ntrk inhibitors: what we learned and where to go · 2020-02-19 · ntrk inhibitors: what we learned...
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NTRKinhibitors:whatwelearnedandwheretogoMichelaCasanova,FondazioneIRCCSIstitutoNazionaledeiTumoriMilano,Italy
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TRKreceptorsmediateneurotrophinsignaling• Neurotrophinsareimportantgrowthfactorsinvolvedinthegrowth,differentiation,andsurvivalofneurons
• NeurotrophinsignalingoccursthroughactivationoftheTRKreceptorfamily
NeurotrophinFamilyofReceptors
TRKReceptor
Gene(Chromosomal
Location)
FunctionsNaturalLigandsDevelopmental Adult
TRKA NTRK1(1q23.1)
Cellulardifferentiation/sensoryneuronsubtypespecificationanddevelopmentofpainandthermoregulationmodalities
Painsignaling,thermoregulation
Nervegrowthfactor(NGF),neurotrophin-3(NT-3)
TRKB NTRK2(9q21.33)
Developmentofsensoryneuronsinthebrain
Regulationofmovement,memory,mood,appetite,bodyweight
Brain-derivedneurotrophicfactor(BDNF),neurotrophin-3/4/5(NT-3/4/5)
TRKC NTRK3(15q25.3)
Neuronaldifferentiation,axonoutgrowth/guidance,andsynapticplasticity
Proprioception NT-3
NeurotrophinSignaling1,3
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Genefusions:animportantclassofoncogenes• Associatedwithadiverserangeofsolidtumoursand
hematologicmalignancies
• NTRKgenefusionsareassociatedwithmanyhumancancers• Associatedwith≥19tumourtypes
• Implicatedinupto1%ofallsolidtumours
TRKfusionproteinsareprimaryoncogenicdrivers
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TRKfusioncanceroccursacrossawiderangeofchildhoodandadulttumourtypes
Paediatric/youngadult
InfantilefibrosarcomaThyroidcancer
Sarcoma(multiple)
Spitznevi
Adult
Thyroidcancer
IntrahepaticcholangiocarcinomaSecretorybreastcancer
SalivaryMASC
Braincancer(glioma,GBM,astrocytoma)
Lungcancer
Colon
Melanoma
Pancreatic
Sarcoma
Paediatric(infants)high-gradeglioma
Congenitalmesoblasticnephroma
• RaretumourswithhighNTRKgenefusionfrequency
• CommontumourswithlowNTRKgenefusionfrequency
GBM,glioblastomamultiforme;MASC,mammaryanaloguesecretorycarcinoma;NTRK,neurotrophictyrosinereceptorkinase;TRK,tropomyosinreceptorkinase.
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Single-drivertumorsparticularlysuitable
forprecisionmedicine
10
Highunmetneedbothintermsofchanceofrelapsebutalsocurrenttherapiescanleadtosignificanttreatmentburdenandlongtermsideeffects
Whatwearelearning:braintumors
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Whatwelearned:rapidclinicaldevelopment
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• LarotrectinibisthefirstandonlyselectiveTRKinhibitor
• HighlypotentagainstTRKA,TRKB,andTRKC
• IC505–11nM• Highlyselective
• Limitedinhibitionofotherkinases
• Noinhibitionof229otherkinasesat1000nM
• DemonstrateactivityinCNSdisease
Larotrectinib
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Larotrectinib
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Larotrectinib
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Larotrectinib
Whatwelearned:efficacy
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Entrectinib
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Entrectinib
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28childrentreatedbetween5/2016-10/2018
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Entrectinib
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Entrectinib/Larotrectinib Entrectinib ORR Larotrectinib ORR
Extra-CNS NTRK+ 3/3 (3 PR) 100% (29-100%)
32/34 (11 CR, 21 PR)
94% (80-99%)
CNS NTRK + 3/4 (1 CR, 2 PR, 1ong)
75% (19-100%)
5/11 (2 CR, 3 PR) 45% (17-77%)
CNS ROS1 + 2/2 (1 PR, 1 uPR)
Extra-CNS ROS1 + 1/1 (1 PR)
Extra-CNS ALK + Fusion: 2/2 (2 CR) Mut: 1/1 (1CR)
• Differenceresponseratetoextra-CNSandCNStumorrelatedtoCNSpenetrance?• LarotrectinibwasdesignedtohavelimitedCNSpenetrationtoreducethepotential
foron-targettoxicityduetoinhibitionofnormalTRKreceptorsinthebrain• EntrectinibwasfirstdevelopedasanALKinhibitor
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Larotrectinib
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Larotrectinib
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Larotrectinib
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PotentialNTRKinhibitorstoxicities
NodataonlateeffectsThephaseIadulttrialoflarotrectinibenrolledpatientstartinginMarch2015
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Entrectinib
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NTRKinhibitorsapprovedinNTRK-fusionpositivetumours
Larotrectinib
Approved: FDA 2018; Brazil, Canada, EMA 2019
Dose: 25-mg or 100-mg oral capsule or 20-mg/mL oral solution
• Adults and children with BSA ≥1.0m2: 100 mg orally BID
• Children with BSA ≤1.0m2 : 100 mg/m2 orally BID
Entrectinib
Approved: FDA and Japan 2019
Dose: 100-mg and 200-mg oral capsule
• Adults: 600 mg orally once daily
• Children: Recommended dose based on BSA
Indication: For the treatment of patients with solid tumours harbouring NTRK fusions in paediatric or adult patients
Indication: For the treatment of NTRK fusion-positive advanced or recurrent solid tumours in adult patients and paediatric patients aged ≥12 years old
6
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Wheretogo?
IdentificationofNTRKfusionsinpediatricpatients
Treatment:when?howlong?
Toxicityandlateeffects
ResistancesandsecondgenerationNTRKi
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NointumorwithactivatingmutationmutuallyexclusivetoNTRK
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12
Needforspecific
recommendationsforchildren
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Tumourtype Clinicalsummary Screening
methodology Rationale
Infantilefibrosarcoma
• Mostcommonsofttissuesarcomainchildren<1year• Morethanhalfofinfantshaveunresectableormetastaticdiseasethatrequiresneoadjuvanttreatment
IHC/FISH(ETV6and/orNTRK3)RT-PCR;NGSifnegative
HighfrequencyofETV6-NTRK3fusion;variantNTRK3andNTRK1fusionshavebeendescribed
Cellularcongenitalmesoblasticnephroma
• Mostcommonkidneytumourinthefirstmonthoflife• 96%overallsurvivalrate• Mostpatientstreatedwithnephrectomy;~20%treatedwithadjuvantchemotherapy
IHC/FISH(ETV6and/orNTRK3)RT-PCR;NGSifnegative
HighfrequencyofETV6-NTRK3fusion;variantNTRK3andNTRK1fusionshavebeendescribed
Secretorybreastcancer
• Raresubtypeofbreastcancer(<0.02%ofpatients)• Prognosisgenerallygoodwhendiseaseislocalised• Standardtreatmentissurgerywith/withoutradiation• Lymphnodemetastasescanoccur,somepatientswithmetastaticrecurrence
IHC/FISH(ETV6and/orNTRK3)RT-PCR;NGSifnegative
HighfrequencyofNTRK3fusions
MASCofthesalivarygland
• Histologicallyresemblessecretorybreastcancer• Primarilyoccursinadults;somecasesinadolescents• AlmostalltumoursharbourETV6-NTRK3fusions
IHC/FISH(ETV6and/orNTRK3)RT-PCR;NGSifnegative
HighfrequencyofNTRK3fusions
Tumourswithhigh-frequencyTRKfusions(>75%)
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Tumourswithmedium-frequencyTRKfusions(10%to40%)Tumourtype Clinicalsummary Screening
methodology Rationale
Spitzoidmelanomas
• Raremelanocyticlesions(rangingfrombenigntomalignantspitzoidmelanoma)
• 90%ofpatientsdiagnosedare<30yearsold• Childrenaged10–18yearsareatgreaterriskofmetastaticspreadanddeathvsyoungerchildren
• Recently,recurrentkinasefusionshavebeendescribed
IHC/NGS
TRKfusionsoccurin15–25%ofpaediatricmelanocyticneoplasms
Papillarythyroidcancer
• Thyroidcancersaccountfor~4%ofmalignanciesinchildren;>90%ofthesearePTCcases
• Goodprognosis,with>95%overallsurvivalrateat5years• Treatmentconsistsofthyroidectomyforlocalisedtumours,andradioactiveiodineformetastatictumours
• TRKfusionsmaybeassociatedwithhigher-stagedisease
IHC/NGS
TRKfusions(NTRK1andNTRK3)occurinapproximately25%ofchildren,andBRAFactivatingmutationsoccurin~50%ofpatients
High-gradegliomas,especiallyinyoungchildren
• Gliomasarethemostcommonbraintumoursinchildren• Poorsurvivaloutcomesinchildrenwithhigh-gradegliomas(<25%3-yearoverallsurvivalrate)
• NTRKfusionsshowntooccurin~40%ofhigh-gradegliomasinchildren<3yearsold
NGS
TRKfusionsoccur,especiallyintumoursofchildren<3yearsofage;patientshavepoorprognosis;IHChasnotbeenvalidatedingliomas,whichcanhavenormalphysiologicexpressionsofTRK
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Tumourswithunknownorlow-frequencyTRKfusions(<5%)Tumourtype Clinicalsummary Screening
methodology Rationale
Undifferentiatedsarcoma
(withoutknowndefiningfusion)
• LinkwithTRKfusionslargelyanecdotal,sofrequencyhasnotbeenestimated
• Historically,treatmentofundifferentiatedsarcomahasbeenvariable,morerecentlyrisk-basedchemoradiotherapy
NGS
PrevalenceofTRKfusionsunknownbutdescribed;inadditiontoNTRK,othertargetablefusionshavebeendescribed
InflammatoryMyofibroblastic
Tumour
• Locallyaggressiveneoplasms• Medianageatdiagnosis:9years• Metastasesarerare(<5%),andcompletesurgicalresectionisusuallycurative
• PatientswithALKfusions(50–60%ofcases)haveagoodtreatmentresponsewithcrizotinib
NGS
TRKfusiontumoursmayshareinflammatorymyofibroblastictumour-likemorphology;mutuallyexclusivefusionsofALKandROS1alsooccur
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ICH: sensitivityandspecificityishighinmesenchymaltumorsuselessinbraintumors
SIOPENTRKtestingworkshop
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Molecularprofilingprogramsatrelapse
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MYCKIDSTUDY:MOLECULARIDENTITYCARDFORKIDS,ADOLESCENTANDYOUNGADULT
WITHNONRHABDOMYOSARCOMASSOFTTISSUESARCOMA
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EpSSGCountryA
EpSSGCountryB
Center1Localpathology
Center2Localpathology
Center3Localpathology
Center4Localpathology
Utrecht
Frozenmaterial(molecularcharacterization):- Wholeexomesequencing(WES),RNAseqfor
fusiondetection,DNAmethylation- Ancillarystudies(organoids,singlecellRNS
sequencing)
Lyon
FFPEmaterial(molecularcharacterization):- RNAseq,CGH:CINSARC,GI- Transcriptfusion,clustering:diagnosis
EpSSGCountryC
Diagnosispurpose Researchpurpose
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Additionaldataarecominginthenextyearsinadultsandchildren
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LarotrectinibinTreatingPatientsWithPreviouslyUntreatedTRKFusionSolidTumorsandTRKFusion
RelapsedAcuteLeukemia–COGADVL1823
• PrimaryoutcomemeasureORRofchildrenwithinfantilefibrosarcoma(IFS)treatedwith
neoadjuvantlarotrectinibpriortolocalcontrol
• SecondaryoutcomemeasuresEFS/OS/DoRinIFStreatedwithneoadjuvantlarotrectinibORR/EFS/OS/DoRinnewlydiagnosedTRKfusionsolidtumorsotherthanIFStreatedwithneoadjuvantlarotrectinibpriortolocalcontrol
IncidenceofadverseeventsPercentageofpatientswithTRKfusionsolidtumorswithdetectablectDNA
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Chemotherapy Larotrectinib
EV(catheter) Oral
Effective(75%) Effective(>90%),rapidresponse
Acutetoxicity(VOD) Nosevereacutetoxicity
Durationoftherapy:median4months
Durationoftherapy?
Longtermtoxicityonlytosecondlinetherapy(alkylatingagents,anthracycline)
Longtermeffects?
Costs:cheap Cost:veryexpensive
Available Currentavailabilityonlywithintrials
ChemotherapyversusLarotrectinibasfirst-linetherapyinIFS
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DOXO,doxorubicin;ETV6,translocation-Ets-leukaemiavirus;IFS,infantilefibrosarcoma;IFO,ifosfamide;NTRK,neurotrophictyrosinereceptorkinase;VA,vincristine-actinomycin-D1.InfantileFibrosarcomaConsensusRecommendations.ExPO-r-NetProject.2017;2.MarchiòC,etal.AnnOncol.2019;30:1417–27
Newtargetedtherapies
TheuseofTRKinhibitordrugsshouldbecertainlyconsideredwhenconventionalchemotherapyfails
VAregimenrecommendedinitially
IfresponsetoVAisnotsufficienttopermitconservativesurgery,ifosfamideand/orcyclophosphamideand/ordoxorubicinshouldbeadded
IfnoresponsetoVA,theIFO-DOXOregimenshouldbeadopted
TumourassessmentResectabilitywithoutanyfunctionalormutilatingconsequenceswith
ROintent
Yes:Surgeryfirst
No:Neoadjuvantchemotherapyuntilmaximumtumourshrinkage
IRSI–II:nofurthertherapy
IRSIII:chemotherapy Conservativesurgery
RO,R1margins,completenecrosis:nofurthertherapy
R2:post-operativechemotherapy
EpSSG/EXPeRTguidelinesforIFSrecommendconservativesurgeryorneoadjuvantchemotherapyas
first-linetherapy
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ToxicityandlateaffectsNeurocognitiveoutcome
-Veryyoungchildren-Patientswhoremainontreatmentforyears
DiscussionwithparentsonthistopicisessentialMultipleinitiativeBrussels5thFeb:Readdressingtheneedforlong-termfollowupAccelerategroup:DanielleHortonTaylor/MarkKieran
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Acquiredresistancemechanisms
ResistancetoNTRKinhibitionbylarotrectinibandentrectinibismediatedbyrecurrentmutationstothekinasedomainofNTRKgeneatthreedifferentlocations(solvent-frontmutations,gatekeeperandxDFG)Thekinasesolvent-frontmutationismediatedtroughG595RsubstitutionintheTRKAproteinandG623RsubstitutionintheTRKCproteinThegatekeepermutationisfoundatF589LsubstitutionintheTRKAThexDFGmotifmutationisfoundatG667CsubstitutionintheTRKAproteinandG696SsubstitutionintheTRKCprotein
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SecondgenerationNTRKinhibitorsarebeingdevelopedtoovercomeacquiredresistance