T h e n e w e ngl a nd j o u r na l o f m e dic i n e

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original article

Sel­u­me­ti­nib-Enhanced­Radioiodine­Uptake­in­Advanced­Thyroid­Cancer

Alan L. Ho, M.D., Ph.D., Ravinder K. Grewal, M.D., Rebecca Leboeuf, M.D., Eric J. Sherman, M.D., David G. Pfister, M.D., Desiree Deandreis, M.D.,

Keith S. Pentlow, M.Sc., Pat B. Zanzonico, Ph.D., Sofia Haque, M.D., Somali Gavane, M.D., Ronald A. Ghossein, M.D., Julio C. Ricarte-Filho, Ph.D.,

José M. Domínguez, M.D., Ronglai Shen, Ph.D., R. Michael Tuttle, M.D., Steve M. Larson, M.D., and James A. Fagin, M.D.

From the Head and Neck Oncology Ser-vice (A.L.H., E.J.S., D.G.P.) and the Endo-crinology Service (R.L., R.M.T., J.A.F.), Department of Medicine, and the De-partments of Radiology (R.K.G., D.D., S.H., S.G., S.M.L.), Medical Physics (K.S.P., P.B.Z.), Pathology (R.A.G.), and Human Oncology and Pathogenesis ( J.C.R.-F., J.M.D., J.A.F.), and the Epide-miology–Biostatistics (R.S.) and Molec-ular Pharmacology and Chemistry (S.M.L.) Programs, Memorial Sloan-Ket-tering Cancer Center and Weill Cornell Medical College, New York. Address re-print requests to Dr. Fagin at the Memo-rial Sloan-Kettering Cancer Center, 1275 York Ave., New York, NY 10065.

N Engl J Med 2013;368:623-32.DOI: 10.1056/NEJMoa1209288Copyright © 2013 Massachusetts Medical Society.

A BS TR AC T

Background

Metastatic­thyroid­cancers­that­are­refractory­to­radioiodine­(iodine-131)­are­associ-ated­with­a­poor­prognosis.­In­mouse­models­of­thyroid­cancer,­selective­mitogen-activated­protein­kinase­(MAPK)­pathway­antagonists­increase­the­expression­of­the­sodium–iodide­symporter­and­uptake­of­iodine.­Their­effects­in­humans­are­not­known.

Methods

We­conducted­a­study­to­determine­whether­the­MAPK­kinase­(MEK)­1­and­MEK2­inhibitor­sel­u­me­ti­nib­(AZD6244,­ARRY-142886)­could­reverse­refractoriness­to­radio-iodine­in­patients­with­metastatic­thyroid­cancer.­After­stimulation­with­thyrotropin­alfa,­ dosimetry­ with­ iodine-124­ positron-emission­ tomography­ (PET)­ was­ per-formed­before­and­4­weeks­after­treatment­with­sel­u­me­ti­nib­(75­mg­twice­daily).­If­the­second­iodine-124­PET­study­indicated­that­a­dose­of­iodine-131­of­2000­cGy­or­more­could­be­delivered­to­the­metastatic­lesion­or­lesions,­therapeutic­radioiodine­was­administered­while­the­patient­was­receiving­sel­u­me­ti­nib.

Results

Of­24­patients­screened­for­the­study,­20­could­be­evaluated.­The­median­age­was­61­years­(range,­44­to­77),­and­11­patients­were­men.­Nine­patients­had­tumors­with­BRAF­mutations,­and­5­patients­had­tumors­with­mutations­of­NRAS.­Sel­u­me­ti­nib­increased­the­uptake­of­iodine-124­in­12­of­the­20­patients­(4­of­9­patients­with­BRAF­mutations­and­5­of­5­patients­with­NRAS­mutations).­Eight­of­ these­12­patients­reached­the­dosimetry­threshold­for­radioiodine­therapy,­including­all­5­patients­with­NRAS­mutations.­Of­the­8­patients­treated­with­radioiodine,­5­had­confirmed­partial­responses­and­3­had­stable­disease;­all­patients­had­decreases­in­serum­thy-roglobulin­levels­(mean­reduction,­89%).­No­toxic­effects­of­grade­3­or­higher­at-tributable­by­the­investigators­to­sel­u­me­ti­nib­were­observed.­One­patient­received­a­diagnosis­of­myelodysplastic­syndrome­more­than­51­weeks­after­radioiodine­treat-ment,­with­progression­to­acute­leukemia.

Conclusions

Sel­u­me­ti­nib­produces­clinically­meaningful­increases­in­iodine­uptake­and­retention­in­a­subgroup­of­patients­with­thyroid­cancer­that­is­refractory­to­radioiodine;­the­ef-fectiveness­may­be­greater­in­patients­with­RAS-mutant­disease.­(Funded­by­the­Amer-ican­Thyroid­Association­and­others;­ClinicalTrials.gov­number,­NCT00970359.)

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Metastatic disease is the most fre-quent­cause­of­death­related­to­thyroid­cancer.1­ Radioiodine­ (iodine-131)­ re-

mains­ a­mainstay­ of­ therapy­ for­ patients­with­metastatic­thyroid­cancer­of­follicular­origin­(i.e.,­papillary­thyroid­cancer­or­follicular­thyroid­can-cer).­Unfortunately,­many­patients­have­ tumors­that­do­not­concentrate­ iodine,­resulting­ in­ra-dioiodine­ resistance­and­a­poor­prognosis­ (the­10-year­survival­rate­among­patients­with­meta-static­ thyroid­ cancer­ that­ retains­ radioiodine­avidity­is­approximately­60%,­whereas­it­is­only­10%­if­the­metastases­are­refractory­to­radioio-dine­therapy).2­Several­trials­have­evaluated­strat-egies­to­“redifferentiate”­metastatic­thyroid­can-cers­and­render­them­responsive­to­radioiodine,­including­trials­evaluating­retinoids3-5­and­lithi-um,6­which­only­yielded­a­modest­clinical­benefit.­These­studies­were­also­limited­by­methodologic­issues­such­as­the­inability­to­quantify­radioio-dine­uptake­and­retention­in­tumors,­so­the­ef-fect­of­the­interventions­was­difficult­to­assess.

Approximately­70%­of­papillary­thyroid­can-cers­have­mutually­exclusive­gene­mutations­en-coding­the­growth­factor­receptors­RET­or­NTRK1,­the­three­isoforms­of­RAS­(N,­H,­K),­and­BRAF.7-10­Constitutive­activation­of­these­proteins­stimulates­mitogen-activated­protein­kinase­(MAPK)­signal-ing,­which­inhibits­the­expression­of­thyroid­hor-mone­biosynthesis­genes,­including­the­sodium–iodide­symporter­and­thyroid­peroxidase,­which­facilitate­ iodine­ uptake­ and­ organification,­ re-spectively.11-15­ Cancers­ that­ do­ not­ concentrate­radioiodine­develop­in­transgenic­mice­in­which­mutant­BRAF­is­expressed­in­thyroid­cells.16­When­BRAF­activation­is­switched­off­genetically­or­its­downstream­signaling­ is­ inhibited­with­kinase­inhibitors­targeting­either­MAPK­kinase­(MEK)­or­BRAF,­ the­ tumors­ regain­ the­ability­ to­ trap­radioiodine.

These­ preclinical­ observations­ provided­ the­rationale­ for­ our­ pilot­ clinical­ study,­ in­ which­patients­who­were­found­to­have­metastases­that­were­refractory­to­radioiodine­were­treated­with­the­ selective,­ allosteric­MEK­ 1­ and­MEK­ 2­ in-hibitor­ sel­u­me­ti­nib­ (AZD6244,­ARRY-142886),17­and­changes­in­iodine­uptake­were­assessed­by­means­ of­ serial­ iodine-124­ positron-emission­tomography­(PET)–computed­tomography­(CT).­The­use­of­iodine-124­PET-CT­rather­than­tradi-tional­ whole-body­ iodine-131­ scintigraphy­ al-

lowed­for­precise­quantification­of­iodine­uptake­before­and­after­sel­u­me­ti­nib­treatment­ in­indi-vidual­metastatic­ lesions­ (“lesional­ dosimetry”)­and­ prediction­ of­ the­ dose­ of­ radiation­ that­could­be­delivered­with­iodine-131.18,19

Me thods

Study Conduct

The­trial­was­conducted­in­accordance­with­the­study­protocol,­available­with­the­full­text­of­this­article­at­NEJM.org.­All­patients­provided­written­informed­consent.­The­study­was­approved­by­the­research­committees­of­the­Departments­of­Med-icine,­Radiology,­and­Medical­Physics­at­Memo-rial­Sloan-Kettering­Cancer­Center­(MSKCC)­and­by­the­center’s­institutional­review­board.­All­au-thors­vouch­for­the­data,­the­fidelity­of­the­study­to­the­protocol,­and­the­analysis.­No­one­who­is­not­listed­as­an­author­contributed­to­the­manu-script.

Patients

Patients­were­required­to­have­differentiated­thy-roid­carcinoma­of­follicular-cell­origin,­or­its­re-spective­variants,­histopathologically­confirmed­at­the­MSKCC.­Patients­also­had­to­meet­at­least­one­ of­ the­ following­ criteria­ for­ radioiodine-­refractory­disease:­an­index­metastatic­lesion­that­was­not­radioiodine-avid­on­diagnostic­radioio-dine­ scanning­performed­up­ to­ 2­ years­ before­enrollment;­a­radioiodine-avid­metastatic­lesion­that­ remained­ stable­ in­ size­ or­progressed­de-spite­ radioiodine­ treatment­ 6­ months­ or­ more­before­entry­into­the­study;­and­18F-fluorodeoxy-glucose­ (FDG)–avid­ lesions­ on­ PET­ scanning­(FDG­avidity­ is­ indicative­of­ less­differentiated­thyroid­ tumors­ with­ impaired­ iodine­ uptake20­and­resistance­to­radioiodine,21­which­are­associ-ated­ with­ a­ poor­ prognosis22).­ (For­ additional­inclusion­and­exclusion­criteria,­see­the­Supple-mentary­Methods­section­in­the­Supplementary­Appendix,­ available­ at­ NEJM.org.)­ Thyrotropin­alfa­(Thyrogen)­was­provided­by­Genzyme,­and­sel­u­me­ti­nib­ was­ provided­ by­ AstraZeneca.­ IBA­Molecular­provided­the­iodine-124­for­the­study.­These­companies­did­not­participate­in­any­as-pect­of­the­study­design,­data­accrual,­data­anal-ysis,­ or­manuscript­ preparation.­ The­ investiga-tional­new­drug­application­for­sel­u­me­ti­nib­was­held­by­MSKCC.

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Study Design

After­ adhering­ to­a­ low-iodine­diet­ for­5­days,­patients­underwent­a­thyrotropin­alfa–stimulated­iodine-124­PET-CT­study,­followed­by­treatment­with­sel­u­me­ti­nib­at­a­dose­of­75­mg­given­orally­twice­daily­for­4­weeks.­In­the­fourth­week­of­sel-u­me­ti­nib­treatment,­patients­underwent­a­second­iodine-124­PET-CT­study.­Spot­urinary­iodine­mea-surements­were­performed­before­each­iodine-124­PET­evaluation­(median­urinary­iodine­value­dur-ing­the­study,­99­μg­per­liter;­range,­0­to­374)­to­rule­out­clinically­significant­iodine­contamina-tion­before­each­scan.­Patients­discontinued­the­study­if­the­second­iodine-124­PET­evaluation­did­not­show­an­increase­in­iodine­uptake­to­a­pre-specified­dosimetry­threshold.­If­this­dosimetry­threshold­was­met,­then­patients­continued­to­re-ceive­sel­u­me­ti­nib­(and­a­low-iodine­diet)­as­thyro-tropin­ alfa–stimulated­ whole-body­ and­ blood­dosimetry­studies­were­performed­to­determine­the­maximum­tolerable­activity­pursuant­to­the­standard­of­care­at­MSKCC.23­After­determina-tion­of­the­maximum­tolerable­activity,­a­thera-peutic­dose­of­iodine-131­was­administered­after­stimulation­with­thyrotropin­alfa.24­Sel­u­me­ti­nib­was­ continued­ until­ 2­ days­ after­ ingestion­ of­therapeutic­iodine-131.­Toxic­effects­were­moni-tored­for­30­days­after­the­last­dose­of­sel­u­me­ti-nib.­ Patients­ continued­ to­ receive­ suppressive­thyroid­hormone­treatment­throughout­the­pro-tocol.­The­second­iodine-124­PET-CT­study­in­one­patient­was­delayed­by­a­week­because­of­a­tem-porary­shortage­of­ the­ iodine-124­radionuclide;­this­study­showed­no­appreciable­change­in­io-dine­uptake.

In­patients­who­received­ iodine-131,­CT­ im-aging,­magnetic­resonance­imaging,­or­both­was­performed­ 2­ and­ 6­ months­ after­ radioiodine­therapy.­One­radiologist­assessed­the­radiologic­response­in­all­patients,­as­compared­with­prestudy­scans,­ according­ to­ the­ Response­ Evaluation­Criteria­ in­ Solid­ Tumors­ (RECIST)­ version­ 1.1.­Levels­of­serum­thyrotropin,­free­thyroxine,­thy-roglobulin,­ and­ thyroglobulin­ antibodies­ were­measured­1,­2,­and­6­months­after­administra-tion­of­radioiodine.

Iodine-124 PET-CT Studies

Patients­received­0.9­mg­of­thyrotropin­alfa­intra-muscularly­once­daily­for­2­consecutive­days,­and­then­6­mCi­of­iodine-124­orally­the­next­day.­Two­

days­later,­imaging­was­performed­with­the­use­of­a­PET-CT­scanner­(Discovery­STE,­GE­Health-care),­without­the­administration­of­contrast­ma-terial.­The­patient­was­scanned­from­the­cantho-meatal­line­(the­line­between­the­center­of­the­ear­canal­and­ the­ junction­of­ the­upper­and­ lower­eyelids)­to­the­midthigh­with­the­use­of­seven­to­nine­bed­positions,­with­scans­of­6­minutes­per­bed­position.­The­images­in­all­the­patients­were­interpreted­ in­ a­ blinded­ fashion­ by­ the­ same­board-certified­nuclear-medicine­physician,­and­the­number,­size,­and­maximal­standardized­up-take­value­of­the­lesions­in­each­body­region­were­recorded.

If­ the­ second­ iodine-124­PET-CT­study­ indi-cated­increased­iodine­uptake­in­the­index­lesion­(or­lesions),­an­estimate­was­made­of­the­admin-istered­activity­of­iodine-131­required­to­deliver­a­projected­absorbed­dose­of­2000­cGy­or­more­to­the­lesion.­This­estimate­was­based­on­the­le-sion­activity­concentration­measured­on­PET­mul-tiplied­by­a­recovery­coefficient­based­on­the­lesion­dimensions­measured­on­CT­and­on­an­assumed­biologic­half-life­of­at­least­2­days.­If­it­appeared­that­one­or­more­lesions­could­be­treated­with­a­dose­of­2000­cGy­or­more­with­an­iodine-131­ad-ministered­activity­of­up­to­300­mCi,­the­patient­was­ then­ eligible­ for­ the­ standard­ iodine-131­dosimetry­protocol­to­determine­the­actual­ac-tivity­to­be­administered.­In­addition,­as­previ-ously­described,­an­ imaging­analysis­ tool­was­used­with­the­GE­PET­volume­computer-assisted­reading­system­to­localize­individual­iodine-124­uptake­to­a­specific,­corresponding­lesion­on­CT.25

Tissue Genotyping

Mutation­detection­in­DNA­isolated­from­formalin-fixed,­paraffin-embedded­archival­samples­was­performed­with­the­use­of­the­mass-spectrometry­genotyping­assay­(MassArray,­Sequenom),­as­pre-viously­ described.26­ This­ assay­ interrogated­ for­mutations­in­some­of­the­most­common­thyroid­oncogenes,­including­BRAF, NRAS, KRAS, PIK3CA, and­ AKT1.­ Since­ the­mass-spectrometry­ assays­for­codons­12­and­13­of­HRAS­were­not­informa-tive,­ these­ sites­ were­ evaluated­ by­ means­ of­Sanger­sequencing.­If­mass­spectrometry­analy-sis­failed,­samples­were­assayed­for­BRAF, NRAS, KRAS,­and­HRAS­mutations­by­means­of­Sanger­sequencing.­Samples­that­were­wild-type­for­on-cogene­point­mutations­were­ screened­ for­ RET­

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and­ PAX8–peroxisome­proliferator–activated­ re-ceptor­ gamma­ (PPARG)­ rearrangements.­ Tumor­complementary­DNA­(cDNA)­was­used­as­a­tem-plate­ for­ a­ quantitative­ polymerase-chain-reac-tion­assay­to­identify­unbalanced­expression­of­exons­10­and­11­ relative­ to­12­and­13­of­RET,­which­flank­the­rearrangement­site­in­intron­11­(Table­S1­in­the­Supplementary­Appendix).­Sam-ples­with­greater­expression­of­exons­12­and­13­than­of­exons­10­and­11­were­considered­to­be­positive­ for­ an­ RET/PTC­ translocation.­ Cell-line­cDNA­from­medullary­thyroid­cancers­(TT­cells)­and­papillary­thyroid­cancers­(TPC1­cells)­were­used­as­positive­controls­for­expression­of­full-length­RET­and­RET­fusion­messenger­RNA,­re-spectively.

Statistical Analysis

The­primary­end­point­was­the­percentage­of­pa-tients­with­sel­u­me­ti­nib-induced­increases­in­io-dine­uptake­in­the­index­tumor­(or­tumors),­as­quantified­by­iodine-124­PET­at­baseline­and­af-ter­4­weeks­of­sel­u­me­ti­nib.­We­adopted­as­ the­

null­hypothesis­an­ increase­ in­ iodine-124­PET–quantified­iodine­uptake­in­5%­of­patients,­with­increased­uptake­in­25%­of­patients­considered­to­be­desirable.­With­a­type­1­error­of­5%­and­a­power­ of­ 85%,­ increased­ iodine­ uptake­ in­ the­second­ iodine-124­ PET­ scan­would­ need­ to­ be­observed­in­at­least­three­patients­for­the­study­to­be­considered­positive.­A­second­primary­end­point­was­the­tumor­response­at­approximately­2­and­6­months­after­iodine-131­treatment­according­to­RECIST,­version­1.1.

A­secondary­end­point­was­an­assessment­of­whether­treatment­with­iodine-131­after­sel­u­me-ti­nib­was­associated­with­decreased­serum­thy-roglobulin­levels­at­2­and­6­months.­A­Wilcoxon­signed-rank­test­for­paired­samples­was­used­for­this­landmark­comparison­at­each­follow-up­as-sessment.­Undetectable­thyroglobulin­values­clin-ically­reported­as­less­than­0.2­ng­per­milliliter­were­assigned­a­value­of­0.2­ng­per­milliliter­for­calculations.­An­additional,­exploratory­end­point­was­an­assessment­of­differences­in­sel­u­me­ti­nib­efficacy­for­enhancing­radioiodine­uptake­between­patients­with­BRAF­mutations­and­patients­with­wild-type­BRAF­(additional­details­of­the­statisti-cal­ design­ are­ included­ in­ the­ Supplementary­Appendix).­We­used­descriptive­statistics­for­this­assessment.

R esult s

Study Population

Between­August­2010­and­December­2011,­a­total­of­24­patients­were­referred­and­screened­for­the­study.­ Two­ patients­ were­ ineligible­ because­ of­baseline­measurements­of­ the­QT­ interval­ cor-rected­for­heart­rate­which­were­outside­the­study­range.­Two­patients­were­enrolled­but­discontin-ued­the­study­before­sel­u­me­ti­nib­was­adminis-tered:­ 1­ in­whom­ a­ new­ brain­metastasis­was­diagnosed­and­1­in­whom­iodinated­contrast­ma-terial­was­used­for­a­diagnostic­scan­that­revealed­a­pulmonary­embolism.

Baseline­clinical­characteristics­of­the­20­pa-tients­who­could­be­evaluated­are­listed­in­Table­1.­Five­patients­(25%)­had­classic­papillary­thyroid­cancer,­ 8­ (40%)­ had­ tall-cell–variant­ papillary­thyroid­cancer,­and­7­(35%)­had­poorly­differen-tiated­ carcinoma.­ Nine­ patients­ had­ a­ BRAF V600E­mutation,­5­had­an­NRAS­mutation­at­co-don­ 61­ (Q→R­or­K),­ 3­ had­ RET/PTC­ rearrange-

Table 1. Baseline Characteristics of the 20 Patients.

Characteristic Value

Age — yr

Median 61

Range 44–77

Sex — no.

Male 11

Female 9

Type of tumor — no./total no. (%)

Classic papillary 5/20 (25)

Tall-cell papillary 8/20 (40)

Poorly differentiated 7/20 (35)

Tumor genotype — no./total no. (%)

BRAF V600E 9/20 (45)

NRAS Q61R and Q61K 5/20 (25)

RET/PTC 3/20 (15)

Wild type 3/20 (15)

Median no. of prior radioiodine treatments per patient 2.1

Other treatments for thyroid cancer — no. of patients/ total no. (%)

External-beam radiation therapy 7/20 (35)

Targeted therapies* 2/20 (10)

* These patients received sorafenib in combination with an mTORC1 (mamma-lian target of rapamycin complex 1) inhibitor before enrollment in the study.

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ments,­and­3­had­tumors­that­were­wild-type­for­all­genes­examined.­No­PAX8-PPARG­ rearrange-ments­ were­ detected.­ One­ BRAF-mutant­ tumor­and­one­RET/PTC­ tumor­were­poorly­differenti-ated­carcinomas;­the­remaining­tumors­of­these­genotypes­ were­ papillary­ thyroid­ cancers.­ All­five­NRAS-mutant­tumors­were­poorly­differenti-ated­carcinomas.

Efficacy

Figure­ 1A­ shows­ the­ protocol­ design.­ Of­ the­­20­patients­who­could­be­evaluated,­12­(60%)­had­iodine-124­ uptake­ that­ was­ new,­ increased,­ or­both­ after­ sel­u­me­ti­nib­ (Fig.­ 1B).­ In­ 8­ patients­(40%),­the­second­iodine-124­PET­study­indicated­that­ the­ absorbed­ radiation­ dose­ in­ the­ lesion­would­equal­or­exceed­2000­cGy­with­300­mCi­of­radioiodine­or­less;­these­patients­continued­to­re-

ceive­sel­u­me­ti­nib,­and­they­received­therapeutic­radioiodine.­In­all­5­patients­with­NRAS-mutant­tumors,­this­dosimetry­threshold­was­exceeded,­and­these­patients­were­treated­with­radioiodine.­In­contrast,­4­of­9­patients­with­BRAF­mutations­had­sel­u­me­ti­nib-induced­increases­in­iodine-124­uptake,­but­only­1­had­an­increase­that­exceeded­the­threshold­for­radioiodine­treatment.­Two­of­­3­patients­with­RET/PTC­and­1­of­3­patients­with­wild-type­tumors­had­greater­ iodine­uptake­on­the­ second­ iodine-124­ PET­ study;­ 1­ patient­ in­each­ of­ those­ genotype­ groups­ went­ on­ to­ be­treated­with­iodine-131.­Increases­in­iodine­up-take­were­achieved­in­patients­with­papillary­thy-roid­cancers­and­those­with­poorly­differentiated­carcinomas­(Table­S2­in­the­Supplementary­Ap-pendix),­as­well­as­in­patients­in­each­protocol-specified­ category­of­ radioiodine­ refractoriness­

B

A

4/95/52/31/3

12/20

1/95/51/31/3

8/20

TumorGenotype

Patients with IncreasedIodine Uptake in a Lesion

after Selumetinib

Patients WhoReceived

Radioiodineno./total no. of patients

BRAF NRAS RET/PTCWild-typeTotal

Week 1 Week 2–4 Week 5

Selumetinib, 75 mg twice a day for 4 wk

124IPET-CT

124IPET-CT

Thyrotropinalfa injections

Thyrotropinalfa injections

Inadequate responseon 124I PET-CT

Positiveresponse on124I PET-CT

Discontinueselumetinib

Continueselumetiniband receiveradioiodine

therapy

Serial radiologicscans and

measurement ofserum thyro-

globulin levels

Figure 1. Protocol Design and Changes in Iodine Uptake.

Panel A shows the protocol design. Baseline iodine avidity in the lesion was first assessed with thyrotropin alfa–stimulated iodine-124 positron-emission tomographic–computed tomographic (PET-CT) scanning. Patients were then treated with sel u me ti nib at a dose of 75 mg given orally twice a day for 4 weeks. In the final week of treatment, a second thyrotropin alfa–stimulated 124I PET-CT study was performed. The double arrows indicate the two thyro-tropin alfa injections. Patients with 124I dosimetry that predicted tumor uptake of less than 2000 cGy discontinued the study. If the absorbed dose of radioiodine in the lesion was predicted to be 2000 cGy or greater, full dosimetry with iodine-131 was performed to calculate the maximum tolerable activity that could be administered safely. Patients then received a therapeutic dose of radioiodine the next week after preparation with thyrotropin alfa. Sel u me ti nib was continued until 2 days after the administration of therapeutic radioiodine. Thyroglobulin levels and the radio-graphic response were assessed at 2 and 6 months after radioiodine administration. Panel B shows a summary of the changes in iodine uptake quantified by 124I PET-CT and the number of patients who met the criteria for treat-ment with iodine-131.

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(Table­S3­in­the­Supplementary­Appendix).­Of­the­10­patients­with­no­detectable­iodine-124­uptake­at­baseline,­2­had­increased­uptake­after­receiv-ing­sel­u­me­ti­nib,­1­of­whom­went­on­to­receive­iodine-131.

The­ sel­u­me­ti­nib-induced­ changes­ in­ the­ io-dine-124­PET-CT­ scans­ are­ shown­ in­Figure­2.­The­ only­ patient­ with­ a­ BRAF­ mutation­ who­qualified­ for­ radioiodine­ therapy­ had­ dramatic­increases­ in­ iodine­ uptake­ in­ a­ right­ cervical­lymph­node­and­lung­metastases­that­showed­no­uptake­ at­ baseline­ (Fig.­ 2A).­ In­ other­ patients,­

iodine­uptake­was­enhanced­both­in­lesions­with­low-level­iodine­avidity­and­those­with­no­avidity­at­baseline­(Fig.­2B).­Striking­increases­in­sel­u-me­ti­nib-induced­ iodine-124­ uptake­ were­ also­observed­in­bone­metastases­(Fig.­2C­and­2D).

Quantification­of­baseline­and­post-sel­u­me­ti-nib­ iodine-124­in­each­tumor­in­a­patient­with­an­NRAS­mutation­who­qualified­for­radioiodine­therapy­ revealed­ either­ new­ iodine­ uptake­ or­more­than­a­100%­increase­in­uptake­in­nearly­every­lesion­(Fig.­3).­Analysis­of­every­lesion­in­all­eight­patients­treated­with­radioiodine­showed­

C

A

D

B

Baseline After Selumetinib

Baseline After Selumetinib

Baseline After Selumetinib

Baseline

AfterSelumetinib

Figure 2. Iodine-124 PET-CT Scans Obtained before and after Sel u me ti nib Treatment in Selected Patients with Positive Responses.

Panel A shows whole-body maximum-intensity projection images of a patient with a BRAF-mutant papillary thyroid cancer. New iodine uptake is shown in nearly all previously negative lung and neck metastases. Panel B shows fused axial PET-CT images of a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Both new and signifi-cantly increased iodine uptake in lung metastases is shown. Panels C and D show PET-CT images from another pa-tient with an NRAS-mutant, poorly differentiated thyroid cancer. In Panel C, fused axial PET-CT images show signifi-cantly increased iodine uptake in a sacroiliac bone metastasis after administration of sel u me ti nib (right). In Panel D, fused axial images (top and bottom left) show new iodine uptake in a previously negative site as well as increased avidity in a large left parietal skull metastasis. Three-dimensional rendering highlights changes in the left parietal skull metastasis before and after sel u me ti nib (top and bottom right).

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that­sel­u­me­ti­nib­increased­iodine-124­uptake­in­nearly­ all­ lesions,­ with­ more­ than­ a­ 100%­ in-crease­in­uptake­in­most­lesions­(Fig.­S1­in­the­Supplementary­Appendix).­Iodine­uptake­in­sali-

vary­glands­was­not­significantly­affected­by­sel-u­me­ti­nib­ (Fig.­ S2­ in­ the­ Supplementary­Appen-dix);­this­suggests­that­the­effect­was­restricted­to­thyroid­tumors.

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(−50%)

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Figure 3. Quantification of Iodine-124 PET Uptake in a Lesion in a Patient with an NRAS Mutation Who Later Received Radioiodine.

Panel A shows the maximal standardized uptake value (SUVmax) for iodine in all tumors in a patient with an NRAS-mutant, poorly differentiated thyroid cancer. Each bar represents one malignant lesion identified on the iodine-124 PET-CT scan. The bars to the left indicate the increases in iodine-124 avidity achieved after sel u me ti nib administra-tion in lesions that absorbed some iodine at baseline. The bars on the right indicate sel u me ti nib-induced changes in lesions that were negative for iodine at baseline. Panel B shows the SUVmax in every metastatic lesion identified in the same patient before and after the administration of sel u me ti nib. The dashed lines mark points on the graph cor-responding to different degrees of change in the SUVmax in the lesion after the administration of sel u me ti nib. The red dashed line demarcates no change in iodine uptake after the administration of sel u me ti nib (0%). Dashed lines to the left of the red dashed line represent graded percentage increases in iodine-124 uptake (+25%, +50%, and +100%), whereas the lines to the right represent graded percentage decreases (−25%, −50%, and −75%). Nearly all the metastatic lesions in this patient (circles) had more than a 100% increase in iodine uptake after administration of sel u me ti nib. The SUVmax for a sternal metastasis was off the scale (it increased from 220 to 599 with sel u me ti nib) and thus could not be included in these graphs without obscuring the data for the other 54 lesions analyzed.

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During­6­months­of­follow-up,­a­reduction­in­the­ size­ of­ target­ lesions­ was­ observed­ in­ all­patients­after­the­administration­of­radioiodine,­with­confirmed­partial­responses­in­five­patients­and­ stable­ disease­ in­ three­ as­ the­ best­ overall­response­(Fig.­4A,­and­Fig.­S3­in­the­Supplemen-tary­Appendix).­ Significant­ decreases­ in­ thyro-tropin-suppressed­serum­thyroglobulin­levels­af-ter­radioiodine­administration­were­achieved­in­all­eight­patients­at­2­months­and­6­months­after­radioiodine­ administration,­ with­ mean­ reduc-tions­of­89%­(P­=­0.004)­and­80%­(P­=­0.004),­re-spectively,­as­compared­with­the­value­measured­

within­ 3­ weeks­ before­ radioiodine­ administra-tion­ (Fig.­ 4B).­ In­ seven­ of­ the­ eight­ patients,­confirmed­partial­responses­and­stable­disease­outcomes­were­durable­over­the­6-month­period­of­ follow-up­ after­ radioiodine­ administration.­The­remaining­patient­had­a­48%­reduction­ in­tumor­dimensions­2­months­after­receiving­ra-dioiodine­ but­ then­ had­ tumor­ progression­ at­­6­months,­ representing­a­best­overall­ response­of­stable­disease.

Safety

All­patients­who­could­be­evaluated­completed­the­full­course­of­sel­u­me­ti­nib­without­a­dose­re-duction­or­delay­in­administration.­All­toxic­ef-fects­attributed­to­sel­u­me­ti­nib­were­grade­1­or­2­and­were­consistent­with­adverse­events­reported­in­larger­studies­of­sel­u­me­ti­nib,27,28­including­fa-tigue­ (in­80%­of­patients),­maculopapular­ rash­(70%),­and­acneiform­rash­(25%).­Fourteen­pa-tients­(70%)­had­grade­1­elevations­in­liver­ami-notransferase­levels,­possibly­related­to­sel­u­me­ti-nib;­these­levels­reverted­to­baseline­values­after­drug­discontinuation.­(Tables­S4­and­S5­in­the­Supplementary­Appendix­list­all­the­toxic­effects­reported­during­the­study.)­One­patient­who­was­treated­with­139­mCi­of­radioiodine­during­the­study­received­a­diagnosis­of­the­myelodysplastic­syndrome­more­than­51­weeks­later;­the­disease­eventually­progressed­to­acute­leukemia.­Before­enrollment,­this­patient­had­received­three­cours-es­of­radioiodine­(a­cumulative­prestudy­dose­of­976.2­mCi),­as­well­as­8640­cGy­of­external-beam­radiation­therapy,­for­prostate­cancer,­and­throm-bocytopenia­ developed­ when­ the­ patient­ was­treated­ with­ sorafenib­ and­ temsirolimus­ in­ a­clinical­trial.

Discussion

Previous­ studies­ using­ various­ compounds­ to­promote­radioiodine­uptake­in­refractory­meta-static­thyroid­cancers­have­not­shown­a­clinically­significant­benefit.3,6­The­approach­undertaken­in­this­study­was­facilitated­by­several­develop-ments:­the­discovery­that­genetic­alterations­that­constitutively­activate­MAPK­signaling­can­pro-mote­ the­ dedifferentiation­ of­ thyroid-cancer­cells,12,29,30­the­clinical­availability­of­a­selective­MEK­inhibitor,17­and­the­development­of­iodine-124­PET-CT­technology­to­quantify­the­uptake­of­iodine­in­a­lesion.18

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100 57 14

Figure 4. Response to Iodine-131 Therapy with Sel u me ti nib Treatment.

Panel A shows a waterfall plot of the maximum change in target lesions (relative to a prestudy scan) in the eight patients who received therapeutic radioiodine. The best overall response in each patient according to the Re-sponse Evaluation Criteria in Solid Tumors, version 1.1, is also shown. The dashed line indicates a 30% reduction in tumor dimensions. WT denotes wild-type. Panel B shows serum thyroglobulin values in the eight patients treated with radioiodine. NA denotes not available.

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Selumetinib and R adioiodine Uptake in Thyroid Cancer

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Our­ results­ show­ that­ inhibition­ of­ the­MAPK­pathway­with­sel­u­me­ti­nib­can­renew­the­therapeutic­efficacy­of­ radioiodine­by­enhanc-ing­uptake­in­patients­with­thyroid­cancer­that­is­ refractory­ to­ radioiodine.­ All­ five­ patients­with­NRAS-mutant­tumors­had­increased­iodine­uptake­ in­ response­ to­ sel­u­me­ti­nib;­ four­ had­confirmed­partial­responses­and­one­had­stable­disease­ after­ radioiodine­ administration.­ This­finding­is­of­particular­interest,­given­the­well-documented­challenges­of­developing­therapeu-tic­approaches­for­RAS-driven­cancers,­and­it­is­consistent­with­preclinical­data­showing­that­a­RAS­ mutation­ can­ suppress­ thyroid-specific­gene­ expression­ in­ a­ MEK-dependent­ man-ner.12,31­ Only­ one­ of­ nine­ patients­ with­ BRAF­mutations­ received­ radioiodine­ therapy.­ That­patient­had­a­particularly­striking­conversion­of­lesions­from­negative­to­positive­on­iodine-124­PET­after­treatment­with­sel­u­me­ti­nib­and­had­a­confirmed­ partial­ response.­ Three­ other­ pa-tients­with­BRAF­mutations­also­had­increased­uptake­on­the­post-sel­u­me­ti­nib­iodine-124­PET­study,­ even­ though­ the­ threshold­ required­ for­therapy­ was­ not­ reached.­ The­ differences­ ob-served­ between­ RAS-mutant­ and­ BRAF-mutant­

tumors­remain­to­be­explained,­but­it­is­possi-ble­that­MAPK­signaling­is­incompletely­inhib-ited­ in­ some­ BRAF-mutant­ tumors­ because­ of­higher­f lux­through­the­pathway.

These­results­provide­a­proof­of­principle­that­MEK­inhibitors­can­induce­iodine­uptake­and­re-tention­in­thyroid­tumors.­An­advantage­of­this­therapeutic­strategy­over­long-term­treatment­with­small-molecule­kinase­inhibitors­alone32­is­that­only­a­short­course­of­drug­therapy­is­required­to­elicit­a­durable­clinical­effect.­Enhanced­iodine­uptake­ was­ also­ observed­ in­ bone­ and­ nodal­metastases,­niches­that­have­been­comparatively­refractory­to­treatment­with­kinase­inhibitors.

Supported­by­grants­from­the­American­Thyroid­Association,­the­Society­of­Memorial­Sloan-Kettering­Cancer­Center,­the­Na-tional­ Institutes­of­Health­ (RO1-CA50706­and­RO1-CA72598),­AstraZeneca,­and­Genzyme,­as­well­as­funding­from­the­Lefkof-sky­Family,­Margot­Rosenberg­Pulitzer,­Byrne,­and­J.­Randolph­Hearst­foundations.­The­iodine-124­PET­studies­were­supported­in­part­by­a­grant­from­the­In-Vivo­Cellular­and­Molecular­Imag-ing­Center­(P50­086438-10).­Dr.­Domínguez­was­supported­in­part­by­a­grant­from­Pontificia­Universidad­Católica­de­Chile­and­Becas­Chile­(76100021),­and­Dr.­Deandreis­by­a­grant­from­Fon-dation­de­France­(2010-12521).

Disclosure­forms­provided­by­the­authors­are­available­with­the­full­text­of­this­article­at­NEJM.org.

We­thank­the­research­study­staff,­particularly­Susan­Korte,­Alex­F.­Mak,­Brynna­Lipson,­Donna­Lisa,­and­Lisa­Cox,­R.N.

References

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