimmah
`
`Nimlumah plus ipilimunlah
`
`2}) monlhs
`NI.)
`
`5.5 monlhs
`3.? months
`
`1.9 munlhs
`
`37 weeks
`
`HM monlhs
`12.6 months
`NR
`17.3 months
`
`NI)
`4“ months
`
`NSCIL‘
`
`("I‘X [(“l‘X-nai've pls]:
`
`4.3 monlhs
`
`3.3 months
`
`l’elnl'nmlimmab
`
`Ill—3'." necks"
`
`SI neeks
`
`|-_\‘ear: if) fit
`3-year:
`l2—l7 9?
`Buyeur: 220 ‘5'}
`J‘s-ear: 2! ‘3’}
`1-year:
`(3‘) Eli
`1—year: ()3 fit
`fi—year: 4|
`‘St
`1-year: (15 ‘9?
`1-year: 35 ‘9}
`2-year: 7‘) ‘9?
`|-_\rear: 3‘) {'1'
`2-year:
`l8 9.5
`NI)
`
`Niwnlumuh ipreviously-lI’ealcd pts:
`
`2.3 months
`
`9.9! nlonlhs
`
`1-year: 43 {it
`3-year: 34 G?
`1-year: 19 ("Ir
`3-year: t 25 “.4
`25-year: k 35 ‘9}
`l-year: 4t} ‘3?
`_ year
`IS "t
`1-year: 4T ‘3:
`| Ll Inunlhs
`4.“ months
`lpilimnmah
`
`
`IS. 21]
`
`H]
`I2”
`|7|
`IZZ
`
`IE}!
`IE—H
`
`113]
`
`|25--27l
`
`|28|
`
`|2*J|
`|3tl- HI
`[331
`Hill
`
`||?|
`
`R(‘{"
`
`(‘RPC
`
`Nix-'oltnnah [(‘TX-na'l're plst
`Soral'enih
`l‘vl'n-‘olumal:l
`
`Placebo
`
`3o.l weeks
`3.6—5.7 months
`3.1—4.2" months
`
`1| nlnnllts
`
`NR
`l I.(l- 10.2 months
`”.2443“ months
`Ill.” mnnllts
`
`('Ri’t‘.‘ eastration—resistant ln'oslale cancer. (TX chemotherapy. ND no data. NR nnl reached. N.S'('I.(' non small-cell
`survival. I’I'ZS' progressiondl‘ree survival. prs pallenls. Rt‘t’ renal cell carcinoma
`"
`lmporlanl: data an: not from head-lo-head Irials. and the II'ials dil't'cr It}; patienl characteristics. paliem numhcrs. and length nl' follow-up.
`lhcrel'ore direct comparisons across Irials and agenls have limited validilyz trials in tumor Iypes wilh l’l"S and ()3 data were included
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`l‘J‘Jo
`—___—___—————_——-———
`
`placebo group. while lltc median dttration ol‘ response was
`19.3 versus til months for the dacarbaaine plus placebo
`group. Responses lasting at least 2 years were observed in
`both treatment groups. The 3—year survival rate with ipi—
`litntunab plus dacarbaxine was significantly higher than
`dacarbazine plus placebo: 20.8 versus IEQ ‘9’? ti" 6 l).(l[l| l.
`lpilimumab was evaluated as adiuvant therapy INIou-ing
`complete resection of stage Ill melanoma ill a phase III
`trial
`in patients at high risk ol' recurrence I34]. Patients
`receiving ipilimtttnab had a signilicantly increased median
`US as compared with patients receiving placebo: lot
`versus Ill months {P _' (liltilil.
`'l'he 3~ycar
`rates ol‘
`recurrence—tree survival were 47 9:
`for
`ipilimumab and
`35 ‘Ii- for placebo.
`chemotherapy can
`that
`suggest
`Preclinical
`studies
`indttce the release ol‘ tumor—specific antigens. thereby ini—
`tiating 'l'—cell activation and sensitizing tumor cells to
`’l‘—cell—tnediated killing I35l. These observations provided
`the rationale t'or combining inmmnotlterapy with cytotoxic
`agents to improve responses in patients with melanoma.
`and also led to the initiation of clinical
`trials evaluating
`
`ipilimumab with chemotherapy in lung cancer. A phase II.
`randomized study provided evidence that sequential
`ipi—
`Iiinumab is more effective than concurrent
`ipilitnumab
`when administered with paelitaxeltearbtiplatin in chemo—
`therapy—naive stage. [“8er patients with non—small-cell
`lttng cancer INSCII). The median 08 with sequential
`i—
`pilimumab. concurrent
`ipilimumab. and the control
`regi—
`men was IZQ. 9.7. and 8.3 months. respectively.
`In this
`trial. patients with squamous histology exhibited better
`outcomes [median immune-related progression-tree sur—
`vival
`|irPliSl and US) with sequential
`ipilimumah dosing
`than did patients with non-squamous histology list. Based
`on these findings. a phase III trial evaluating ()S in patients
`with squamous NSCLC.‘ receiving sequential
`ipilimumab
`alter chemotherapy was initiated [Table 3 | loll.
`lpilitnumah is also being investigated in the setting of
`metastatic castration—resistant prostate cancer ('m('RP('}. in a
`
`phase lll trial ot' ipilimumab versus placebo in post—docetasel
`patients with mC‘RPC receiving a single dose of radiother—
`apy, the primary endpoint of ()5 was not reached: hoWever.
`pre-spccilied subset analyses suggested that ipilitntttnab may
`he more active in patients with favorable prognostic l'actors.
`including no visceral disease. alkaline phosphatase (11.5
`upper
`limit ol' normal. and hemoglobin :ll gi’dl.
`ll7l.
`Rcsults from this study support
`the investigation ol‘
`ipi-
`limumab in the ongoing phase it]. (.‘Alti—l—U95 study among
`chemotlierapy—naive patients with m(‘Rl’(’ t'l‘able 3 [top
`
`2.2.2 7i‘t'mct't'mttmrth
`
`Tremelimtmiab is a hilly human immunoglobulin (E tlg(.it-
`2 monoclonal antibody targeting ("ILA—4 Iol t'l'able I H
`
`A Adis
`
`loll. 'l'rcmelimunuib provided durable responses in (if) "/0
`ol' patients in a phase [[
`trial of patients with advanced
`melanoma. as compared with the objective response rates
`(ORRsl of 5.7 and 10.9 ‘24 seen in the phase Ill
`trial ot'
`
`ipilinttttnab with or without vaccine I4. bl. However. the
`phase.
`[ll
`trial of tremelinmmab monotherapy failed to
`demonstrate a statistically significant survival advantage
`over chemotherapy in lirst~1inc treatment ot~ patients with
`metastatic melanoma till ]. Patient selection criteria. dosing
`
`regimen. anti use of ipilimumab as salvage therapy for
`patients in the control arm were potential reasons for the
`lack of survival benetit.
`
`'l‘remelimumab showed evidence of activity against
`
`previously treated malignant mesothelioma in a small
`tN : 29} phase It single—arm trial l36|.
`l't‘out’ patients had
`partial
`responses. and It patients had stable disease at
`median duration 7.? months {range 2.(i—|6.6+l. with a
`median ()8 til I 1.3 months. Based on these results. a phase
`
`trial of tremelimumab in malignant mesothelioma has
`II
`been initiated t'l'able J | loll.
`
`2.3 Sat'ety ol‘ (TIA—4 Inhibitors
`
`The cumulative safety data across many trials show that
`agents that inhibit ("FLA-4 are generally safe. with unique.
`but usually manageable. side el’t‘ects that are linked to their
`tnechanistn ol' stimulating immune responses. Multiple
`phase It and III
`trials have characterized these immune-
`related adverse events tit'Al‘Ls) of CTLA-4 inhibition.
`()verall.
`irAlis vvere observed in SSw-(fl ‘70 of patients
`
`treated with ipilimumab. with 5—26 % of patients experi—
`encing grade 3:4 irAEs I4. [7. 3?] {Table 414.18, l2—l4.
`ii. 2t. 2.3. 2b. 28. 3h. 38-401).
`In the phase III
`trial
`investigating ipilimumab treatment with or without vac—
`cine. skin—related irALis (including pruritus. rash. and ery—
`themal and gastrointestinal
`irAlis (including diarrhea and
`colitis} were the tnost common. occurring in 29—44 9t.- ot‘
`patients; endocrine disorders were reported in 4—8 9?: ot‘
`patients Hf. Some of the more rare adverse events (Alisl
`
`reported during treatment with ipi—
`for each)
`til'l Ci
`litmtmah include uveitis. conjunctivitis. and neuropathy
`[37].
`Interestingly. when ipilimumah was given with
`dacarbarine.
`immune-mediated grade 314 hepatitis occur—
`red in 32 Ut- of patients. while the rates of gastrointestinal
`events. such as coiitis. were lower titan expected based on
`previous trials I5I. As adjuvant therapy. ipilimttmah had a
`sal'ety prolile generally consistent with that seen in patients
`with advanced melanoma. although the incidence ot‘ some
`irAlis
`leg. endoerinopathiesl was higher. Also.
`live
`patients (I 9t ] in the ipilimumab artn died due to treatment-
`related Alis versus {1 patients in the placebo group [34L
`'l'remelimumab has a similar irAli profile to ipilimumab.
`The most
`common
`irAlis with
`tremelimumab were
`
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