2014, Vol. 74, No. 17 (pp. 1983-2104)
`ISSN: 0012-6667(Print); 1179-1950 (Online)
`
`NO. 17 (2014
`ral Collection
`R89292G
`11-26 10:43:42
`
`
`
`
`
`
`Drugs
`
`
`
`
` PXPepermaclie
`
`
`LES
`ativefateh
`
`:ee, ofovir DF
`Extended-Release Ta
`
`
`Current Opinion
`PhosphodiesteraseInhibitors . fo)urs
`
`
`a
`Leading Article
`CheckpointInhibitors as Novel( PinteaeWits)
`
`
`
`
`
`
`PROPERTY OF THE
`NATIONAL
`LIBRARY OF
`ie)
`PUIBR.
`eee=MEDICINE
`
`Maia.aa
`Sle Anticoagulants
`
`>;
`
`Genome & Co. v. Univ. of Chicago
`IN iNdis PGR2019-00002
`-—
`UNIV. CHICAGO EX. 2034
`
`

`

`Drugs
`
`Aims and Scope
`Drugs promotes optimum
`pharmacotherapy by providing a
`programmeofreview articles covering
`the most important aspects ofclinical
`pharmacologyandtherapeutics.
`
`The Journal includes:
`
`* Leading/current opinionarticles
`providing an overview of emerging or
`contentious issues
`Definitive reviews of drugs and drug
`classes andtheir place in patient
`Management
`Therapy in Practice articles including
`recommendations for specific clinical
`situations
`
`High-quality original clinical research
`Adis Drug Evaluations reviewing the
`properties and place in therapy of both
`newerandestablished drugs
`Adis R&D Insight Reports summarising
`development at first global approval
`
`All manuscripts are subject to peer
`review by international experts. Letters
`to the editor are welcomedand will be
`considered for publication.
`
`Copyright Information
`For Authors
`As soon as anarticle is accepted for
`publication, authors will be requested
`lo assign copyright of the article (or
`to grant exclusive publication and
`dissemination rights) to the publisher
`(respective the owner if other than
`Springer). This will ensure the widest
`possible protection and dissemination of
`information under copyright laws.
`More information about copyright
`regulations for this journal is available at
`www.springer.com/40265
`For Readers
`While the advice and informationin this
`
`journal is believed to be true and accurate
`at the date ofits publication, neither the
`authors, the editors, nor the publisher can
`accept any legal responsibility for any
`errors Or omissions that may have been
`made. The publisher makes no warranty,
`express or implied, with respect to the
`material contained herein.
`
`4 Adis
`
`The Americas (North, South, Central
`America and the Caribbean)
`Springer Journal Fulfillment
`233 Spring Street, New York
`NY 10013-1578, USA
`Tel.: 800-SPRINGER (777-4643):
`212-460-1500 (outside North America)
`journals-ny@springer.com;
`servicio-ny@springer.com
`(Central and South America)
`
`Outside the Americas
`
`Springer Customer Service Center GmbH
`Haberstr. 7, 69126 Heidelberg, Germany
`Tel.: +49-6221-345-4303
`
`subscriptions@springer.com
`
`Advertisements
`E-mail contact: advertising@springer.com
`or anzeigen@springer.com
`
`Disclaimer
`Springer publishes advertisements
`in this journal in reliance uponthe
`responsibility of the advertiser to comply
`with all legal requirements relating to the
`marketing andsale of products or services
`advertised. Springer andthe editors are
`not responsible for claims madein the
`advertisements publishedin the journal.
`The appearance of advertisements in
`Springer publications does not constitute
`endorsement, implied or intended, of the
`product advertised or the claims made for
`it by the advertiser.
`
`Office of Publication
`Springer International Publishing AG,
`GewerbestraBe 11,6330 Cham, Switzerland
`
`SpringerInternational Publishing is part of
`Springer Science+Business Media
`
`Editorial Staff
`Editorial Director: Diana Faulds
`Editorial Assistant: Carole Pearson
`
`All articles publishedin this journal
`are protected by copyright, which covers
`the exclusive rights to reproduce and
`distribute the article (e.g., as offprints),
`as well as all translation rights. No
`material published in this journal may
`be reproduced photographically or
`stored on microfilm, in electronic data
`bases, on video disks, etc., without
`first obtaining written permission from
`the publisher (respective the copyright
`owner if other than Springer). The use
`of general descriptive names, trade
`names, trademarks, etc., in this
`publication, evenif not specifically
`identified, does not imply that these
`hames are not protected by the relevant
`laws and regulations.
`Springer has partnered with Copyright
`Clearance Center's RightsLink service
`to offer a variety of options for reusing
`Springer content. For permission to
`reuse our content please locate the
`material that you wish to use onlink.
`springer.comor on springerimages.com
`and click on the permissions link or
`go to copyright.com andenter the
`title of the publication that you wish
`to use. Forassistance in placing
`a permission request, Copyright
`Clearance Center can be contacted
`directly via phone: +1-855-239-3415,
`fax: +1-978-646-8600 or e-mail:
`info@copyright.com.
`
`© SpringerInternational Publishing
`Switzerland 2014
`
`Journal Website
`
`www. springer.com/40265
`Electronic edition: link.springer.com/
`journal/40265
`
`Subscription Information
`Drugsis published 18 times a year.
`Volume74 (18 issues) will be published
`in 2014,
`
`ISSN: 0012-6667 print
`ISSN: 1179-1950 electronic
`
`Forinformation on subscription rates
`please contact Springer Customer
`Service Center:
`
`

`

`Drugs
`yolume 74 - Number17 -
`
`2014
`
`CURRENTOPINION
`
`1983
`
`Phosphodiesterase Inhibitors for Chronic Obstructive Pulmonary Disease:
`What Does the Future Hold?
`
`M.G. Matera - P. Rogliani- L. Calzetta - M. Cazzola
`
`LEADING ARTICLE
`
`1993
`
`Clinical Impact of Checkpoint Inhibitors as Novel Cancer Therapies
`K. Shih - H.-T. Arkenau- J.R. Infante
`
`2015
`
`2033
`
`205
`
`ot
`
`2065
`
`2079
`
`REVIEWARTICLES
`
`NewOral Anticoagulants for the Treatment of Venous Thromboembolism:
`Understanding Differences and Similarities
`P.P. Dobesh- J. Fanikos
`
`Updated National and International Hypertension Guidelines: A Review
`of Current Recommendations
`S. Kjeldsen - R.D, Feldman - L. Lisheng - J.-J. Mourad » C.-E. Chiang » W. Zhang-
`Z. Wu: W.Li- B. Williams
`
`ADIS DRUG EVALUATIONS
`
`Extended-Release Tacrolimus: A ReviewofIts Use in De Novo Kidney
`Transplantation
`P.L. McCormack
`
`Riociguat: A ReviewofIts Use in Patients with Chronic Thromboembolic
`Pulmonary Hypertension or Pulmonary Arterial Hypertension
`K.P. Garnock-Jones
`
`Emtricitabine/Rilpivirine/Tenofovir Disoproxil Fumarate Single-Tablet Regimen:
`A ReviewofIts Use in HIV Infection
`E.D, Deeks
`
`R&D INSIGHT REPORT
`
`2097
`
`Dulaglutide: First Global Approval
`M. Sanford
`
`Furtherarticles can be foundat link.springer.com
`
`Indexed in MEDLINE, EMBASE, International Pharmaceutical Abstracts (IPA), BIOSIS Previews, BIOSIS
`Reviews Reports and Meetings, Current Contents/Clinical Medicine, Current Contents/Life Sciences,
`SciSearch, Science Citation Index, Journal Citation Reports/Science Edition, Prous Science Integrity,
`CINAHL, PASCAL, Chemical Abstracts Service, Sociedad theroamericana de informacion Cientifica
`(SNC), and Jowrnalsa@OVvip
`
`Instructions for authors for Drives are available at www.springer.com/40265
`
`A\ Adis
`
`

`

`
`
` This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Drugs (2014) 74: 1993-2013
`DOL LO. L007/s40265-014-0305-6
`
`LEADING ARTICLE
`
`Clinical Impact of Checkpoint Inhibitors as Novel Cancer
`Therapies
`
`Kent Shih + Hendrik-Tobias Arkenau -
`
`Jeffrey R. Infante
`
`Published online: 25 October 2014
`
`© The Author(s) 2014, This article is published with open access at Springerlink.com
`
`inhibitors suggest these agents may have the potential
`markedly improve outcomes for patients with cancer.
`
`to
`
`KeyPoints
`
`Immune checkpoint inhibitors are designed to
`interrupt inhibitory immune signals and restore
`immune responses against tumors.
`
`Numerous immune checkpoint inhibitors are in
`advancedstages of development and show activity
`across multiple tumortypes, including advanced
`melanoma and advanced non-small-cell lung cancer.
`
`Understanding the mechanism-associated adverse
`events and response patterns 1s important to the
`management of patients as these drugs are moved
`into the clinical practice setting.
`
`1
`
`Introduction
`
`Immune responses are tightly regulated via
`Abstract)
`signaling through numerous co-stimulatory and co-inhibi-
`tory molecules. Exploitation of these immune checkpoint
`pathways is one of the mechanisms by which tumors evade
`and/or escape the immune system. A growing under-
`standing of the biology of immune checkpoints and tumor
`immunology has led to the development of monoclonal
`antibodies designed to target co-stimulatory and co-inhib-
`itory molecules in order to re-engage the immune system
`and restore antitumor immune responses. Anti-cytotoxic
`‘T-lymphocyte-associated antigen 4 (CTLA-4) antibodies
`were among the first
`to be tested in the clinic, andipi-
`limumab was
`the
`first
`immune checkpoint
`inhibitor
`approvedfor an anticancer indication. Agents targeting the
`programmeddeath | (PD-1) pathway, either PD-1 or one of
`its
`ligands, programmed death ligand 1, are in active
`clinical development
`for numerous cancers,
`including
`advanced melanoma and lung cancer. Understanding the
`different. mechanisms of action,
`safety profiles,
`and
`response patterns associated with inhibition of the CTLA-4
`and PD-| pathways may improve patient management as
`these therapies are movedinto the clinical practice setting
`and may also provide a rationale for combination therapy
`with different
`inhibitors. Additional
`immune checkpoint
`Rudolph Virchow may have been one ofthe first physi-
`molecules with therapeutic potential, including lymphocyte
`cians in modern times to observe the link between the
`
`activation glucocorticoid-induced—tumorgene-3 and
`
`
`immune system and malignancy in what he termed “lym-
`necrosis factor receptor-related gene, also have inhibitors
`phoreticular infiltrates”. These infiltrates were leukocytes
`in early stages ofclinical development. Clinical responses
`surrounding malignant
`tumors, and he hypothesized that
`and safety data reported to date on immune checkpoint
`
`proinflammatory states might
`induce normal
`tissues to
`become malignant [1]. Since then, we have learned a ereal
`This article is part of the topical collection on Immuno-Oncology.aESSeSeeee
`deal about how the immune system responds andreacts to
`tumors, which tumor-specific antigens are recognized as
`foreign, and how immune responses can be manipulated
`and harnessed to enhance tumorcell killing.
`
`K. Shih (>¢) - H.-T. Arkenau - J. R. Infante
`Sarah Cannon Research Institute and Tennessee Oncology PLLC,
`Nashville, PN 37203, USA
`e-mail kshih@tnone.com
`
`4 Adis
`
`

`

`K. Shih et al.
`1994
`
`
`Recently, it has been recognized that, on its own, tumor
`peptide presentation by major histocompatibility complex
`(MHC) to T-cell
`receptors is
`inadequate for successful
`T-cell activation and immune destruction of cancercells.
`Co-regulatory signals, either inhibitory or stimulatory, are
`also required [2, 3]. T cells play a critical role in cell-
`mediated tumor immunity, and do so through an intricate
`counterbalance of co-stimulatory and co-inhibitory cell-to-
`cell signals between various components of the immune
`system. This system of checks and balances is necessary
`not only to allow a powerful destructive response against
`both pathogens and malignancies, but also to prevent
`immune responses from being generated against normal
`tissues. Critical
`‘checkpoints’ control and fine-tune the
`immune system through regulation of this complex net-
`work of co-stimulatory and co-inhibitory signaling [3]. In
`this paper, we review some of the important
`immune
`checkpoint molecules elucidated to date, as well as efforts
`to block these molecules in order to shift
`the balance
`
`towards antitumor immunity. We also describe some ofthe
`complexities
`and challenges encountered using these
`checkpoint inhibitors in the clinic.
`
`2 Cytotoxic T-Lymphocyte-Associated Antigen
`(CTLA)-4
`
`2.1 Background
`
`More than 40 years ofresearch has led to the development
`of a two-signal
`theory of T-cell activation: antigenic
`simulation of the T-cell receptor (TCR) (signal 1) together
`with co-stimulation by other molecules on the cell surface
`(signal 2) [2, 3]. One ofthe key co-stimulatory mechanisms
`involves the interacuon of CD28 on the surface of the T
`cell with B7 molecules CD80 or CD86 on antigen-pre-
`senting cells. CTLA-4, a transmembrane glycoprotein with
`considerable homology to CD28, binds to the same B7
`ligands, as such (Fig. 1). Upon TCR stimulation by anti-
`gens, T cells express CTLA-4, which can bind B7 mole-
`cules; however, unlike CD28, CTLA-4 inhibits T-cell
`responses and is
`important
`for maintenance of immune
`tolerance. Expression of CTLA-4 raises the activation
`threshold and attenuates clonal expansion; thus, a produc-
`tive T-cell response ensues only upon a net co-stimulatory
`signal.
`
`2.2 Efficacy of CTLA-4 Inhibitors
`
`2.2.1 Ipilimumab
`
`{[pilimumab, one ofthe best-studied monoclonal antibodies
`targeting CTLA-4 (Table |
`[4—16]), has been evaluated in
`
`4\ Adis
`
`Antigen presenting cell/Tumor
`
`T cell
`
`MHCclass| orIl ,
`
`GALS
`
`CD80 or CD86 em
`|
`
`CD80 or CD86
`
`PD-L1 or PD-L2
`
`1 T-cell activation and immune checkpoint pathways. T-cell
`Fig.
`activation requires two signals: (1) presentation ofantigenic peptides
`by MHC to the TCR and(2) co-stimulation, typically via CD28:CD80
`or CD28:CD86ligation.
`Immune checkpoint pathways comprising
`receptors on T cells and ligands on antigen-presenting cells and/or
`tumors fine-tune immune responses via T-cell activation or inhibition.
`CTLA-4 cytotoxic T-lymphocyte-associated antigen 4, GALY galec-
`tin-9, G/TR glucocorticoid-induced TNFreceptor-related gene, G/T-
`RLglucocorticoid-induced TNF receptor-related gene ligand, LAG-3
`lymphocyte activation gene-3, MHC major histocompatibility com-
`plex, PD-/ programmed death-1, PD-L/ programmed death ligand1,
`PD-L2 programmeddeath ligand 2, 7CR T-cell receptor, 771M3 T-cell
`immunoglobulin and mucin domain 3, 7WF tumor necrosis factor
`
`a clinical trial program of more than 2,000 patients with a
`variety of solid tumors [4, 5, 17-19]. [pilimumab (Yer-
`voy), administered every 3 weeks for four doses, gained
`US FDAapproval in 2011 for the treatment of unresectable
`or metastatic melanoma, based on data from two phase III
`randomizedtrials showing improvement on median overall
`survival (OS) over control arms in patients with melanoma
`[4, 5, 20]. One of the pivotal phase III
`trials evaluated
`ipilimumab with or without gplO0 vaccine in previously
`treated patients with advanced melanoma. Although the
`best overall response rates were modest, 10.9 % in the i-
`pilimumab-alone group and 5.7 %in the ipilimumab plus
`gpl00 vaccine group, some patients in both groups main-
`tained an objective response for at least 2 years [4]. In this
`trial, the 3-year OS rate for ipilimumab monotherapy was
`20 %|4|, which compares favorably with the 3-year OS
`rate of 17 %for historical control patients receiving stan-
`dard of care chemotherapy in a separate clinical trial [21|
`(Table 2 [4, 5, 7, 18, 19, 21-33]). The other pivotal phase
`[I trial was conducted in treatment-naive patients with
`metastaic melanoma
`and compared ipilimumab plus
`dacarbazine versus dacarbazine plus placebo [5]. Although
`the dose and schedule were slightly different,
`the rate of
`best overall
`response was 15 % in the iptlimumab plus
`dacarbazine group versus 10 %for the dacarbazine plus
`
`

`

`Immune Checkpoint Inhibitors in Cancer
`
`1995
`
`Table 1
`
`immune checkpoint inhibitors in clinical development [4-16]
`
`
`
` Name Company Description of agent
`
`
`
`Ipiimumab |4, 5]
`‘Tremelimumiab [6]
`Pembrolizumab (MK-3475) [7]
`Nivolumab (BMS-936558) [8]
`Pidilizumab (CT-O11) [9]
`AMP-224 [10]
`MPDL3280A [11], 12]
`BMS-936559 [13
`MEDI4736 [14]
`IMP321 [IS]
`TRXSI1& [16]
`
`Human IgGl mAb against CTLA-4
`Bristol-Myers Squibb
`Human IgG2 mAb against CTLA-4
`Medimmune/AstraZeneca
`Humanized leG4 mAb against PD-|
`Merck
`Human IgG4+ mAb against PD-1
`Bristol-Myers Squibb
`Humanized leG! mAb against PD-|
`CureTech
`PD-L2-leG recombinant fusion protein
`Amplimmune; GlaxoSmithKline
`Human IgG mAb against PD-L1
`Genentech/Roche
`Human leG4+ mAb against PD-L|
`Bristol-Myers Squibb
`Human mAb against PD-L1
`MedImmune/AstraZeneca
`Soluble LAG-3 Ig fusion protein and MHC class IL agonist
`Immutep
`
`GITR, Inc Humanized mAb against GITR
`
`CTLA-4 cytotoxic T-lymphocyte-associated antigen 4, G/7TR glucocorticoid-induced tumor necrosis fictor receptor-related gene, /gG immu-
`noglobulin G, LAG-3 lymphocyte activation gene-3, mAb monoclonal antibody, MHC major histocompaubility complex, PD-/ programmed
`death 1, PD-L/ programmed death ligand 1, PD-L2 programmeddeath ligand 2
`
`inhibitors or controls from individual (not head-to-head) trials” [4.5, 7, 17, 18,
`Table 2 Preliminary efficacy data with immune checkpoint
`2133]
`
`
`
`
`
`
`
`Advanced tumorsetting©Agent or control Median PFS Median OS Survival rate Reference(s)i
`
`
`
`Melanoma
`
`CTX (CTX-naive pts)
`
`ND
`
`91-107 months
`
`Ipilimumab
`Tremelimumab
`Pembrolizumab
`Nivolumab
`
`Pidilizumab
`Nivolumab plus ipilimumab
`
`2.9 months
`ND
`5.5 months
`3.7 months
`
`1.9 months
`27 weeks
`
`10.1 months
`12.6 months
`NR
`17.3 months
`
`ND
`40 months
`
`NSCLC
`
`CTX (CTX-naive pts)
`
`4.2 months
`
`8.3 months
`
`Pembrolizumab
`Nivolumab (previously-treated pts)
`
`10-27 weeks”
`2.3 months
`
`St weeks
`9.9 months
`
`l-year: 36%
`3-year: 12-17 %
`3-year: = 20 %
`3-year: 21%
`l-year: 69 %
`I-year: 63 %
`3-year: 41%
`l-year: 65 %
`I-year: 85 %
`2-year: 79 %
`l-year: 39 %
`2-year: 18%
`ND
`I-year: 42 %
`3-year: 24%
`
`(5, 21]
`
`\4]
`[21]
`7}
`[22
`
`[23]
`[24]
`
`[18]
`
`[25-27]
`[28]
`
`[29]
`l-year: 75° %
`NR
`36.1 weeks
`Nivolumab (CTX-naive pts)
`[30-32]
`3-year: = 25 %
`11.0-19.2 months
`3.65.7 months
`Sorafenib
`RCC
`
`
`Nivolumab 2.74.2" months—18.2-24.7° months—2.5-year: = 35 % [33]
`Placebo
`CRPC
`3.1 months
`10,0 months
`I-year: 40 %
`117]
`2-year: 15 %
`I-year: 47 %
`11.2 months
`4.0 months
`Ipilimumab
`2-year: 26%
`
`[17]
`
`CRPC castration-resistant prostate cancer, C7X chemotherapy, ND no data, NRK not reached, NSCLC non-small-cell lung cancer, OS overall
`survival, PFS progression-free survival, pty patients, RCC renal cell carcinoma
`“
`Important: data are not from head-to-head trials, und the tnials differ by patient characteristics, patient numbers, and length of follow-up.
`therefore direct comparisons across trials and agents have limited validity; trials in tumor types with PFS and OS data were included
`hy
`‘oe
`*
`Based on differing studies and data-cuts
`
`© Dose-dependent
`
`/\ Adis
`
`

`

`K. Shih et al.
`1996
`mS
`
`placebo group, while the median duration of response was
`19.3 versus 8.1 months for the dacarbazine plus placebo
`group. Responses lasting at least 2 years were observedin
`both treatment groups. The 3-year survival rate with ipi-
`limumab plus dacarbazine was significantly higher than
`dacarbazine plus placebo: 20.8 versus 12.2 % (P =< 0.001).
`[pilimumab was evaluated as adjuvant therapy following
`complete resection of stage [If melanoma in a phase III
`trial
`in patients at high risk of recurrence [34]. Patients
`receiving ipilimumab had a significantly increased median
`OS as compared with patients receiving placebo: 26.1
`versus
`17.1 months (P = 0.0013). The 3-year
`rates of
`recurrence-lree survival were 47 % for
`ipilimumab and
`35 %for placebo.
`chemotherapy can
`that
`suggest’
`Preclinical
`studies
`induce the release of tumor-specific antigens, thereby ini-
`tiating T-cell activation and sensitizing tumor cells to
`T-cell-mediated killing [35]. These observations provided
`the rationale for combining immunotherapy 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 phaseHL,
`randomized study provided evidence that sequential
`ipi-
`limumab is more effective than concurrent
`ipilimumab
`when administered with paclitaxel/carboplatin in chemo-
`therapy-naive stage IIIB/IV patients with non-small-cell
`lung cancer (NSCLC). The median OS with sequential
`i-
`pilimumab, concurrent
`ipilimumab, and the control regi-
`men was 12.2, 9.7, and 8.3 months, respectively.
`In this
`trial, patients with squamous histology exhibited better
`outcomes (median immune-related progression-free sur-
`vival [irPPS] and OS) with sequential
`ipilimumab dosing
`than did patients with non-squamous histology [18]. Based
`onthese findings, a phase [1 trial evaluating OS in patients
`with squamous NSCLC receiving sequential
`ipilimumab
`after chemotherapy was initiated (Table 3 [16]).
`Ipilimumab is also being investigated in the setting of
`metastatic castration-resistant prostate cancer (MCRPC). Ina
`phase IL trial of ipilimumabversus placebo in post-docetaxel
`patients with mCRPC receiving a single dose ofradiother-
`apy, the primary endpoint of OS was not reached; however,
`pre-specified subset analyses suggestedthat ipilimumab may
`be more active in patients with favorable prognostic factors,
`including no visceral disease, alkaline phosphatase <1,5
`upper
`limit of normal, and hemoglobin =11 g/dL.
`[17].
`Results from this study support
`the investigation of ipi-
`limumab in the ongoing phase II, CAT84-095 study among
`chemotherapy-naive patients with mCRPC (Table 3 | 16]).
`
`2.2.2 Tremelimumah
`
`Tremelimumab ts a fully human immunoglobulin G (leG)-
`2 monoclonal antibody targeting CTLA-4 [6] (lable |
`[4
`
`4\ Adis
`
`16|). Tremelimumab provided durable responses in 6.6 %
`of patients in a phase II
`trial of patients with advanced
`melanoma, as compared with the objective response rates
`(ORRs) of 5.7 and 10.9 % seen in the phase IL trial of
`ipilimumab with or without vaccine [4, 6]. However, the
`phase U1
`trial of tremelimumab monotherapy failed to
`demonstrate a statistically significant survival advantage
`over chemotherapy in first-line treatment of patients with
`metastatic melanoma[21]. Patient selectioncriteria, dosing
`regimen, and use of ipilimumab as salvage therapy for
`patients in the control arm were potential reasons for the
`lack of survival benefit.
`Tremelimumab showed evidence of activity against
`previously treated malignant mesothelioma in a small
`(N = 29) phase If single-armtrial [36]. Four patients had
`partial
`responses, and 11 patients had stable disease of
`median duration 7.7 months (range 2.6-16.6+), with a
`median OS of 11.3 months. Based onthese results, a phase
`Il
`trial of tremelimumab in malignant mesothelioma has
`been initiated (Table 3 [16]).
`
`2.3 Satety of CTLA-4 Inhibitors
`
`The cumulative safety data across many trials show that
`agents that inhibit CTLA-4 are generally safe, with unique.
`but usually manageable, side effects that are linked to their
`mechanism of stimulating immune responses. Multiple
`phase If and HE trials have characterized these immune-
`related adverse events (irAEs) of CTLA-4 inhibition.
`Overall,
`irAEs were observed in 58-63 % of patients
`treated with ipilimumab, with 5-26 %ofpatients experi-
`encing grade 3/4 irAEs [4, 17, 37] (Table 4 [4, 7, 8, 12-14,
`17, 21, 23, 26, 28, 36, 38-40]).
`In the phase TIL
`trial
`investigating ipilimumab treatment with or without vac-
`cine, skin-related irAEs (including pruritus, rash, and ery-
`thema) and gastrointestinal
`irAEs (including diarrhea and
`colitis) were the most common, occurring in 29-44 %of
`patients; endocrine disorders were reported in 4-8 %of
`patients [4]. Some of the more rare adverse events (AEs)
`(<I % for each)
`reported during treatment with ipi-
`limumab include uveitis, conjunctivitis, and neuropathy
`[37].
`Interestingly, when ipilimumab was given with
`dacarbazine,
`immune-mediated grade 3/4 hepatitis occur-
`red in 32 % of patients, while the rates of gastrointestinal
`events, such as colitis, were lower than expected based on
`previous trials [5]. As adjuvant therapy, ipilimumab hada
`safety profile generally consistent with that seen in patients
`with advanced melanoma, although the incidence of some
`endocrinopathies) was higher. Also,
`five
`irAEs
`(e.g.
`patients (1 %) in the ipilimumab armdied due to treatment-
`related AEs versus 0 patients in the placebo group [34].
`Tremelimumab has a similar irAE profile to ipilimumab.
`COMMON
`The most
`irAEs with
`tremelimumab were
`
`

`

`
`
`ooo
`daynuaptpeuy, /Aaeuudpareuwnsysiuiodpue[rotuiy>asels[PULLBumaswawroarp|[RUEJase
`
`
`
`
`
`
`
`
`
`
`
`609SRTIOLIN2d/S10TdwSOArewig=(076=")Bunin2ay—_DTDSNsnowenbswanna]adeigILjexeujoed+qeumuntdy
`
`
`
`
`
`POLS8SLOLINLLOT4ONGLIArewg(pp)=)SunimioayBUIOUG[SET[BIA/)Il/lqeumunyidy
`
`
`
`
`
`
`80S61TLOLOINS107APNSddyluowr-g:Cewlig(¢9=u)SulosugBUIOUR[SULSNEISEIS}AYI]aplwojozowa+qrumunyidy
`
`
`
`
`
`
`TOLGOLIOLON9107[nrSQiAreutlig(R¢]=u)BulosuQg—uolssauBoidyABWOUR]OWpoouRApyIl"saqeumutrpidy
`
`
`
`
`
`
`
`
`6RISISLOLONaaqy/elozdasSO:AseugMNNEISEIAWJoa[qeidasaiuylll“SABY¢qeunuydy LS6S8S10OLOINSLOTFVIN/ELOTIMLSddalMaewg=(pl|=)BulmioaypurSuseSoneisriauJoapqeioasaiuyI]0paepuryssaqeumnunytd](QOL=¥)Sulodug—-PMIOURAW!
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`89L9E900.LINedwyelocAineSayAreuilig(O66=4)SurosugJAPBUIOUR]AW[]]AsPISYSU-YsIyIllogaarid“saqeunutyidyCOSFFSIOIONLLOTpasurapepayanunA[snomadgIUqeuinpoatu“saqeuununyidySEEPLTLOLONlocSPINSQ“[RAIAINSdaiyj-asuauinoayPUIOUR[AWATJO[]]adRIsYsu-ysipyllasop-ysiy“svqrumnutyidyOISLSOIOLONLOTAON/SLOTUEPSORw(Q09=4)Suwsug-uewlg=(QOS|=4)SunmioayPO/VLOTPOSOcAreung=(¢[6=tf)Sunnoay daoursayrisoidoneisniayyIloqaoryd"saqeuinutyidy
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`L9LOSPLOLONABIN/S10TAONSOcArewug (O0OLT=¥)SunmisayTDSS889SIp-SalsuayxyIl/episodors+qrumnunyidy
`
`
`
`
`
`
`
`
`
`COFFORIOLONSny/PlOTanysasuodsaiaUNLULUT“Mjayeg:AIRULg(99=W)BulosuQ=dadurPdAPISRIAW!SalssaITOlgIEL-[@onayndis+qemuamsoud
`
`
`
`
`
`
`
`uonajdwosjeuy(sluaned‘ou)aseydyoroiddequauneaiy
`
`
`
`
`
`9L0ZCS“YOd“YOd“YAO”“SddsAaepuosagSy/Sw(OI
`
`
`
`
`910YAO"“Sdd“SO=MepUoassjaxeqypaed‘sauneydoqirs
`
`
`
`
`
`fepisodoja“sawinuneyd:;slotahumuneyd“tocYO“WAOS“S44!“SO‘Aepuosas
`
`
`epadisoup.
`
`
`
`
`SIOZDALJ-SASPISPIALLURISIP“GQ:ABPUdIAgjeaouias[ea1uns
`
`
`
`
`
`
`TOO“JayeWolg[T-dd“WUAO“Sad‘AtepuoragPUOURauqeunyoaru+geuunupidtssa
`
`
`
`
`
`100"YAO"“YOC-ATEpuoesUd[ONUODasRasIp[eNIULaye(Quownranal)<desapoways
`
`
`
`
`
`TOD“Mayes:Arepuosas[PAOWWAL[ROBINSJaye4C-©-NAl
`;~qeuinutyidt
`:unejdoqies
`
`
`
`
`
`
`
`
`
`Immune Checkpoint Inhibitors in Cancer
`
`1997
`
`
`
`
`
`
`
`c10csasuodsal[Rolla‘asuodsalySq<Aepuosag
`
`
`
`
`
`aun“uolssausoidured07own“S4qAlepuosag
`
`
`
`SayeSuNUUUt
`
`
`
`JOO“Mayes"Barus
`
`SO:Auepuosag
`
`aquapid]
`
`gaouraSun]
`
`FVILLOD
`
`PUIOUR[ATY
`
`
`
`JOIURDD1PISO1g
`
`
`
`
`
`
`
`Diuais<s[PUOLIOY-UOUJUANbasgnsoO}
`
`
`
`
`
`WYO!“SO"Sdd‘AlEpuosag
`
`
`
`Mayes“Adrsayy
`
`
`
`Jasurajpasrydosaoused
`
`aRD
`
`
`
`JOURSSLISED
`
`4\ Adis
`
`[91]stonqiyurluiodysayaaunwwJospeupeoryyypurppaseydSurosug¢apqey
`
`
`

`

`1998
`
`K. Shih et al.
`
`arpuonaydiuos
`
`
`sPYNUAPT[LLL
`
`jeuy/Umuudpawnsy
`
`
`
`stutodpuajroiuty
`
`
`
`(stuaned‘ou)
`
`
`
`aris[PUL
`
`PLeePSlOLON
`
`s10cUp
`
`LS9S061T0.LON
`UzOTURLS10Tdas
`
`L8TPOLIOLON
`O10TUPL/SLOCJPN
`
`61£998TOLOIN
`
`OSLOFRIN/FTOT[OF
`
`OLOSS0TOLIN
`
`S10TJPIN/S10T29d
`
`
`
`
`
`“YO“AAO“Sdd“HOC-Mepuosas
`
`
`
`Md“100“Aiayes
`
`LO8ELOLOLON
`
`
`SLOCAON/FLOCSON
`
`
`
`OO“ULL‘WOMsaywo1g
`
`
`
`
`
`I1-d“SddPassasse-ay]:Ampuosas
`
`
`
`
`
`
`
`“YUNG|1-Cd“Sad“WAO:Arepuosag
`
`adSud
`
`OLS8TOLOLON
`
`SLOTSW/e1OTUeL
`
`
`
`MAOpassasse-sowsnsaauy:Arepuooas
`
`
`
`sayrewuoig“Ayayes
`
`
`
`
`
`“YOd"AYO“Sd“SAd4!“SO:Arrpuosag
`
`[1S9L81TO.LON
`
`L10cUne
`
`MOU“SAdtt:Aaeurttd
`
`([L=)Suntnisay
`
`
`
`MIPS“SO“ALL“S4d‘Arepuosag
`
`
`
`
`
`
`
`asuodsarsasvisriowumig:{impuosas
`
`
`
`
`
`
`
`MOG"YANO‘Awepuosas
`
`MUO:Arepuosag
`
`
`
`NOC“NNO‘Ampuosas
`
`JTOSN
`
`
`
`
`
`Advaayisod19y7euoissaudoid
`
`RUOUP]au
`
`[]29snowenbs-uousneiseieuw
`
`JTOSN
`
`PUOILAYyOsaut
`
`
`
`penunuos¢aqey
`
`quununjauaa|Ts
`
`SO‘Arewug
`(O81=4)Bunmusay
`
`luPUsiewayqrisasaauyy
`
`
`ogasr|d“saqruumunyatwary
`
`RWOLAayOsayy
`
`
`
`BunlasWawraf
`
`aseyd
`
`Puy
`
`
`
`yoroiddejuaunrary
`
`
`
`ada}sown,
`
`1a
`
`I-dd
`
`6EL1CLIOLON
`SLOTFA/PFLOTFA
`WAOPassasse-Y]cA
`(OOl=4)sulOsUg
`
`snowenbsoneisrlawJOpasueapy
`
`Il
`
`
`
`soudT=UMDTOSN[199
`
`
`
`SUSLUIDALSTUIAYSAS
`
`
`
`JaaurduojOD
`
`Il
`
`qrunzyoiquiag
`
`
`
`Jaaurauojog
`
`QeRUIn[OAIN
`
`daouraSun]
`
`qQDUINJOMN
`
`FOOTYLOLOIN
`
`
`SLOTSNV/P10TBNW
`
`
`SO“UNOpassasse-Dyy:AwwLig
`
`(P97=Uv)Bulosug
`
`
`JOPAOURAPRpowellAPSNOlAald
`
`[AXB1AIOP“SAGRUIN[OAIN
`
`tl
`
`asuodsalJOWINSAIeUWLd
`
`
`(OT1=“)Suniniday
`
`
`JIOSNoneIsPIeWlUaLINI[y
`oneuasida+qrumjoain
`
`ll
`
`suruid
`
`Maes“Sod“SQsAurwig
`
`
`(076=&)Sunins9ay
`
`
`aatusod-[]-GdpaivaAjsnotacig
`
`
`[eXB1OSOp"SAqruinzlpomqiuag
`
`IL/
`
`qaouroSuny]
`
`SO‘Sad‘Auruwiig
`
`(O1S=4)Sulosug
`
`YIMRUWOURTOLUpasuraApy
`
`I
`
`
`
`“SA.QPLUNZI]OIqUIag
`
`Adesayrouray>
`
`BLUOURayy
`
`SO‘Sad‘Arruiig
`
`(cpg=u)Buninioay
`DNEISTIALJOalquidasaluy]
`
`
`qruuniuryidt"saqeuunziyoiquiag
`
`II
`
`asuodsayy:Auruttlig
`
`(F9=¥)Bunins.ay
`YIMJIOSNJOewouryayy
`
`il
`
`qrunzipoiquiag
`
`
`
`SasPIStIAlUleIgpalvanun
`
`
`
`SOSPISPIAWUItIgpayranun
`
`UUMJIOSNJ0Btuourayy
`
`
`
`
`
`DIOSN[129snowenbssueisriaw
`
`
`
`
`
`SO‘Arewug
`
`(ple=uv)Suiosug
`
`
`JOpaourapepaiwanA]snolacig
`
`JAXBIAS0pQRUINJOAIN“SA
`
`
`ill
`
`
`
`
`
`(CLPE-NIV)qolantiyosgiuiad
`
`
`
`

`

`
`
`Jaynuapleu|peuy/sAmmudwawPay=[PLLwa],poweunsysquiodpuayRomty5BSUS[PLLBuas
`
`
`
`
`
`
`
`
`
`
`
`
`6IFLT6I0LOINSLOTSVIN/FLOT[nLWAOiAwewg(O€1=U)BulosugQ—-ayqeioasaaun‘pareanunAjsnotaalgll"SAQeuinuutidt+qeuinjorry
`
`
`
`
`
`OFLITLIOLONQIOTURL/CLOTARNSO“WYOAru,(O6¢=U)BulosugYIMBWOURLAWpasueApyIllJODUIZRQIROEP“SAQRUUNJOAIN
`
`
`
`
`
`
`709960LO.LONt10TdasAxo]:Arewg(cL=uv)SuninioayNYWlaULDOBA+QRUINZI[IPld
`
`
`
`
`
`
`
`SOSPPSOLINLIOTPO/OL0TFOSOAreuug(C16=&)SundayajgrioasaiunpowanunA[snoiaaigIll40QPLUNJOAIN
`PSL899101LINperan-algUlSNLUJOIAAD“SAQRUUINJOAINLILLIOZOLINS107UELSO“Aleyeg:AIPULd(QOT=HM)SunmuseyPUWIOSP|GONSlUuauNndayTlJOQPUINJOATN,€EGREOTOLONYLOT424MAOAww,(OT!=¥)Sunmmisay aSuryasnyyipAuoiesyeuaopasdryayllqeuinjOAIn9F9SOITOLONLIOTuNg/OTOTunrSO“SddBuninsoayPURprayINPISPIAWJOIUaLNIAYIlQPUIN[OAINS960CFIO.LINLIOTPa/P1OT2G=AOwOYyOaun“AUpqise-y:AurutLig(Lg=¥)SunmssaypaourapyIlL-[pongindis+qewinzuewug=(08=&)910T924SQ:Arewg=(Z7B=UV)Buninusay—-ANPIseIaUJOPadURApE Jaouroairsoid[pid
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Se6ESl[OLIN6l10OTUPL/FLOTBNWMaesuewiig=(OO,=4)Sunmisay=PUOUR]AUJNFISIAUJOpasuBApyllqrunuyid:+qrunjoain
`
`
`
`
`
`TLLITLIOLONSLOTAON/STOTdasSOewig=(OF=4)Sunmusay—saquisasazunpayranunAysnotaaigllSUIZEQIROEPQRLUNJOAIN“SA
`
`
`
`
`
`
`
`Let+S¢LO.LONPLOTUNCLELOTACWSad‘AseWwiud(OS]=4)Buiosug—«{99-swa]9aneisPlaulJOpasurapyilQRUINJOAIN,
`
`
`
`
`
`aiepuonaduos(sluaned‘ou)aseydysroiddeywauneasy,
`
`
`
`Wareoworg[dd“Sad:-ATepdosaseununpidrgayeuotssarsoidaxepord/une;doqiraq[erste
`
`
`
`
`
`
`1SAdPUPAAO“Sdd-ArepuosasPLUOUPRJSUESHPISPIAWJOqeumnunyidi
`
`
`
`Idd“MOC“UUO‘Sdd‘4epuosagQOY[22-19]
`
`
`
`
`WHO‘Sdd"WAD“AOC:Atepuooageuoydwia)[[ao-g
`
`
`
`(dd“HHO“Sad-MepuosasPWOUR[AW!INPISTISLUJO‘SAqeunWtid!+qrunjoatu
`
`
`
`
`SO“UUAO“SddArepuorag"SAquummutntyid:+qrunyjoal
`SO‘Sdd:Asepuosagapuurydsoydojaso+
`
`
`
`
`Oo“JayFEWIOIGqeunuutypidt
`
`Eaxel}Ne[Goq,
`
`
`
`
`
`OO‘siuanedqurinwyyy
`
`
`
`Yd“WYO:Arepuorag
`
`3100
`
`
`
`
`
`
`
`MdSUC“Mayeswsyewoig
`
`TOOFHyewWoIg
`
`SO“NYO"
`
`
`
`*S4d‘Aurpuosas34
`
`
`
`WAO“AyRpuasaseWOUIIIRDYoU
`
`
`
`
`
`
`
`sown)‘asuodsasounutuy:Asepuosag
`
`dL‘uowsarsor
`
`
`
`4N Adis
`
`
`
`SAIUPUDT[PUSIGO[OTRWAH
`
`
`
`(7/0-£D)Qounztiple
`
`
`
`JOURSaIRISOI
`
`Immune Checkpoint Inhibitors in Cancer
`
`1999
`
`
`
`
`
`
`
`IT-dd“YYO“Sad*AsepuosagPWOUP[AUINEISRIOUJO
`
`panunuos¢aqey
`
`adsown
`
`PWIOUPAPY
`
`qeuinziorasq
`
`JOA
`
`JO
`
`
`
`

`

`2000
`
`K. Shih et al.
`
`
`
`Oorrs[TOLOIN
`
`ccoUnf
`
`
`
`SO‘Sdd:Areuig
`
`Sunimni3ey
`
`SSFILOTOLIN
`
`
`
`SLOTJPN
`
`LeT8O0TO.LON
`
`socung
`
`:5100
`
`‘SO‘Sdd“YO:Arepuosag
`
`Md“Alayes
`
`CEYSOLTOLOIN
`S10IME/SLOTSON
`
`CrCPR6LO.LIN
`
`9LOTTRIN
`
`
`
`SO“YO"YO“SAdstAaepuosag
`
`_Md
`
`dod
`
`
`
`
`
`*S4d“UO“Mayes:Auepuosag
`
`EcPLROCOLIN
`Q10TURLS10TAdy
`
`
`
`“SO“UOC“Sdd“YO:Mtepuoseg
`
`Md‘Alares
`
`
`
`
`
`‘SO“Sdd“YOU‘Aepuosag
`
`
`
`
`
`“Alayes“SHd“YOsAgepuoras
`
`OIP9PSTO.LON
`
`SLOTAPIN
`
`£66£0610.LIN
`
`
`L10cJPIN/9L0CJEN
`
`
`
`‘Sdd“HO“HAO:Auepuoras
`
`Md‘Alayes
`
`6S6LLOTOLIN
`
`L10cune
`
`Md“SO“d_LL‘Aiepuosag
`
`
`
`alepuonaduos
`
`
`JOYNUAPL[PLL
`
`jeuy/Aurwudparunisy
`
`
`
`siurodpua[rom
`
`
`
`(squaned‘ou)
`
`
`
`D5vIS[RU
`
`JIOSNJeiseiaw
`
`
`
`angrywounesdgaye
`
`SIOSNseisriauw
`
`aunjimywinuneydaye
`
`
`
`
`
`Md“Alayes“Sd
`
`“SAdil“Mares“ypyQ.-Arepuosag
`
`
`
`Jo}pouyapun=uv)
`
`ao
`
`(Apmsqns
`
`eee
`
`“MO“CLIN‘Areurng
`
`
`(¢¢=u)Suninipay
`
`WIN“toisesjartopasdrjay
`
`II
`
`apluoplruay+qrumnzi[iptd
`
`WMwWOiueMLg
`
`(OF|=¥)Suntnisay
`
`
`JOpasueapeAypeooyaatusod-[]-qd
`
`SO:Alrwig
`(O0¢=4)Suninoay
`
`DIOSNoneisriawJopasurapy
`
`il
`
`
`
`
`
`[@XBIADOP“SAYORTETAdIN
`
`Vosce1ddw
`
`VOSTETdIV
`
`
`
`Jeouessun]
`
`I'I-dd
`
`MMOcueWwLg
`(00=4)Bunmssay
`
`Jopaourapeaantsod-|-]-qd
`
`Il
`
`VOSTETGIN
`
`SO:Airuug
`(OSS=4)Suninisay
`
`DIOSNdmisriewJOpasurapy
`
`Il
`
`
`
`
`
`
`
`
`
`JOXPIOSOP"SAVOSTETUdW
`
`eee
`
`YAOewig
`
`(Ogg=™)Sunmisay
`
`DNNISPIAWJOpaosurApeA][PI07]
`
`I]
`
`
`
`
`
`Jaouvssappeyq[etpayjoin
`
`WAO‘AsvewUg
`
`
`(O1T=4%)BuuIniday
`
`DNRISPIAW1OPaduRApRA][eI0"T
`
`IL
`
`
`
`owaisdsJoudT=YIMDIOSN
`
`SUSURAL
`
`
`
`DIOSNsnowenbspasurapy
`
`IL
`
`
`
`[eXF1290P“SAOF/FIC
`
`(Apnis-qns)
`
`
`
`Vosce1ddw
`
`qiuniuns
`
`9eLrFIddNw
`
`JaoursSuny
`
`9ELFIGAIN
`
`Sdd‘Areutg
`(OS|=“)Bunmuoay
`
`
`A[[Ro0]paiwanunA|snoiwaig
`
`DOYMise!10paourapr
`
`"SAQRUUNzionaaq+YOSTETCdIN
`
`
`
`40WosceTddw
`
`JO
`
`
`
`Bulllesawa|
`
`asryd
`
`fea,
`
`tee
`
`penunuos¢alqEey,
`
`
`
`yovouddeluawnraly,
`
`
`
`ada)sowny
`
`JOSIE
`
`A\ Adis
`
`
`
`

`

`2001
`Immune Checkpoint Inhibitors in Cancer
`
`ressionrate,DSDdurationofstabledisease.DSRdeepsustainedresponse./FNinterferon,irBORR
`
`
`
`
`
`
`
`
`
`
`metastases-freesurvival.DORdurationofresponse,DRSPRdisease-relatedsymptompro
`
`oe=
`
`-lymphoevte-associatedantigen4.DCRdiseasecontrolrate,DMFSdistant
`
`
`
`
`
`
`
`
`
`eteremissionrate,CTLA-4cytotoxicT
`
`
`