biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor...

PRINCIPLES & PRACTICE OF ONCOLOGY: RECENT ADVANCES

Biological Rationale and Current Clinical ExperienceWith Anti–Insulin-Like Growth Factor 1 Receptor Monoclonal

Antibodies in Treating SarcomaTwenty Years From the Bench to the Bedside

David Olmos, MD,*† Daniel S. W. Tan, MBBS,†‡ Robin L. Jones, MBBS,*†§ and Ian R. Judson, MBBS*†

Abstract: Two decades have elapsed since insulin-like growth factor-1receptor (IGF-1R) signaling was initially implicated in sarcoma biology tothe first clinical experience of IGF-1R blockade in sarcoma. During these 21years, the IGF pathway and its key mediator IGF-1R have been implicated inthe genesis, growth, proliferation, metastasis, and resistance to conventionaltreatment in several sarcoma subtypes. In addition, IGF-1R has been vali-dated, both in vitro and in vivo, as a target for the treatment of sarcoma.Several radiologic and clinical responses to IGF-1R monoclonal antibodieshave been reported in Ewing sarcoma patients enrolled in early clinicalstudies. Furthermore, these therapies were well tolerated, and thus far severetoxicity has been rare. The early clinical evidence of antitumor activity hassupported the initiation of various phase II clinical trials in Ewing and othersarcoma subtypes, the results of which are eagerly awaited, as well as studiesassessing IGF-1R monoclonal antibodies in combination with traditionalcytotoxics or other targeted therapies. Despite these encouraging results, notall patients benefit from IGF-1R inhibition and consequently there is anurgent need for the identification of predictive markers of response.

Key Words: sarcoma, Ewing sarcoma, insulin-like growth factor-1 receptor,figitumumab, R1507, robatumumab, AMG479, SCH-717454, cixutumumab,IMC-A12

(Cancer J 2010;16: 183–194)

Sarcomas represent a diverse group of tumors that arise fromconnective tissue that account for approximately 1% of all adult

tumors, but represent up to 12% of pediatric malignancies.1–3 Ad-vances have been made in the classification, staging, and multimodaltreatment of these heterogeneous conditions including surgical ad-vances in functional preservation, the use of radiotherapy as adjunct

to other modalities and the identification of active systemic therapiesfor certain sarcoma subtypes.4–6 Despite these advances, prognosisfor these patients remains poor, and many of them will still succumbdue to the development of recurrent or refractory disease.7

The key reasons for the bleak outlook include challenges indetermining histologic classification, as well as the biologic heter-ogeneity of sarcomas. Ongoing efforts to unravel the genetic aber-rations involved in the genesis and progression of sarcomas have ledto improved delineation of subgroups with distinct molecular fea-tures. It is precisely these molecular alterations that cause or drivethese malignancies that have emerged as novel therapeutic targets.Furthermore, these genetic alterations tend to be durable, eg, KITmutations, chromosomal translocations, and coupled with the factthat tumors typically arise from a single molecular lineage, sarcomashave provided an ideal disease model for molecularly targetedtherapies. Indeed, one of the early successes in targeted therapieswas the use of imatinib, a KIT, and platelet-derived growth factorreceptor tyrosine kinase inhibitor, in the treatment of gastrointestinalstromal tumor (GIST).8,9 GIST is now known to be the commonestsarcoma in the gastrointestinal tract, but when imatinib trials beganthe association with activating KIT mutations had only recently beenreported and the disease prevalence was unclear. These early trialshave not only dramatically transformed the management and prog-nosis of GIST but also led to key advances in our understanding ofthe mechanisms of response and resistance to tyrosine kinase inhib-itors (TKIs).

In the last decade, an expanding number of exciting putativetargets have emerged, dramatically changing the therapeutic land-scape in solid tumor management. In sarcoma, a promising class ofnovel targeted agents is the monoclonal antibodies (mAbs) to theinsulin-like growth factor-1 receptor (IGF-1R). IGF-1R was firstlinked with sarcoma biology approximately 20 years ago.10,11 Sincethen, a considerable body of preclinical work has led to the intro-duction of drugs targeting this receptor in early clinical trials. Thepurpose of this manuscript is to review the biologic rationale fortargeting the insulin-like growth factor (IGF) system and the dataand clinical experience from early clinical trials with anti–IGF-1RmAbs in sarcoma.

IGF SIGNALLING SYSTEMIn vertebrates, the IGF system plays a key role in the

growth and development of normal tissues and regulates theoverall growth of organisms.12–14 This system is part of a morecomplex insulin-related signaling network, and in the evolution-ary process, the insulin-related and IGF systems have developedfrom a single, common ancestral receptor15,16 to a more complexsystem that involves 3 ligands (IGF-I, IGF-II, and insulin) and at

From the *Sarcoma Unit, The Royal Marsden NHS Foundation Trust, London;†Drug Development Unit, The Royal Marsden NHS Foundation Trust andThe institute of Cancer Research, Sutton, United Kingdom; and ‡Departmentof Medical Oncology, National Cancer Centre Singapore, Singapore. §R.L.J.is currently at the Fred Hutchinson Cancer Research Center, Seattle, WA.

This work was supported by a translational research fellowship from the SpanishSociety of Medical Oncology (SEOM) (to D.O.) and a Young InvestigatorAward from the American Society of Clinical Oncology (ASCO) Foundation(to D.S.W.T.). The Drug Development Unit of the Royal Marsden NHSFoundation Trust and the Institute of Cancer Research is supported in part bya program grant from Cancer Research U.K. Support was also provided by theExperimental Cancer Medicine Centre (to the Institute of Cancer Research)and the National Institute for Health Research Biomedical Research Centre(jointly to the Royal Marsden NHS Foundation Trust and the Institute ofCancer Research).

Reprints: David Olmos, The Royal Marsden Hospital, Downs Road, Sutton, SM25PT, United Kingdom. E-mail: [email protected].

Copyright © 2010 by Lippincott Williams & WilkinsISSN: 1528-9117/10/1603-0183

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least 4 receptors (IGF-1R, IGF-IIR, insulin receptor [IR], andhybrid receptors).17

IGF-1R is activated by IGF-I and IGF-II,18 whereas IGF-2Rbinds only IGF-II; although the latter receptor has no tyrosine-kinaseactivity and does not transduce any signals.19 The IR has 2 isoforms,IR-A and IR-B, the synthesis of which is controlled by alternativesplicing. IR-B, the classic IR, is activated by insulin that in turnregulates glucose uptake and has a low affinity for IGF-I. IR-A is afetal isoform, lacking exon 11, and is activated by IGF-II, leading tosubversion of apoptosis.18,20 Increasing complexity arises from thefact that both functional IGF-1R and IR are dimers and theirmonomers can also form hybrid receptors, ie, half-IGF-1R and ahalf-IR. Functionally, these hybrid receptors can be activated byIGF-I and IGF-II, and their affinity for insulin is an area of greatinterest.18 The levels and activity of IGF-1 are regulated systemi-cally by growth hormone (GH), although the primary regulatoryfactor for IGF-II remains unknown.12 In addition, the IGF systemalso includes 6 binding proteins (insulin-like growth factor bidingproteins [IGFBPs]) and IGFBP proteases.21 Both binding proteinsand proteases play a key role in regulating ligand bioavailability.Hence, the bioavailability of IGF-1 is influenced by IGFBPs, andthat of IGF-II is influenced by both IGFBPs and IGF-IIR,22 whileinsulin has direct access to its receptors. Figures 1A, B illustrate theendocrine, paracrine, and autocrine regulation of the IGF pathway.

The activation of IGF-1R by IGF-I results in proliferation andinhibition of apoptosis.12 More precisely, the binding of the ligand tothe IGF-1R causes phosphorylation of the tyrosine-kinase domainand subsequently the activation of the binding sites of a series ofdocking proteins, including the IR substrates (IRS)-1 to -4 and theSrc homology and collagen domain protein (Shc). Activation ofthese signals result in the downstream cascades involving phospha-tidylinositol-3-kinase-AKT and rat sarcoma viral oncogene ho-molog/murine sarcoma viral oncogene homolog/mitogen-activatedprotein kinase pathways.23–25 Figure 1B illustrates intracellular cas-cade of the IGF pathway.

RATIONALE FOR TARGETING IGF-1R IN SARCOMASRecent comprehensive reviews have addressed the role of the

IGF system in the genesis, maintenance, and progression of differentmalignancies, including sarcoma.26–29 Experimental30–34 and epi-demiogic35–38 studies have linked the dysregulation of the IGF-Isystem with a higher risk of developing cancer. In sarcoma, there isalso extensive experimental and clinical evidence supporting a keyrole of the IGF-1 system in tumorigenesis. Initially, the involvementof the IGF system in sarcoma was postulated on the basis ofepidemiologic data, primarily the higher incidence of some of thesediseases at younger ages. During postnatal linear growth and devel-opment, GH functions are mediated by IGF-1, leading to the pos-tulation that alterations in genes involved in GH and IGF signalingmay result in increased cell growth and risk of tumorigenesis.39

Further support for this association is provided by the observationthat the peak incidence of Ewing sarcoma coincides with the burst ofGH during puberty.40

It has been established that different mechanisms are respon-sible for the increased activity or dependency on the IGF axis invarious sarcoma subtypes, depending on the molecular pathogenesisof the individual subtype (Table 1). For example, Ewing sarcoma,which are characterized in 85% of cases by the translocation EWS/FLI-1 (Ewing sarcoma gene/Friend leukemia virus integration 1),3have been associated with enhanced IGF-1R activity, via an auto-crine/paracrine mechanism, through the inhibitory binding of theEWS/FLI-1 fusion protein to the IGFBP-3 promoter, consequentlyreducing IGBP-3 levels, and thus increasing the level of free IGF-1Rligands.41 In alveolar soft part sarcomas and desmoplastic small

round cell tumors, the respective PAX3-FKHR fusion protein andthe EWS-WT1 fusion gene have been linked to increased IGF-1Rexpression, resulting in enhanced axis signaling.42–46 An increase inIGF-II levels has also been suggested in leiomyosarcomas, synovialsarcoma, and rhabdomyosarcomas. Loss of heterozygosity (LOH)and loss of imprinting (LOI) are the common underlying geneticevents implicated in increased IGF-II transcription in the 2 majorrhabdomyosarcoma subtypes, namely alveolar and embryonal rhab-domyosarcomas47–51; whereas in synovial sarcomas, IGF-II up-regulation seems to be mediated by the characteristic SS18 fusiongenes, which have been shown to induce epigenetic changes in theIGF-II promoter region, rather than LOI that occurs infrequent-ly.52,53 LOI has also been associated with high IGF-II expression insome uterine leiomyosarcomas.54,55 In osteosarcoma, there is noclear evidence that IGF-1 or IGF-II have major involvement in thegrowth and development of this subtype,56 despite the fact that theIGF system plays an important role in the formation and homeosta-sis of bone.40 More recently, a single nucleotide polymorphism inIGF-2R has been found to be associated with an increased risk ofosteosarcoma, possibly implicating IGF-2R in the pathogenesis.57

Finally, in some wild-type and pediatric GIST, gene amplification orincreased expression of IGF-1R has been described, resulting inmuch higher levels of expression of IGF-1R in wild-type comparedwith mutant GIST.58–60 In addition, IGF-I or IGF-II have beenfound to be increased in almost all mutant GIST, with high expres-sion levels associated with a more aggressive phenotype.61

However, despite the strong etiologic link between IGF-1Rand sarcoma, the appeal of IGF-1R–targeting strategies onlyemerged after proof-of-concept preclinical studies demonstratingantitumor efficacy through disruption of IGF-1R–mediated signal-ing. A variety of approaches have been studied, both in vivo and invitro, in different sarcoma subtypes, but especially in Ewing sar-coma and rhabdomyosarcoma models. These include the use ofIGF-1R antisense oligonucleotides,62,63 dominant negative recep-tors,64 mAbs,65–67 and small-molecule TKIs.68–70 Overall, thesestrategies consistently revealed inhibition of sarcoma proliferation,reduced tumorigenesis, tumor invasion and metastasis, and ulti-mately prolonged survival.63–71

THERAPIES AGAINST IGF-1R: IGF-1R MABSEssentially, the strategies for blocking or disrupting IGF-1R

activity in patients may include (a) the reduction of ligand levels orbioactivity or (b) the inhibition of the receptor function usingreceptor-specific antibodies or small-molecule TKIs.27 At the timeof this review, mAbs against IGF-1R represent the most concreteoption in sarcoma with initial promising results in early clinicalstudies and several ongoing phase II studies.

Several anti-IGF-1R mAbs intended for clinical use havebeen developed through the humanization of mouse mAbs, im-munization of genetically engineered mice that produce fullyhuman antibodies, or the selection of specific antibodies fromphage display libraries. These antagonistic IGF-1R mAbs workthrough 2 major mechanisms: first by immediate inhibition ofligand binding, and second by a delayed effect on the down-regulation of IGF-1R. At present, 8 different mAbs (Table 2)have been tested in clinical trials: Figitumumab (also known asCP-751,871, Pfizer), AMG479 (Amgen), R1507 (also known asrobatumumab, Roche), cixutumumab (also known as IMC-A12,ImClone Systems), SCH-717454 (or 19D12, Schering-Plough),MK0646 (or h7C10, Merck), AVE-1642 (Sanofi-Aventis), andBIIB-022 (Biogen Idec).72

These mAbs are IgG1 idiotype66,73–77 with the exception offigitumumab and BIIB022, which are IgG278 and IgG479 class,respectively. There are significant pharmacokinetic and immuno-

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logic differences between IgG1, IgG2, and IgG4 isotypes. First,IgG2 mAbs seem to have longer half-lives than IgG1 and IgG4mAbs.80 This is exemplified by the results of early clinical trials inwhich figitutumab, an IgG2 mAb, has been administered over longerintervals (3- or 4-weekly basis)81–83 compared with others such ascixutumumab (weekly)84 or AMG479 (2-weekly),85 both IgG1

mAbs. These isotypes also differ due to differences in their Fcfragment or their capability to activate the classic complementpathway, the complement-dependent cell-mediated cytotoxicity, andthe antibody-dependent cellular cytotoxicity (ADCC).80 IgG1 mAbsare usually potent activators of classic complement pathway, com-plement-dependent cell-mediated cytotoxicity, and ADCC, whereas

FIGURE 1. Endocrine, paracrine, and autocrine IGF pathway regulation. The endocrine, paracrine, and autocrine regulationof the IGF-1R pathway and therapeutic strategies for its disruption. A, Systemic regulation at the endocrine level. The GH-IGF-IGFBP is directed by the hypothalamus-hypophysis axis in which GH is produced and mediated by the hypothalamus GH re-leasing factors (which include GHRH and somatostatins). In the liver, GH stimulates the production and secretion of both li-gands, IGF-I and IGF-II (the latter is also regulated by genomic imprinting mechanisms), as well as the IGFBPs. The free-ligandlevels are regulated by the presence of 6 different IGFBPs. The disruption of the effector signals in the IGF pathway and endo-crine regulation has been studied at different levels. First, the disruption of the hypothalamus and hypophysis axis, and thusthe GH release inhibition, has been attempted with somatostatin analogues, ie, octreotide in a phase III123; however, this trialfailed to meet the endocrinologic and clinical endpoints. Recently, pegvisomant (Pfizer), a human recombinant GH receptorantagonist, has been tested successfully for the treatment of acromegaly.124 This pegylated recombinant human analogue ofGH can decrease the production and release of IGF-I. Cancer studies have been designed based on this effect. Other strategiesin preclinical development resulting in the reduction of the proportion of free ligand include antiligand mAbs125 or recombi-nant IGFBPs. B, Free-ligand levels at tissue level are also regulated by the presence of the different IGFBPs. Furthermore, differ-ent tissue can also produce IGFBP related proteins (IGFB-rP) which also bind, but with low affinity, to the free ligands. Both,IGFBPs and IGFB-rP levels are regulated by specific proteases. Insulin, IGF-I, and IGF-II bind the different receptors with differ-ent (IGF-1R, IGF-2R, IR-A, IR-B, and hybrid IGF-1R/IR) affinity. Each receptor triggers different intracellular signaling cascades.IGF-1R after binding IGF-I or IGF-II triggers its autophosphorylation which subsequently results in the stimulation of the adap-tator proteins IRS-1 to -4 and Shc. The former activation prompts different signaling cascades through the phosphatidylinosi-tol-3-kinase (PI3K)-AKT and the rat sarcoma viral oncogene homolog/murine sarcoma viral oncogene homolog/MEK/ERKpathways. These activated signaling cascades result in stimulation of the cell cycle and translation, leading to increased prolif-eration and growth and inhibition of apoptosis. IGF-2R ligand binding does not result in intracellular signal activation, butregulates the IGF-II and IGF-I free levels. IGF-1R also has some role in the regulation of glucose metabolism, and IR-A activa-tion has been associated with proliferation, growth, and differentiation. In addition to the above therapeutic strategies, theIGF-1R pathway could be disrupted by using anti-IGF-1R mAbs and TKIs, as described in this review. Another potential strat-egy is represented by the inhibition of downstream intracellular tyrosine kinase proteins, ie, multiple small molecule inhibitorsagainst PI3K, AKT, murine sarcoma viral oncogene homolog, and MEK are under development, with mammalian target ofrapamycin inhibitors being the most representative category in sarcoma.90

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IgG2 are weak activators or are unable to trigger these immunologicresponses. For example, whereas SCH 71745466 and mk064676

(both IgG1) are associated with ADCC, antibodies such as figitu-mumab (IgG2)78 or BIIB022 (IgG4) do not seem to induce anyimmunologic-mediated responses.

CLINICAL EXPERIENCE WITH IGF-1R MABS INSARCOMA

Recently, final results of 2 early studies involving theexploration of IGF-1R mAbs in sarcoma patients have beenpublished. The larger study, by Olmos et al,81 enrolled 29patients treated with figitumumab at the recommended dose of 20mg/kg every 3 weeks in an unselected cohort of sarcoma patientswith a variety of histologic subtypes (n ! 14). In addition, a 4weekly schedule at 20 mg/kg was explored in a second cohortspecifically for Ewing sarcoma (n ! 15). All but one of thesepatients had received at least 1 line of systemic chemotherapy

(median of 3 lines), and notably 6 teenage or pediatric patients(older than 12 years) were included in the sarcoma expansioncohort. The second study, by Tolcher et al,85 was a phase I studyof AMG479, which included 15 sarcoma patients, including 12Ewing sarcoma treated at the expanded dose levels of 12 and 20mg/kg every 2 weeks. In this study, patients received AMG479on days 1, 15, and 29; and this was followed by a 28-daystreatment-free period before resuming the treatment.

The initial experience with R1507 in sarcoma was firstreported at the AACR-NCI-EORTC Molecular Targets and Can-cer Therapeutics meeting in 2007. Two phase I trials werereported, one of which included a cohort of 4 Ewing sarcomapatients treated at 9 mg/kg weekly, all of whom had a partialresponse (PR) or prolonged stable disease (SD) (!12 weeks).86

The encouraging results of this phase I trial led to the SarcomaAlliance for Research through Collaboration (SARC) 011 study,a phase II study with a planned recruitment figure of approxi-

TABLE 1. Sarcoma Genetics and IGF-1R Pathway Activation

Sarcoma SubtypeCharacteristic

Cytogenetic Alteration Genetic Alteration Biological Function Relevance

Ewing sarcoma t(11;22)(q24;q12) Otherless frequentalterations

Fusion gene EWS/FLI-1Other less common

The resulting fusion oncoproteinacts as an aberranttranscriptional activator withstrong transforming capabilities

Ewing sarcoma cells are verydependent on the IGF-1Rsignaling both in vitro and invivo. EWS-FLI1 decreasedIGFBP-3 levels, which resultsin an IGF-1R activationthrough increased ligandbinding

Synovial sarcoma t(x;18)(p11;q11) Fusion gene SS18-SSX1 orSS18-SSX2

These fusion proteins may functionas transcriptional repressors

IGF-1R and IGF-II are involvedin tumor progression andrelated with the SS18-SSXinduced transformation

RhabdomyosarcomaAlveolar t(2;13)(q35;q14)

t(1;13)(p36;q14)Fusion gene PAX3-FKHR

or PAX7-FKHRThese chimeric transcription

factors increases transcriptionalactivity and target generecognition.

IGF-1R and IGF-II are involvedin the pathogenesis amongother oncogenic events, ie, asecond hit in alveolar subtypefollowing the PAX-FKHR-induced transformation. IGF-IIis increased in bothrhabdomyosarcoma subtypesand functions as an autocrinegrowth factor

Embryonal Often LOH of 11p15.5Usually complexkaryotypes

LOH of IGFII LOH in IGFII alleles resulting inincreased IGFII expression

Desmoplatic smallround cell tumor

t(11;22)(p13;q12) Fusion gene EWS-WT1 This fusion protein acts as atranscriptional activator that failsto suppress tumor growth

IGF-1R transcription is increasedby EWS-WT1 fusedtranscription factor

Gastrointestinalstromal tumors(GIST)

Complex karyotype KIT or PDGFRA activatingmutations

IGF-1R amplification rare(juvenile/childhoodGIST)

Growth factors receptor involvedin the cell signaling

IGF-1R could be expressed inwild-type GIST

IGF-I and -II expressionassociated with worseprognosis

Congenitalfibrosarcoma

t(12;15)(p13;q25) ortriosomy ofchromsome 11

Fusion gene ETV-NTRK3 This chimeric transcripts seems tohave oncogenic activity in bothmesenchymal and hematologicalcells

IGF-1R is required for theETV6-NTRK3 inducedtransformation

Leiomyosarcoma Complex karyotype Occasional LOI of IGFII Epigenetic change resulting in anincreased expression of IGF-IIdue to the loss of the normalgenomic imprinting regulationfor this gene

The PI3K pathway is highlyactivated possibly throughIGF-1R.

IGF-II could also be increase

Osteosarcoma Complex karyotype Activation of IGF-1R by IGF-Istimulates in vitro and in vivogrowth of osteosarcoma cells



TABLE 2. IGF Pathway Targeting Strategies in Development

Name Class Route Company Phase Remarks in Sarcomas Ref.

Anti–IGF-1 receptormonoclonal antibodies

AVE1642 Humanized IgG1 IV Sanofi-Aventis I–II AVE1642 " docetaxel: SD !12 wk inan epithelioid sarcoma patient

77

SCH-717454 Fully human IgG1 IV Schering Plough II PRs seen in EWS patients. 88Phase II in relapsed EWS or

osteosarcomaCP-751,871 figitumumab Fully human IgG2 IV Pfizer II–III CR and PR in 2 patients with EWS.

Prolonged SD in patients with EWS,synovial sarcoma and fibrosarcoma

81

Phase II trial in patients with ESFTongoing, not recruiting

IMC-A12 cixutumumab Fully human IgG1 IV ImClone Systems I–II Preclinical activity in EWS, RMS,osteosarcoma models

84, 119

Phase II with 5 tiers: EWS, synovial,RMS, adypocitic and leiomyosrcomas

BIIB022 Fully human IgG4 IV Biogen Idec I Phase I dose-escalation ongoing in allsolid tumors

79

MK-0646 Humanized IgG1 IV Merck II Phase I dose-escalations studies ongoing 92, 93SD in 2 patients: EWS and DSRCT,

respectivelyR1507 robatumumab Fully human IgG1 IV Hoffman-La Roche II Several PRs and prolonged SD in pts

with EWS, RMS, ASPS, andosteosarcomas

86, 87, 103

Phase II in multiple sarcoma subtypeshalted since 12/22/2009

AMG-479 Fully human IgG1 IV Amgen II CR and PR in 2 EWS patients 85Phase II ongoing in relapsed Ewing’s

and DSRCTAnti–IGF-1-receptor small

molecule/tyrosinekinase inhibitors

INSM-18 Small molecule TKI PO Insmed I–II An ATP competitive and reversible TKI,which also inhibits HER2

BMS-754807 Small molecule TKI PO Bristol MyersSquibb

I An ATP competitive and reversible TKI 119In vitro activity against in EWS, RMS,

liposarcoma cell linesOSI-906 Small molecule TKI PO OSI

PharmaceuticalsI An ATP competitive and reversible TKI 120

Prolonged SD (#8 m) in a patient withmyxoid chondrosarcoma

XL-228 Small molecule TKI IV Exelixis I An ATP competitive TKI of IGF-1R,Aurora, FGFR and Src

121

Prolonged SD in 2 patients withleiomyosarcoma (!7 m) andliposarcoma (! 5 m), respectively

BVP-51004 cyclolignan,PPP

Small molecule TKI PO Biovitrum I A non-ATP competitive TKI 109In vitro activity in multiple sarcoma

resistant cell lines, includingosteosarcoma

A-947864 Small molecule TKI PO Abbott Preclinical An ATP competitive TKIBMS-554417 Small molecule TKI PO Bristol Myers

SquibbPreclinical An ATP-competitive and reversible TKI 122

In vitro activity in EWS andosteosarcoma cell lines

NVP-AEW541 NVP-ADW742

Small molecule TKIs PO Novartis Preclinical ATP competitive and reversible TKIs 69, 70In vitro and in vivo activity in EWS

GSK1904529AGSK1838705A

Small molecule TKIs PO GlaxoSmithKline Preclinical ATP-competitive, reversible, TKIs ofIGF-1R and IR

105, 106

In vitro activity in EWS cell linesAG1024 (tyrphostin) Small molecule TKI N.A. Merck Preclinical Used mainly in preclinical drug testing,

non-ATP competitive

IgG indicates immunoglobulin G; EWS, Ewing’s sarcoma; ESFT, Ewing’s sarcoma family of tumors; RMS, rhabdomyosarcoma; DSRCT, desmoplastic small round cell tumor;and m, months.



mately 300 patients in 5 arms (Ewing sarcoma, osteosarcoma,rhabdomyosarcoma, synovial sarcoma, and others).87 Finally,another preliminary report, in this case with the mAb SCH-717454, was presented by Anderson et al88 in the 2008 AnnualCTOS Meeting. This ongoing study included patients with re-fractory/resistant Ewing sarcoma, and cohorts of other sarcomasincluding osteosarcoma, synovial sarcoma, and rhabdomyosar-coma, treated at a dose of 9 mg/kg every week.

ActivityThe first patient with sarcoma to respond to an IGF-1R mAb

was reported in the 2007 American Society of Clinical Oncologyannual meeting.89 The final results from this Phase I study of

AMG479 included a radiologic complete response (CR) maintainedfor 30 months and an additional unconfirmed PR in Ewing sarcomapatients. No other objectives responses or cases with prolonged SDwere reported.85

A larger series of sarcoma patients were treated in the figi-tumumab study.81 In the 28 patients evaluable for response, 2ongoing radiological objective responses in Ewing sarcoma patientswere observed, which included a pathological CR (21" months) ina 12-year-old boy (as illustrated in Fig. 2) and a confirmed PR (11"months) in a young adult male. In addition, 6 and 4 Ewing sarcomapatients were free of disease progression at 3 and 6 months,respectively (Fig. 3). Furthermore, 5 of these Ewing sarcoma pa-

FIGURE 2. A 12-year-old patient with metastatic Ewing sarcoma (from pelvic bone) treated with figitumumab 20 mg/kg ev-ery 4 weeks. Patient progressed on first-line vincristine, ifosfamide, doxorubicin, and etoposide, and subsequently receivedhigh-dose (HD) melphalan plus busulfan with peripheral blood stem cells rescue achieving an incomplete response (non CR).Further pelvic irradiation with 54 Gy in 30 fractions resulted in complete local control. Patient progressed with new lung me-tastases detected just 8 months after HD and peripheral blood stem cells. A, Baseline computed tomography (CT)-scan at pre-sentation (prefigitumumab) with a target right hilar lesion (3.2 cm in longest Ø) and multiple subcentimetre lung metastaticnodules (data not shown). B, CT scan after 6 cycles of figitumumab, size of hilar mass reduced by about 60%, with remainingcentral calcification. Other lung nodules were completely eradicated (images not shown). C, CT scan after 24 cycles of figitu-mumab showed maintained complete response (white arrow pointed prior target lesion localization). Pathologic complete re-sponse was confirmed after 12 cycles. D, High magnification of a hematoxilin-eosin (H-E) staining showing a uniform popula-tion of small round-to-oval cells with a high nuclear to cytoplasmic ratio typical for Ewing sarcoma. E, High magnification ofstrong membranous immunohistochemical staining for CD99 (also known as MIC2 or single-chain type-1 glycoprotein; a pro-tein nearly universally expressed by Ewing’s sarcomas). F, A representative dual-color fluorescent in situ hybridization EWSbreak apart assay result: the encircled cell shows a pair of probe signals (orange: 5$ EWSR1; green: 3$ EWSR1) split apart dueto an EWS (22q 12) region rearrangement, whereas the other pair are intact with normal fused signals. G, RT-PCR run on 2%agarose gel electrophoresis stained with ethidium bromide. Bands from left to right showed an EWS/FLI-1 type 1 (Exons 7–6fusion) positive control; an EWS/FLI-1 type 2 (Exon 7–5 fusion) positive control; patient sample (tumor mRNA) showing a EWS-FLI-1 type 1 fusion; negative control that did not contain RNA; last band is the DNA marker. "-Actin transcripts were also co-amplified as an internal positive control for each sample. Adapted from Lancet Oncol. 2010;11:129–135.



tients with prolonged SD had shrinkage of the target tumor lesions.Small decreases in tumor size were also seen in patients withchondrosarcoma, fibrosarcoma, and synovial sarcoma. Overall, thenonprogression rate at 3 months was 34% (95% CI 10–58) and at 6months was 28% (95% CI 5–51) for all sarcoma patients included inthe study. However, being a phase I expansion cohort, the study wasnot powered to formally detect antitumor activity as an end point.81

However, the reported antitumor activity of figitumumab, at least inEwing sarcoma, compares favorably with those of other targetedagents in sarcoma. Preliminary data for the mammalian target ofrapamycin (mTOR) inhibitor, ridaforolimus (previously known asdeforolimus), have shown a nonprogression rate of 30% at 16 weeksin bone sarcomas.90 The mTOR inhibitor was deemed active and aphase III trial comparing ridaforolimus with placebo, as mainte-nance therapy, has recently completed recruitment. Other targetedagents have also been explored, and in a recent trial of varioussarcoma subtypes treated with imatinib, no activity was seen inpatients with Ewing sarcoma, with no objective responses and nopatient remaining on the drug longer than 4 months.91

Supporting the preliminary activity reported with R1507 of 2PRs in the phase I study,86 multiple radiologic responses in Ewingsarcoma and other sarcoma subtypes (including rhabdomyosarcoma,osteosarcoma, and alveolar soft part sarcoma) have been reported inthe initial SARC011 study presentation at the 2009 AmericanSociety of Clinical Oncology Annual Meeting.87 The final results ofthis study are eagerly anticipated. Finally, 3 additional PRs in Ewingsarcoma and a prolonged SD in an osteosarcoma patient wereobserved in the ongoing SCH-717454 study.88

ToxicityIn general, IGF-1R mAbs are well tolerated drugs, the most

common toxicities being mild and occasionally moderate. Severe(grade 3) or life-threatening (grade 4) adverse events are rare. Thecurrent reported adverse event profile, in all patients treated withIGF-1R mAbs in early clinical studies, with the exception offigitumumab in which specific toxicity data for sarcoma have beenreported,81 are summarized in Table 3.

Grade 2 lymphopenia was the most common hematologicadverse event observed with figitumumab81 in sarcoma patients.Other potential grade 3 and 4 hematologic adverse events reported inthe initial Phase I trials included thrombocytopenia.70,85,87,92 Grade3 and 4 nonhematologic adverse events with figitumumab in sar-coma patients included deep venous thrombosis (n ! 1), vomiting(n ! 1), and back pain (n ! 1). Grade 3 fatigue was also describedwith figitumumab in nonsarcoma patients.82,83 Other relevant grade3–4 nonhematologic adverse events described with other IGF-1RmAbs include fatigue,84,85,93 arthralgia,85 chills,93 pneumonitis,92

nausea or vomiting,93 rash and/or pruritus,93 pain,88,93 gastrointesti-nal bleeding,92 and dyspnea.87,88

In addition, hyperglycemia grade 3 (13.9–27.8 mmol/L) hasbeen reported with MK2206,93 IMC-A12,84 and SCH-717454,88

while mild (6.5–8.9 mmol/L) to moderate (9.0–13.9 mmol/L) hy-perglycemia has been described with the other IGF-1R antibod-ies.77,85,87 Mild hyperglycemia was also reported in 4 sarcomapatients treated with figitumumab and an additional patient devel-oped grade 2 hyperglycaemia requiring metformin and glibencam-ide.81 The mechanism for this hyperglycaemia is unclear, althoughIGF-1R may be involved in glucose metabolism via cross-talk andheterodimerization with the IR.94–97 This observation and the in-creased plasma insulin levels reported after treatment with IGF-1RmAbs83,98 suggest compensatory insulin secretion and associatedinsulin resistance, the latter possibly secondary to increased IGF-1and growth-hormone levels.27,99 Other severe laboratory abnormal-ities observed in sarcoma patients included uric acid elevation andtransaminitis.81

Interestingly, despite the expression of IGF-1R in vascularsmooth muscle and endothelial cells100 and the potential cardiotox-icity associated with mAbs, no cardiac toxicity has been reported todate. In the case of sarcoma patients treated with figitumumab, it isnoteworthy that three quarters of the patients were pretreated withanthracyclines and none developed cardiotoxicity.81

Theoretically, IGF-1R mAbs would be expected to have aninhibitory effect on IGF and GH-mediated growth. Thus, IGF-1Rblockade could cause linear and somatic growth delay in a childhoodand teenage population, as supported by the identification of patientswith genetic defects in the IGF-1 axis such as IGF-1 deficiency.101

This potential long-term adverse event is extremely important in themanagement of sarcoma patients, which tend to affect a youngpopulation.1 Current clinical experience is too limited to definitivelyaddress this question.81 Detailed assessments of growth and hor-mone levels have been included in ongoing phase II trials recruitingpediatric and prepubertal teenage patients, and it is hoped that thesestudies will provide insights to the effect of IGF-1R targeted therapyon growth during childhood and puberty.

Ongoing StudiesIn addition to the previously described SARC011 study, other

2 single-agent phase II studies with IGF-1R mAbs have completedrecruitment and final results are anticipated: (1) a study of figitu-mumab in Ewing sarcoma family of tumors (www.clinicaltrials.gov,NCT00560235) with approximately 130 patients, including pediat-ric patients 10 years or older and (2) a study of AMG479 in patientsaged 16 years or older with Ewing sarcoma or desmoplastic small

FIGURE 3. Waterfall plot of best response by RECIST forfigitumumab. Waterfall plot representing responses, in per-cent decrease of tumor size by RECIST criteria, of the targetlesions in the 22 evaluable patients. The white bars representpatients with increase in target lesion size; the gray bars rep-resent patients with a decrease in size of the target lesions.The numbers above/below the bars represent the number oftreatment cycles administered to patients before their with-drawal due to disease progression. ‡PR in soft tissue diseasebut PD with a new bone lesion. *Patients still on study. **Pa-tient with a partial response (PR) after 6 cycles by RECISTdue to residual calcification (Fig. 2), then confirmed patho-logic response. ***Patient with a PR after 2 cycles of treat-ment and radiotherapy to the mediastinum. Adapted fromLancet Oncol. 2010;11:129–135.



TABLE 3. Reported Adverse Effects and Maximum Grade With Anti-IGF-1R Monoclonal Antibodies

Toxicity/Adverse Event (NCICTC AE Version 3.0)

Figitumumab CP-751,87181–83,98

RobatumumabR150786, 87 AMG47985

CixututumumabIMC-A1284 SCH-71745488 MK-064692,93

AVE164277 (Only1st Cycle)

Hematologic/bone marrowLymphopenia G2 G3Anemia G2 G2 G1/2Thrombocytopaenia G4 G3 G4

Allergic/hypersensivityHypersensivity reactions G1/2 G1/2

CardiacHypertension G2

Constitutional symptomsAnorexia G2 G2 G2 G1/2 G3Weight loss G2 G2 G1/2Fatigue G3 G2 G3 G1/2 G2 G1/2Pyrexia G1 G3Chills/rigors G2 G3

Dermatology/skinRash/urticaria/eczema G2 G2 G2 G1/2 G2 G3 G1/2Bruising G1Injection site reaction G2Purpura G2

EndocrineHypothyroidism G2

GastrointestinalNausea G2 G2 G2 G2 G3Vomiting G3 G2Diarrhea G2 G2 G3Dysgeusia G1Dyspepsia G2Mucositis/stomatitis G1Constipation G3

Hemorrhage/bleedingAdrenal hemorrhage G3Gastrintestinal bleeding G3

InfectionSkin infection G2Oral/vaginal Candidiasis G2

Lab abnormalitiesHyperglycemia G3 G3 G3 G3 G3 G3 G1/2Elevated ALT/AST G4 G3 G3Elevated GGT G4Hyperbilirubinemia G3Hyperuricemia G4Hypophosphatemia G2Elevated creatinine G2 G1/2Proteinuria G4

LymphaticsPeripheral edema G1/2

MusculoskeletalLimb cramps G2Muscular weakness G2

NeurologyDizziness G1 G1 G1/2Paresthesia G1/2Tremor G1

(Continued)



round cell tumors (www.clinicaltrials.gov, NCT00563680) with anestimated enrolment of 38 patients. In addition to these studies, 2other phase II trials are still recruiting patients: (1) a study ofSCH-717454 in osteosarcoma and Ewing sarcoma with patientsaged 4 years or older (www.clinicaltrials.gov, NCT00617890) witha planned recruitment of 190 patients; and (2) a study of cixutu-mumab (www.clinicaltrials.gov, NCT00668148) with 185 patients(!12 years) and 5 arms: Ewing sarcoma, rhabdomyosarcoma,leiomyosarcoma, adipocytic sarcomas, and synovial sarcoma.

Despite these promising results and ongoing trials in sarcoma,the disappointing initial results of the randomized phase III trialswith figitumumab and chemotherapy in lung cancer have led topremature study closure, representing a setback to the developmentof IGF-1R mAbs in cancer.102 Indeed, following figitumumab re-sults in lung cancer, Roche103 has recently decided to halt furtherdevelopment of the anti–IGF-1R mAb R1507 in all tumor types. Itremains uncertain if this decision will impact on the final outcomesreport of the SARC011 trial, as it is likely to be pivotal to the futuredevelopment of this family of targeted therapies in sarcoma, espe-cially in Ewing sarcoma.

FUTURE DIRECTIONS IN IGF-1R TARGETING INSARCOMA

Tyrosine Kinase Inhibitors of IGF1-RThere are a number of small molecule TKIs of IGF-1R

currently undergoing clinical evaluation (Table 2). Some of thesesmall molecules also inhibit IR-A, a component of IGF-R hybridreceptors.72 Although this can potentially result in greater antitumoractivity, it may also be associated with a higher incidence ofmetabolic toxicity. From the results of clinical trials of mAbs andTKIs in other tumor types, it is apparent that predicting differencesin efficacy between these 2 classes can be difficult.104 Notably, smallmolecule TKIs do not directly activate the immune response againsttumor cells but may be more effective when activated receptors arelocalized in cytoplasmic caveosomes or endosomes.

Some of these novel IGF-1R TKIs (ie, picropodophylin,GSK183870A, GSK1904529A, BMS-536924, and NVP-AEW541)have already shown promising preclinical activity as single agents or

in combination with different sarcoma models.68–70,105–109 However,clinical differences in sarcoma patients between these 2 mechanismsof IGF-1R blockade currently remain undefined.

IGF-1R mAb CombinationsIGF-1R activation has been associated with chemoresistance

in multiple cancers,110 including some sarcomas such as Ewingsarcoma.11 Indeed, modulation of IGF signaling has been shown toenhance the antitumor activity of cytotoxic drugs in laboratorysarcoma models.111 Thus, a strategy based on the combination offirst- or second-line sarcoma chemotherapy with IGF-1R mAbsseems to be a rational approach in the utilization of these agents.Currently, there are a number of ongoing or planned studies evalu-ating such combinations, including a phase I/II trial of cixutumumabin combination with doxorubicin for advanced and unresectable softtissue sarcomas (www.clinicaltrials.gov, NCT00720174), sponsoredby the National Cancer Institute; and a phase I of SCH-717454 incombination with different commonly used chemotherapies in sar-coma such as vincristine, doxorubicin, and cyclophosphamide orifosfamide and etoposide (www.clinicaltrials.gov, NCT00960063).

Furthermore, clinical studies of rational combinations ofIGF-1R mAbs with other targeted therapies are in progress. Exam-ples of such regimens are the use of mTOR inhibitors in combina-tion with IGF-1R antibodies.112,113 Studies evaluating this approachinclude a trial of temsirolimus with cixutumumab in sarcomas,sponsored by the Memorial Sloan Kettering Cancer Centre and theNational Cancer Institute (www.clinicaltrials.gov, NCT01016015)and a trial of RAD001 (everolimus) in combination with figitumumabsponsored by the Dana-Faber Cancer Institute (www.clinicaltrials.gov,NCT 00927966). Other rational combinations could include regimenswith Heat shock protein 90114 or EGFR/HER2 inhibitors,107 becausethese have been implicated as potential mechanisms of IGF-1Rinhibition resistance in sarcoma cell lines.

Patient SelectionDespite robust preclinical evidence supporting the role of

IGF-1R targeted agents in Ewing sarcoma, clinical results show thatonly a proportion of patients derive significant benefit, with manyprogressing or developing resistance to IGF-1R mAbs quickly.

TABLE 3. (Continued)

Toxicity/Adverse Event (NCICTC AE Version 3.0)

Figitumumab CP-751,87181–83,98

RobatumumabR150786, 87 AMG47985

CixututumumabIMC-A1284 SCH-71745488 MK-064692,93

AVE164277 (Only1st Cycle)

Ocular/earDry eye G2Deafness/discomfort G2

PainArthralgia G3Back pain G3 G2 G3 G2Headache G2 G2 G2Myalgia G2 G1

Renal/urinaryPoliakiuria G2Difficult urination G1

RespiratoryDyspnea G3Pneumonitis G3

VascularDVT/pulmonary embolism G3 G4Cerebrovascular accident G3



Although initial reports suggested an association between the EWS/FLI-1 type 1 translocation and response in Ewing sarcoma,85 thepurported predictive value of translocation type has not been ob-served consistently.81 Further evaluation of predictive biomarkersfor IGF-1R targeting drugs needs to be pursued. Defining putativepredictive biomarkers—and eventual companion diagnostics—forIGF-1R therapy should be a priority for the further development ofthese agents. Although IGF-1R71 protein expression was not as-sessed in initial studies, preliminary reports suggested that expres-sion alone might not be sufficiently predictive for clinical benefitfrom IGF-1R targeting drugs; and it is likely that a suite of biomar-kers, both in the host and in the tumor,115 will be required for patientselection. Additional biomarker candidates for study may includeIGF-II,27 IRS-1116,117 or IRS-2117 expression, IGF-1R or IGF-2Rpolymorphisms,39,57 and constitutional activation of other relevantplayers in the IGF-1R downstream pathway.71,114 Larger, correlativestudies, coupled with clinical response data, such as the SARC011parallel biomarker study, which involved collecting tumor tissue andblood samples, will hopefully address some of these questions.

CONCLUSIONSThere is a large amount of preclinical data supporting the use

of agents targeting IGF-1R in sarcomas. This rationale has beenconfirmed by the early report of clinical activity with severalIGF-1R antibodies in Ewing sarcoma, as well as other sarcomasubtypes. However, the benefit of this therapeutic approach does notextend to all patients and there is an urgent need to identifypredictive biomarkers to improve patient selection, as well as toelucidate the mechanisms of resistance to these drugs, therebyfacilitating the development of rational combination regimens. De-spite the former, this novel group of drugs constitutes a promisingtherapy for sarcoma, especially in Ewing sarcoma, and has thepotential to drastically change the outcome of this devastatingdisease.

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biological rationale and current clinical experience with anti-insulin-like growth factor 1 receptor...

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