Immuno-oncology&Radiotherapy:advancesandpracticalissuesinthemanagementof

NSCLCBrainMetastases:mechanisms,hope…andquestions

PrElizabethCohen-JonathanMoyalMD,PhDRadiationOncologyDepartment

TeamTumorRadioresistance:fromsignalingpathwaytoclinicaltrial’INSERMU1037

InstitutUniversitaireduCancerToulouseOncopoleToulouse,France

Declarationofconflictofinterest

Type CompanyEmployment full time / part time Company

name/None

Research Grant Astra-Zeneca; Merck-Serono

Other research support Company name/None

Speakers Bureau / Honoraria Astra-Zeneca; Accuray

Ownership interest (stock, stock-options, patent or intellectual property

None

Consultant / advisory board Merck Serono; Accuray

Brain metastasis

NewgoalsforBrainMettreatments:BrainlocalcontrolWithoutneurocognitivedeteriorationIfpossible:increaseofOverallsurvival

Lung:10%initially present Brain mets30-50%will developp Brain Metsduring thecourseoftreatment

BreastMelanomaWas considered asatermal event :WBRTorpalliativecareNow :longterm controlforsystemic disease :Brain Metsbecomes achronic disease

Radiosurgery or Stereotactic hypofractionnated radiotherapy (SRS)

AblativeradiotherapyMonofraction :18-25GyHypofractionated :30Gyin5fractions;24-27Gyin3fractions(frameless)Comparabletosurgery interm oflocalcontrolCurrently recommended for1to4Brain MetsFeasible for5-10BMet:OSdon’t differ from patientswith 2-4BMet(YamamotoLancetOncol 2014)Nomorelate effects for5-10BMets compared to1-4BMets (Yamamotoetal,IntJradiat Biol Phys 2017)Nobenefit toadd WBRTtoSRS(NO574trial)(Brownetal,Jama 2016)

Less cognitivedeterioration forSRSalone compared toSRS+WBRTBut :Shorter timetointracranial failure forSRSaloneNodifference inOSbetween SRSvsSRS+WBRT

SRSorHFRTarethemainradiotherapy treatment forBrainMets

RadioBiology of SRS

Apoptosis

Acid sphingomyelinase

ceramide

Tumor cell death

Endothelial cells(>10 Gy)

Garcia-Barros et al, Sciences 2003; 300:1155-9.Albert et al, Int J Radiat Biol Phys, 2006; 65:1536-43.

Mitotic cell death

AutophagySenescence

• SRS Induces presentationof Tumor Antigens to T cells

• SRS increases T cellinfiltration

• SRS (20-25 Gy) efficacyrequires CD8+T cells (Lee et al Blood 2009)

• 15-20 Gy X1-3 f >3-5 Gy x 4-5 f for increasing T cellinfiltration

• SRS opens the BBB in a few hours allowingcheckpoints inhibitorspenetration in the brain

Immune effect

Indirect effect : Immune cell death

• 12 Gy Irradiation increases PDL-1 expression in Tumor cells and Dentritic cells (Deng, JCI 2014)

Radioresistance

Checkpoint inhibitorsAnti-CTLA4Anti-PD1Anti-PDL1

(Paz-Ares ESMO 2017)

Radiosensitization

(Zeng et al, Int J Radiat Biol Phys 2012)

Blocking PD-1 in association with 10 Gy stereotactic irradiation significantly abrogates GBM tumor through CD8+T cells

However the impact of radiation doses and fractionation on tumor immunity isstill matter of debate :• Single High dose > fractionated for

local effect• Fractionated > high dose for abscopal

effect ?

Indirect effect : Bystander effect (Abscopal) : effet outside the irradiation field

Bystander effect rather obtained for low doses <1Gy but also for high dose per fraction >10 Gy (SRS)

How to optimize the radiotherapy effect in lung Brain Mets?

SRS+TKIorImmunotherapy?Timingandtypeofcombination

RTbeforeorafterTKI?RTEbeforeorafterimmunotherapy?

Targeting intra-cellular radioresistance pathway : another way to radiosensitize Lung B Mets

Radiosensitization• EGFR inhibitor (TKI)• ALK inhibitor

ALK Crizotinib

EGFR TKI inhibitors and radiotherapy vs TKI aloneComparison between TKIalone,WB+TKIorSRS+TKIPooled analysis ofEGFRTKI+RT(Luo,Oncotarget 2015):significant benefit interm ofobjectiveresponse rate,timetointra-cranial progressionandOSDohertyetal,Radiother Oncol,2017:retrospective study 184patient(mainlyEGFRmutated;only 21patientsALK+;WBRT+TKI(120),SRS+TKI(37),orTKI(27)

Significant increase inTimetoIntracranial progressioninfavor ofWBRT(TTIP50,5vs12vs15months)butsame OS.

Zhuetal,Oncotarget 2017:133patients,67treated with TKI+RT(63WBRT)and66received TKIalone

Significant increase inOSandPFSforpatientstreated with RT+TKIExon21mutation:

increased OSinthecombined treatment vsTKI(22mvs13,5m)(p=0,004)Increased PFSintheRT+TKIvsTKI(14months vs9,5m)(P=0,001)

Exon19deletions :Nodifference inOS(20,5mvs18,5)orPFS(16vs16m)

Seems that at least for patients with exon 21 mutation, RT+TKI >TKI alone

EGFR TKI inhibitors and radiotherapy: RT upfront or after TKI?

Magnuson etalJCO2017Comparison between TKIalone followed byRTat intracranial progression,WBfollowed byTKIorSRSfollowed byTKI

351patientsfrom 6institutionswith EGFRmutantNSCLCmOS forSRS+TKI (n=100),WBRT+TKI(n=131)EGFR-TKI(n=120)was 46,30and25m(P<0,001)Multivariate analysis :SRSvsTKI,WBRTvsTKI,age,performancestatus,EGFRexon19andnoextra-cranial M+associated with improved OS.NB:WBRTcohort less favorableprognosis

ALK inhibitors and RT

ALKinhibitor andRTCrizotinib radiosensitizes NSCLConly inALKpositivecells (Sunetal,MolcancerTher 2013)Retrospective study performed onvery small number (21)ofpatientsALK+(Dohertyetal2017):nodifference between WBRT+TKI;TKIorSRS+TKI

TKInaive patientsat thetimeofBmets presentation andtreated with radiation+TKIhaveaalmost doublemOS (54.8m)compared tononnaive TKIpatientsatthetimeofirradiation(28.4m)inaretrospective study (Johung etal,JCO2016)Current clinical trials

Phase2NCT02314364:SRS(within 6months initiating aTKIforStageIVNSCLC)+any TKIALKinhibitor

Phase2NCT02513667:Ceritinib before SRSandthen after inALK+NSCLC

Immunotherapy and SRS in BMets : clinical data (mainly in Melanoma)Timing:Concurrent(checkpointinhibitors within 4weeks ofSRS)> nonconcurrent(Qianetal,Cancer2016)(same results than Kiess etal,IntJRadiat Biol Phys2015)

:retrospective studies

Typeofimmunotherapy :PDL-1inhibitor >Anti-CTLA4(Qianetal2016;Choong etalEur JCancer2017)

• Best OS and Brain control for anti PD1 and Braf inhibitors (12,7 m) compared to CTLA4 (7,5 m) when associated with SRS

Immunotherapy and SRS in BMets : clinical data : one retrospective study on Lung Bmets(Ahmed et al J Neurooncol 2017)

Smallpopulation:17patients49lesionsTreatedwithSRS(40lesions)orHFSRT(9lesions)Mainlyanti-PD1(11);anti-PDL1(6)WelltoleratedHigherDistantbraincontrolwhenSRSbeforeorconcomitanttoanti-PD1/PDL1treatmentAntiPD1/PDL1duringorafterSRSassociatewithhigherOSinunivariateanalysis

SuggeststhattimingSRS/checkpointinhibitorisanimportantissue

KEYNOTE-001 phase 1 trial : a secondary analysis(Shaverdian et al Lancet Oncol 2017)

98patientswith advanced ormetastatic NSCLCTreated with anti-PD1pembrolizumabSubgroups :patientswho previously received radiotherapy (any),thoracicradiotherapy ornoradiotherapy before pembrolizumab treatmentWell balanced subgroupsSignificant difference inPFSandOSin

patientswho previously received radiotherapyRegardless ofEGFRorKras mutations

Suggest theability ofradiotherapytoenhance anti-tumor immuneresponseinNSCLC

Extracranial RT

Extracranial RT

Any RT

Any RT

Clinical data in lung cancer (phase III Pacific trial stade III NSCLC)(Paz-Ares et al ESMO 2017; Antonia et al, NEJM 2017))

Radio-chemotherapy followed byDurvalumab upto12months orplaceboPrimary objectives:PFSandOS

Significant increase inPFSinallsubgroupsSignificant increase inORR(28,4%vs16%,p<0,001)with durableresponse

Strongly suggest that IrradiationbySRSfollowed orcombined with antiPDL1could increase localcontrolofLungbrain Mets

Patientsreceiving Durvalumab havealower incidenceofnewlesionsincluding brain metastasis

Could increase thebrain controlaswell asOS(abscopal effect ?)Howtoevaluate theefficacy?Risk ofpseudoprogression (iRANO)Needs multimodalimaging forclinical trialevaluation

Pseudo-progression/Radionecrosis vs True progression

6 months after SRS and anti-PD1 treatmentBefore SRS

Pseudoprogression after SRS and anti-PD1 treatment for a lung BrainMetastasis. 6 months after SRS and anti-PD1 treatment, increase of the irradiatedBrain Metastasis on T1 gado MRI without vascularization on perfusion.

8 months after treatment

Immunotherapy + SRS for Lung Brain Mets : what population?

WildTypeEGFRMutatedALK:TKIvsSRS+TKI?MutatedEGFR:

Exon19mutationdifferentfromexon21mutationSRSafterTKIvsSRS+TKI(randomizedtrial?)SRS+immunotherapy(antiPD1?antiPDL1?,antiCTLA-4?)afterfirstlineTKI?RandomizedtrialbetweenSRS+TKIvsSRS+immunotherapy?

Conclusion

SRSis oneofthemainstandardstrategies forBMets treatment (onBmetsandCavity)Encouraging results obtained with combination ofRTandTKIorimmunotherapyOptimalSRSdoseinassociationwith targeted drugs/immunotherapy ?Localandabscopal effect ofradiation+immunotherapy :Brain control+++Optimalschedule SRS/TKIorSRS/checkpointInhibitors tobe defined :SRSbefore vsafter TKI?PlaceofSRS+checkpointinhibitors inthecourseoftreatment (comparedtoTKI?)Trialsshould be histologically andbiologically driven,especially inassociationwith targeted drugsWith quality oflifeandneurocognition assessmentWith multimodalimaging (radionecrosis;pseudoprogression vstrueprogression)Stratificationwith extracranial status