merck imaging tip sheet for recist 1.1 and irecistnps-training.com/courses/other mylearning...

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Merck Imaging Tip Sheet for RECIST 1.1 and iRECIST Version 1.0 September 2017

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Merck Imaging Tip Sheet RECIST 1.1 and iRECIST

p3. Glossary p15. iRECISTintroduction

p15. New Response Categories

p16. iRECIST begins at RECIST PD

p17. ResolvingInitialiUPD

p18. FactorscausingiCPDafteriUPD

p18. FactorscausingiUPDafteriSD/iPR/iCR

p19. ResolvingSecondiUPD

p20. Cases scenarios

p20. iRECIST Example 1









p4. TargetLesionSelectionatBaseline

p5. Non-TargetLesionSelectionatBaseline

p6. TargetLesionmeasurementatallvisitsafterbaseline

p6. Special Cases: Measuring lesions that split at follow up

p6. Special Cases: Measuring Target lesions that merge at followup

p7. Special Cases: Target lesions that become too small to measure (TSTM)

p7. Target Lesion Response: Complete Response (CR)

p7. TargetLesionResponse:PartialResponse(PR)

p8. Target Lesion Response: Progressive Disease (PD)

p8. Target Lesion Response: Stable Disease (SD)

p9. Target Lesion Response: Not Evaluable (NE)

p9. Non-TargetLesionsatvisitsafterbaseline

p9. Non-Target Lesions: What is unequivocal progression?

p10. NewLesionsatvisitsafterbaseline

p10. Special Cases: Lesion Recurrence

p11. CalculationsofResponseandProgression

p12. Summary of Timepoint SOD

p13. AdditionalGuidance-CrossoverPhase

p14. AdditionalGuidance-SecondCourseTreatment

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GlossaryAbbreviation What it stands for What it meansRECIST ResponseEvaluationCriteriaInSolidTumors Response criteria used for primary endpoint in trials. Currently in version 1.1.

iRECIST Immunotherapy RECIST The criteria published in March 2017, developed in consensus with other pharma, academia, and regulators.

LSNIR LesionEvaluationforRECIST/iRECIST TheInFormformforentryofindividuallesioninformation(whenyousee“LesioneCRF”inthisdocument,thisistheformreferenced)

ORIR Oncologic Response – Solid Tumor – RECIST/iRECIST

TheInFormformforentryofresponseinformationateachvisit(whenyousee“ResponseeCRF”inthisdocument,thisistheformreferenced)

DEG Data entry guidelines Instructions for filling out the forms in InForm

CR Complete response ARECIST1.1responseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

PR Partial response ARECIST1.1responseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

SD Stable disease ARECIST1.1responseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

Non-CR/non-PD Non-completeresponse/non-progressivedisease

ARECIST1.1responseappliedspecificallytonon-targetlesions,orasanOverallResponseifnotargetlesionswereidentifiedatbaseline.

PD Progressive disease ARECIST1.1responseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

SOD Sum of diameters Thesumofdiametersfortargetlesionsidentifiedatbaseline(longestdiametersforextranodallesions,andshortaxisdiametersforlymph nodes)

iUPD iRECISTunconfirmedprogressivedisease AniRECISTresponseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

iCPD iRECISTconfirmedprogressivedisease AniRECISTresponseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

iCR iRECIST complete response AniRECISTresponseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

iPR iRECISTpartialresponse AniRECISTresponseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

iSD iRECIST stable disease AniRECISTresponseappliedtoeitheralesioncategory(e.g.targetlesions)ortothesubjectoverallataparticularvisit.

Non-iCR/non-iUPD iRECISTnon-CR/non-PD AniRECISTresponseappliedspecificallytonon-targetlesions,orasanOverallResponseifnotargetlesionswereidentifiedatbaseline.

TL Target lesion Alesionselectedatbaselineforquantitativeevaluationthroughoutthetrial

NTL Non-target lesion Alesionselectedatbaselineforqualitativeevaluationthroughoutthetrial

NL-SOD New lesion sum of diameters The sum of diameters for new target lesions (longest diameters for extranodal lesions, and short axis diameters for lymph nodes)

NL-T New lesion target Anewlesionthatisselectedforquantificationonsubsequentassessments

NL-NT New lesion non-target Anewlesionthatisassessedonlyqualitatively

SOM Sum of measurements TermusedintheiRECISTpublicationinplaceofSOD(meaningisidentical)

BOR BestOverallResponse The most favorable visit (overall) response seen during the trial, per RECIST 1.1

iBOR ImmuneBestOverallResponse The most favorable visit (overall) response seen during the trial, per iRECIST

BL Baseline Assessment of tumor burden before treatment begins, typically at screening

LD Longest diameter The longest diameter of a lesion, measured in the axial plane

SA Short axis The longest measurement perpendicular to the longest diameter of the lesion, in the axial plane

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RECIST 1.1 Concept Images Guidance InForm InstructionsTarget Lesion Selection at Baseline

Must meet RECIST measurability criteriaLymphnodes≥15mminshortaxisNon-nodallesions≥10mminlongestdiameterNote: all measurements to be made on axial images

Identifymaximumof10targetlesions,5perorgan• Nodes are considered an organ system

Targetlesion(TL)selectionconsiderations:• Likelytobereproducibleacrossalltimepoints• Representativeoftumorburden• Larger lesions are preferred, other things equal. • If site decides to perform a biopsy on a lesion

selected as part of response assessment, please contact the clinical team. Some biopsies may render a lesion non-evaluable.

• Focalradiationtherapyafterbaselinewillrenderanylesionaffectedbyitnon-evaluable.Ifthelesionis a target lesion, the visit responses of CR, PR, and SD can no longer be assigned at following visits, and the subject will only be assessable for progression.

Lymph node-use shortaxis≥15mm

Extra-nodal–uselongaxis≥10 mm

MSD approach to RECIST 1.1 allows selectionofuptoten(10)targetlesionsatbaseline,five(5)perorgan,ifclinicallyrelevantviaCTand/orMRIscans

For TLs, a measurement is required at baselineandateveryvisitafterward

• Subcutaneous lesions can be target if they are detected by CT, and in an anatomicallocationcompatiblewithfollow-up CT.

• Lesions that appear measurable, but are located in an area that has been irradiated, can only be used as target lesions if they have demonstrated growthsincethecompletionofradiation.

Lesion eCRF

TumorIdentification=TLselectnodal or extra nodal (extra-nodal =non-nodal),enterlocation,method,TLmeasurement

Report all TLs at baseline

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RECIST 1.1 Concept Images Guidance InForm InstructionsNon-Target Lesion Selection at BaselineAll other lesions, including

Non-measurable lesions, such as: • Extra nodal lesions <10mm in LD• Lymph nodes 10-14 mm in SA• Lesions which may not be reproducibly

measuredacrossalltimepoints ◦ Poorlydefinedmargins ◦ Locationsthatmove(e.g.bowel,lungapex

or bases)• Pleural/pericardialeffusionsandascites• Bonelesionswithoutsofttissuecomponents

reproduciblymeasurableonCT/MR ◦ Bonelesionswithasofttissuecomponent

maybemeasurableifthesofttissuemeetsthe size and reproducibility requirements).

◦ Bonelesionscannotbemeasuredonbonescan, x-ray, or PET.

Measurable lesions beyond those recorded as target.

Lesions at the lung apex or bases are oftenbettertocaptureasnontargetbecauseofmovementwithinspiration.Clustersoflymphnodesareoftenbetterto capture as non target because of the potentialtomerge.

Simple cysts are presumed benign, and thusnotlesionsatall.Complexcysticlesions may be considered measurable, but if solid lesions are also present, they are preferred as target.

Brainlesionsshouldbefollowedasnon-target, for our trials.

Lesion eCRF

TumorIdentification=NT,selectNT,NT nodal or NT extra nodal, enterlocation,method,NTlesionstatus=N/A(baseline)

ReportallNTsatBL

MultipleNTsinthesameorganmaybe recorded as a single item on the eCRF(e.g.multiplelivermetastases).The goal is to document ALL disease present at baseline as either target or non-target, and grouping reduces theeffortrequiredtodocumentnon-target lesions completely.

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RECIST 1.1 Concept Images Guidance InForm InstructionsTarget Lesion measurement at all visits after baseline

Locateimagethatoptimizesthelongestdiameter of the non-nodal target lesion or short axis of target node(s).

Thereisnoneedtogotoanidenticalslicefrombaseline.

SOD=sumofdiameters(longestdiameter for non-nodal or short axis for nodal) of all TL

Enter lesions into Lesion eCRF, per DEGsResponse eCRF• Enter sum of diameters• Enter target lesion response

Special Cases:Measuring lesions that split at follow up

SplittingIf a TL separates, measure the longestdiameterofeachresultinglesion separately.

Lesion eCRF Follow the data entry guidelines ondocumentingeachlesionfragment separately.

Special Cases:Measuring Target lesions that merge at follow up

MergingIfinitiallyseparatetargetlesionscoalesce (merge), record the diameter (or short axis for two target lymph nodes).

Lesion eCRF Create a new InForm entry for themergedlesion,indicatinginthe form which lesions merged to form this. Please see Data Entry Guidelines for further information.

Splitting

3 34

5

34

5

6

Merging

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RECIST 1.1 Concept Images Guidance InForm InstructionsSpecial Cases: Target lesions that become very small• If the lesion is very small, but a clear

measurementisstillpossible,recordtheactualmeasurement

• If the lesion is so small that no accurate measurement is possible, record 5 mm.

• If the lesion has completely disappeared, record 0 mm.

• If too small to measure accurately, on Lesion eCRF record 5 mm

• On Lesion eCRF, if lesion has completely disappeared, record 0 mm

Target Lesion Response: Complete Response (CR)

• All of the non-nodal TLs completely disappear • Target lymph nodes (if any) return to normal

(<10 mm in short axis) BL Visit 1

Note - If lymph node is the only remaining target disease and it is < 10mm in short axis, a CR is possible with a sum of diameters that is not zero.

Lesion eCRF For extranodal lesions, enter zero for diameter. For lymph nodes, enter actual short axis diameter (which should be <10mm).Response eCRF Enter SOD, which may not be zero if there are any target lesions which are lymphnodes.TLresponse=CR

Target Lesion Response: Partial Response (PR)

• ResponseisalwayscomparedtoBL.• Sum of diameters (SOD) of TLs decreases by

≥ 30% compared to BL ◦ Note: percent change is rounded to the

firstdecimalplace. ◦ Eg: 29.56% is rounded to 29.6%, not to 30

BL,singleTL

Visit 1

Enter the decreased size of the TLContinueimagingperprotocol

Lesion eCRF Enter current measurement of TL

Response eCRF Enter SOD for current visit. TLresponse=PR

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RECIST 1.1 Concept Images Guidance InForm InstructionsTarget Lesion Response: Progressive Disease (PD)

If the SOD increases by ≥20% compared to nadir, response =PD• Note: percent change is rounded to the

firstdecimalplace• Example: 19.56% is rounded to 19.6%, not

to 20%

In this example, TL size increases by≥20%comparedtonadir

Nadir=SmallestSODseenprevious to the current visit.See page 12 for example.

Lesion eCRF enter new measurement of TL

Response eCRFTLresponse=PD

Target Lesion Response: Stable Disease (SD)If the sum of the TLs do not reach the criteria tomeetPRorPD(increase≥20%comparedtonadir) the response is SD SD = neither 30% decrease compared to BL nor 20% increase compared to nadir

In this example, TL size decreases by 28.3%

Lesion eCRF enter new measurement of TL

Response eCRFTLresponse=SDBL

Visit1

BL

Visit 1

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RECIST 1.1 Concept Images Guidance InForm InstructionsTarget Lesion Response: Not Evaluable (NE)If any of the target lesions cannot be evaluated for a technical reason such as:• Poor image quality• Changes in lesion or background that obscure the

lesion• Change in imaging method that makes the lesion

size not comparable• Focal therapy of lesion during trialTarget Lesions are then NE, unless the other target lesions show enough growth for PD.

If any TL has become non-evaluable, the only optionsforTLresponseatthisvisitareNEandPD.

If a TL is non-evaluable because of focal intervention(e.g.radiationorablation),butthengrowstoasizelargerthanitwasinitially,the lesion can again contribute to progression.

In the Lesion eCRF, the question“Wasthelesionevaluable”shouldbeanswered“No”forthelesionthat cannot be evaluated.

Do NOT enter "No" if the lesion is visible but too small to measure, or if the lesion has completely disappeared. See earlier guidance.

Non-Target Lesions at visits after baselineEvaluateNTsqualitatively,asawholeOptions:• CR – All NTs resolved, with any lymph nodes

reduced to normal size (must be <10 mm short axis)

• Non-CR/non-PD–AnyNTsstillpresent• PD–UnequivocalprogressionofNTsasawhole

(see below)• NE – One or more NTs are not evaluable, and

remainder do not indicate PD

Responses recorded in the response eCRFs shouldbesupportedbythelesionevaluationsrecorded in the lesion forms.Forexample,ifNTsarecollectivelyassessedas PD, there should usually be worsening of multipleNTs;andiftheNTsareassessedasCR,all NTs should be absent or non-pathological.

Lesion eCRFEnter NT Lesion Status for each lesion

Response eCRF Enter NT Lesion response category, for NT lesions as a whole

Non-Target Lesions: What is unequivocal progression?

Note:UnequivocalprogressioninNTlesionsshouldbeselected only in instances where the disease burden in the non-target lesions, assessed as a whole, has increased so much that it is clear that the treatment has failed, even in the presence of stable disease or a response in the TLs.

BL

Visit 1

Visit 1

Lesion eCRFEnterNTLesionStatus=worsening

Response eCRFNTlesionresponse=PDifNT lesions show worsening collectively

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RECIST 1.1 Concept Images Guidance InForm InstructionsNew Lesions at visits after baselineAre new lesions present at this visit?• Should be unequivocal and not due to

differencesinscanningtechnique• Ifequivocal,assessatnexttimepoint;ifpresent,

PDisthedatethelesionwasfirstseen(notthedateconfirmed)

There are no minimum size criteriatoidentifyanewlesions- use clinical judgment.

If an anatomical region was not scanned at baseline, but is later scanned and shows a lesion, RECIST guidance is that this is presumed to be a new lesion.

Lesion eCRFTumorIdentification=newlesionsincelastevaluation

Response eCRFOverallResponse=PD

ForPRandCR,mustconfirm≥4weeksafterinitialobjectiveresponse seen. PR can be confirmedbyCR

AfterCR,theonlypossibleresponses are CR, PD, and NE. Neither PR nor SD should be selected.

SDispossibleafterPR

Special Cases: Lesion Recurrence

AfteranSDorPR(asanOverallResponse),whena lesion disappears and then reappears, it should continuetobemeasuredandaddedtotheSOD.

AfteraCR(asanOverallResponse),whenalesionreappears, it is treated as a new lesion, and causes PD.

BLVisit1Visit2Visit3

AfteraCR,ifalymphnodere-grows, in order to drive PD it should become unequivocally malignant:≥15mminshortaxis, or 10-14 mm with morphological features of malignancy (consult your radiologist)

Lesion eCRF - enter the measurement for reappearing TLs

NT Lesion Status, enter worsening

Enter response on the appropriate Response eCRF

TL NT New Overall ResponseCR CR No CRCR Non-CR/Non-PD No PRCR NE No PRPR CR,Non-CR/Non-PDorNE No PRSD CR,Non-CR/Non-PDorNE No SDNE CR,Non-CR/Non-PDorNE No NEPD Any Yes or No PDAny PD Yes or No PDAny Any Yes PD

Not PD

PD

Overall Response Per Visit

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BL=BaselineSOD=sum of diameters at that timepointLD =longest diameterSA=short axisTP= timepoint

BL Timepoint 2 Timepoint 3 Timepoint 4 Timepoint 5

Sum of Diameters(includes LD of non-nodal and SA of nodal lesions)

300 270 210 241.5 330

Nadir (smallest SOD seen prior to current visit)

300 270 210 210

Check for PD: IsSODincreasedby≥20%fromnadir,andby≥5mminabsolutemeasurement?• PDformula(SOD-nadir/nadir)• PDThreshold(SOD≥nadirx1.2)

SOD has decreased, so not PD

PD threshold at this visit would be300x1.2=360

SOD has decreased again, so not PD

PD threshold at this visit would be270x1.2=324

SOD has increased, but did it increase enough for PD?

PD threshold at this visit would be210x1.2=252(241.5-210)/210=+15%

This TP does NOT meet threshold of 252 so it is not a PD

SOD has increased, but did it increase enough for PD?

PD threshold210x1.2=252(330-210)/210=+57%

This TP meets threshold of 252 so it is a PD

Check for PR:TargetlesionSODmustdecreaseby≥30%from baseline• ResponseFormula:(SOD-BL/BL)• PRThreshold(SOD≤BLx0.7)

270-300/300=-10%PR threshold300x.7=210This TP doesn’t decrease to 210 for PR or increase to 360 for PD

210-300/300=-30%This TP meets the threshold for PR of 210

SOD has increased and does not meet the PR threshold

TP Response Stable Disease PartialResponse Stable Disease Progressive Disease

RECIST 1.1- Calculations of Response and Progression

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RECIST 1.1 — Summary of Timepoint SOD (Graphical Representation of measurements below)

Merck Imaging Tip Sheet v10.0 RECIST 1.1 and iRECIST

50

100

150

200

250

300

350

Baseline Timepoint2

Timepoint3

Timepoint4

Timepoint5

270mm300mm

210mm

330mm

RECIST 1.1- Summary of Timepoint SOD (Graphical Represenation of measurements above)

For TP3, the nadir is HERE

For TP4 and TP5, the nadir is HERE

241.5mm

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Additional Guidance – Crossover Phase (see Note) InForm InstructionsCrossover Phase Baseline Assessment• IfthemostrecentimagingwasusedtodetermineprogressionintheInitial

Treatment Phase, it may become the new baseline for the Crossover Phase.• The radiologist will review same imaging twice per RECIST 1.1, they will

review: ◦ InitialTreatmentPhase:asthefinalfollow-uptimepoint ◦ Crossover Treatment Phase: as the crossover baseline

• Imaging used as baseline for the crossover treatment phase must be• assessedperRECIST1.1,withselectionoftargetandnon-targetlesions

basedontheappearanceofthoselesionsatthetime• Theseselectionsareindependentoftheinitialtreatmentphasebaseline

target/non-targetdiseaseselection.• Lesionsmaybeassignedtothesamecategoriesasintheinitialphase,

ifappropriate.Forexample,ifapriortargetlesionisstillpresentandmeasurable, it may be chosen as a target lesion again.

• Lesions may change category. For example, if a prior non-target lesion is measurableatthistime,itcanbechosenasatargetlesion,oratargetlesion might have become non-measurable, and now be followed as non-target.

Note: Thissectionisintendedasageneralguidance.Pleasecontactyourprotocolteamforadditionalprotocol-specificguidance.

Lesion eCRF • All crossover baseline lesions (target and non-target) are to be new entries • Existinginitialtreatmentphasetarget/non-target/newlesionsarenotto

beupdatedpostthefinaltimepointassessmentfortheinitialtreatmentphase

Response eCRF• There should not be a response assessment associated with the crossover

baselinetimepointontheform(unlessthesamescanwasusedasthefinaltimepointfortheinitialtreatmentphase).

• All image assessments post-baseline in the crossover phase must have an entry.Thisisindependentoftheentriesfortheinitialtreatmentphase.

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Additional Guidance – Second Course Treatment InForm InstructionsSecond Course Baseline AssessmentTumorimaging(eitherCTorMRI)willbeacquiredwithin[30]*dayspriortorestartingstudytreatmentafterrelapsefrom[SD,PR,orCR].• acquirebaselinescannomorethan[30]*dayspriortothefirstdoseofstudydrug

in Second Course Phase • Imaging used as baseline for second course treatment must be assessed per

RECIST 1.1. • Radiologists should select Second Course baseline target and non-target disease. • Lesionselectionsareindependentofinitialtreatmentphasebaselinetarget/non-

targetdiseaseselectionandtheradiologistdoesnotneedtoadheretothepriortargetandnon-targetselections,butshouldfollowrulesperRECIST1.1forSecondCoursebaselineselection.

*RefertoyourprotocolforspecificguidanceregardingtimingofbaselineimageforSecond Course

General Notes: • Iftheprotocolallowsasecondcourseoftreatment,confirmationofPDper

irRECIST does not apply.• IfprotocolrequirescentralverificationofPD,andprotocolallowsasecondcourse

oftreatment,theverificationrequirementmaynotapplytosecondcourse.Checkthe protocol.

• Note:Thissectionisintendedasageneralguidance.Pleasecontactyourprotocolteamforadditionalprotocol-specificguidance.

Lesion eCRF • All second course baseline lesions (target and non-target) are to be

new entries • Existinginitialtreatmentphasetarget/non-target/newlesionsare

nottobeupdatedpostthefinaltimepointassessmentfortheinitialtreatment phase

Response eCRF• There should not be a response assessment associated with the

secondcoursebaselinetimepointontheform(unlessthesamescanwasusedasthefinaltimepointfortheinitialtreatmentphase).

• All image assessments post-baseline in the second course phase musthaveanentry.Thisisindependentoftheentriesfortheinitialtreatment phase.

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iRECIST Guidance InForm Instructions• AfterRECIST1.1definedPDisidentifiedatanytimepoint,

asubjectmaycontinuetreatmentifclinicallystable,atthediscretionofthesitePI.

• Obtainrepeatimaging4-8weekslatertoconfirmPD.• IfPDisnotconfirmed,treatmentcancontinue.

*Note, if noted in clinical protocol:

IfPDisconfirmedandthesubjectisstillderivingaclinicalbenefit,contactSponsortodiscusscontinuingtreatment,andifgranteddocumentsponsorapprovaltocontinuetotreatbeyondconfirmedPDperprotocol.

TheiRECISTsectionoftheformisfirstcompletedatthetimepoint/visitwhereRECIST1.1PDisseen.

Clinical Stability per protocol includes:• Nosymptomsorsignsindicatingclinicallysignificant

PD including labs.• No decline in ECOG status.• NorapidPDrequiringurgentmedicalintervention.• Document clinical stability.

On Response eCRF, enter the RECIST 1.1 response data up to and including thevisitwherePDisfirstseen.Atthat1st PD visit, enter both RECIST 1.1 response and iRECIST response. At all following visits, enter iRECIST response data only.

Forvisitsafterradiographicprogressionisfirstseen,completethe eCRF for treatment beyond radiographic progression.

OnceiCPD(confirmedprogression)occurs, treatment should generally be discontinued.However,consulttheprotocolforexceptions.

New Response Categories • i__=responsesbasedoniRECIST ◦ AtorafterRECIST1.1PD ◦ e.g.iSD=SDafterRECISTPD

▫ iPR,iCR,non-iCR/non-iUPD• iUPD = Unconfirmed PD

◦ AlwaysthefirstiRECISTvisitresponse ◦ Canoccurmultipletimes,eveninarow

• iCPD = Confirmed PD ◦ OnlypossibleimmediatelyafteriUPD

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Summary of Process:• Startatbaseline(Visit0,orV0),assessthepatientusing

RECIST 1.1 (V1), determine they have progression (V2) ◦ AtV2,PDperRECIST1.1iscallediUPDbyiRECIST

• ForRECIST1.1,anyfurthervisits(V3+),pastthepointofPD, remain PD

• FurtherassessmentsbyiRECIST(V3+)proceedaccordingto rules, covered in ResolvingInitialiUPD and Resolving SecondiUPD

iRECIST begins at RECIST PD

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Summary of Process:• ThecoreofiRECIST:Howdoyouresolvethe

initialiUPD?• AfterinitialiUPD,acquireimaging4–8weeks

later. Four possible outcomes:1. Progressionisconfirmed(iCPD)ifany

original cause of PD worsens OR another cause of PD appears

2. RemainsiUPDiftargetlegions(TLs)wereacauseoftheinitialiUPD,TLshaven’tworsened,buttheyarestillabovethePDthreshold (20% increase from nadir), AND no drivers of iCPD (e.g. no new cause of PD orworseningoftheexistingcause)

3. Resolves to iSD or iPR if TLs are below the PD threshold (whether they were or weren’tattheinitialiUPDscan)ANDnodrivers of iCPD (i.e. no new cause of PD or worseningofanyexistingcause) ◦ Note: TL are weighted more heavily –

only the TL progression has to resolve foriSD/iPRtobepossible

4. Resolves to iCR if all lesions resolve.

Stop treatment(With exceptions)

Continue treatmentNext visit: iUPD, iCPD, or iSD/etc

Continue treatmentNext progression iUPD

Continue treatmentNext progression iUPD

Resolving Initial iUPD

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Target Lesions SODincreases≥5mmfromiUPDSODdoesnothavetoincrease20%fromiUPD

Refer to Example 1

Non-Target Lesions AnyfurtherincreaseinNTLsize(qualitativeassessment)fromaniUPDDoesnothavetomeet“unequivocal”standard

Refer to Example 4, 9

New Lesions There are ANYadditionalnewlesionsORSize of previously detected new lesions increases

TargetNL:NLSODincreases≥5mmNTNL:anysignificantgrowth

Refer to Example 5, 6, 7

Target Lesions SODcrossesPDthreshold(1sttime,oragain)Basedonthenadir(i.e.smallestvalueever)


Non-Target Lesions New unequivocal progressionORIf already showed PD, and did not regress, ANY growth

Refer to Example 9

New Lesions NewlesionsofANYsizeappearforthefirsttime,oradditionalnew lesions appearIfnewlesionshadpreviouslyappeared,andarestillpresent,ANY growth

TargetNL:NLSODincreases≥5mmNT NL: visible growth

NOTE: track nadir for New target lesion SODTotal # of new lesions


Any factor below on the confirmatory scan (after iUPD) indicates iCPD

Any factor below indicates progression (iUPD) after iSD/iPR/iCR

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Summary of Process:• AlmostsameprocessastheinitialiUPD

1. iCPD:Sameasfirst(ifanyoriginalcauseofPDworsens OR another cause of PD appears)

2. iUPD: ◦ TLs stay above the PD threshold without

worsening ◦ OR if the number of NLs increases or the NL-SOD

isstill≥5mmabovenadir ◦ AND no drivers of iCPD (i.e. no new cause of PD

orworseningoftheexistingcause)3. iSD/iPR:

◦ TLs must be below PD threshold ◦ NL-SOD and number of new legions cannot be

increased from their nadir values ◦ AND no drivers of iCPD (i.e. no new cause of PD

orworseningoftheexistingcause4. iCR: All lesions resolved

Resoving Second iUPD (Almost same as first iUPD)

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iRECISTExample 1


iRECIST

Timepoint Baseline Visit 1 Visit 2 SOD 100 130 138 TL Response

NA iUPD iCPD

Overall Response

NA iUPD iCPD

Explanation As SOD >= PD threshold (20 % from nadir and +5 mm in SOD) This is initial PD

As SOD >= 5 mm from iUPD, original cause of PD has worsened. Subj is discontinued from study treatment

InForm Guidance:

Enter measurements of TL LNRIR: Enter measurements of TL ORIR: Enter SOD, overall response = iUPD Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL ORIR: Enter SOD, overall response = iCPD Complete Discontinuation Visit (DV) per protocol/DEGs

Example 1

24 mm

21 mm

32 mm

23 mm

45 mm

30 mm

32 mm

23 mm

33 mm

32 mm

23 mm

50 mm

Timepoint Baseline Visit 1 Visit 2SOD 100 130 138

TL Response NA iUPD iCPD

Overall Response NA iUPD iCPD

Explanation AsSOD≥PDthreshold(20%fromnadirand+5mminSOD)ThisisinitialPD

AsSOD≥5mmfromiUPD,original cause of PD has worsened.Subjisdiscontinuedfromstudytreatment

InForm Guidance: Enter measurements of TL

Lesion eCRF: Enter measurements of TL Response eCRF: Enter SOD,OverallResponse=iUPD

Lesion eCRF: Enter measurements of TL Response eCRF: Enter SOD,OverallResponse=iCPD

Baseline Visit 1 Visit 2

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iRECISTExample 2


Timepoint Baseline Visit 1 Visit 2 Visit 3 SOD 100 130 121 127 TL Response NA iUPD iUPD iCPD Overall Response

NA iUPD iUPD iCPD

Explanation As SOD ≥ PD threshold (20 % from nadir and +5 mm in SOD) This is initial PD per RECIST 1.1 and iUPD per iRECIST

SOD has decreased, but still > PD threshold AND No other driver of iCPD (no new cause of PD or worsening of existing cause) PD is not confirmed, this is iUPD

SOD increased ≥ 5m from previous cause of iUPD original cause of PD has worsened Subj is discontinued from study treatment

InForm Guidance: LSRIR

Enter measurements of TL

LNRIR: Enter measurements of TL ORIR: Enter SOD, overall response = iUPD Complete form for Treatment Beyond Radiographic Disease Progression



Example 2

24 mm

21 mm

32 mm

23 mm

45 mm

30 mm

32 mm

23 mm

39 mm

27 mm

32 mm

23 mm

45 mm32 mm

23 mm

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Timepoint Baseline Visit 1 Visit 2 Visit 3SOD 100 130 121 127

TL Response NA iUPD iUPD iCPD

Overall Response NA iUPD iUPD iCPD

Explanation AsSOD≥PDthresholdThisisinitialPDperRECIST1.1andiUPDper iRECIST

SODhasdecreased,butstill≥PDthreshold ANDNo other driver of iCPD (no new cause of PDorworseningofexistingcause)PDisnotconfirmed,thisisiUPD

SODincreased≥5mmfrompreviousiUPDoriginal cause of PD has worsenedSubjisdiscontinuedfromstudytreatment


Enter measurements of TL




Baseline Visit 1 Visit 2 Visit 3

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iRECISTExample 3


Example 3

Timepoint Baseline Visit 1 Visit 2 SOD 100 130 105 TL Response NA iUPD iSD Overall Response NA iUPD iSD Explanation As SOD ≥ PD threshold (20% from nadir and

+5 mm in SOD) This is initial PD per RECIST 1.1 and iUPD per iRECIST

SOD decreased to less than PD threshold But not below PR threshold (70 mm) AND There is no other driver of iCPD (no new cause of PD or worsening of existing cause) Hence, this is iSD



LNRIR: Enter measurements of TL ORIR: Enter SOD, overall response = iSD Complete form for Treatment Beyond Radiographic Disease Progression

24

21

32

23

45

30

32

2327

23

32

23


TL Response NA iUPD iSD

Overall Response NA iUPD iSD

Explanation AsSOD≥PDthresholdThisisinitialPDperRECIST1.1andiUPDperiRECIST

SOD decreased to less than PD thresholdButnotbelowPRthreshold(70mm)ANDThere is no other driver of iCPD (no new cause of PD or worseningofexistingcause)Hence,thisisiSD

InForm Guidance: Lesion eCRF: Enter measurements of TL Response eCRF: Enter SOD,OverallResponse=iUPD

Lesion eCRF: Enter measurements of TL Response eCRF: Enter SOD,OverallResponse=iSD

mm mm mm

mm mm mm

mm mm mm

mm mm mm


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iRECISTExample 3 (Continued)

Merck Imaging Tip Sheet v10.0 RECIST 1.1 and iRECIST Example 3 (cont’d)

Timepoint Visit 3 Visit 4 Visit 5 SOD 115 120 125 TL Response iSD iUPD iCPD Explanation SOD still below the PD

threshold (120 mm) No other cause to trigger another iUPD

SOD meets PD threshold (Target SOD* ≥ 20% and ≥ 5 mm from nadir) Hence, this is iUPD

SOD increased ≥ 5mm from previous iUPD original cause of PD has worsened Subj is discontinued from study treatment

InForm Guidance:

LNRIR: Enter measurements of TL ORIR: Enter SOD, overall response = iSD Complete form for Treatment Beyond Radiographic Disease Progression



32 mm

28 mm

32 mm

23 mm35 mm

30 mm

32 mm

23 mm40 mm

30 mm

32 mm

23 mm

Timepoint Visit 3 Visit 4 Visit 5SOD 115 120 125

TL Response iSD iUPD iCPD

Overall Response iSD iUPD iCPD

Explanation SOD still below the PD threshold (120 mm)

No other cause to trigger another iUPD

SOD meets PD thresholdHence,thisisiUPD

SODincreased≥5mmfrompreviousiUPDoriginal cause of PD has worsened

InForm Guidance: Lesion eCRF: Enter measurements of TL Response eCRF: Enter SOD,OverallResponse=iSD



Visit 3 Visit 4 Visit 5

24

iRECISTExample 4


Example 4

Timepoint Baseline Visit 1 Visit 2 Visit 3 SOD 100 130 125 120 TL Response NA iUPD iUPD iUPD NTL Response Non-iCR/ Non-iUPD Non-iCR/ Non-iUPD iUPD New Lesions NA NA NA NA Overall Response NA iUPD iUPD iCPD Explanation As SOD ≥ PD threshold (20 % from nadir

and +5 mm in SOD) NTL unchanged This is initial PD per RECIST 1.1 and iUPD per iRECIST

SOD decreased but still above PD threshold NTL stable AND There is no other driver of iCPD (no new cause of PD or worsening of existing cause) Hence, this is iUPD

SOD decreased further. NTLs show unequivocal progression. New cause of PD in subject with iUPD.

LNRIR: Enter TL measurements, NTL status ORIR: Enter SOD, overall response = iUPD Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter TL measurements, NTL status ORIR: Enter SOD, overall response = iUPD Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL Enter details of NTL ORIR: Enter SOD, overall response = iCPD Complete Discontinuation Visit (DV) per protocol/DEGs

24 mm

21 mm

32 mm

23 mm

30 mm

32 mm

23 mm

45 mm 40 mm

30 mm

32 mm

23 mm

30 mm

32 mm

23 mm35 mm

Timepoint Baseline Visit 1 Visit 2 Visit 3SOD 100 130 125 120

TL Response NA iUPD iUPD iUPD

NTL Response Non-iCR/Non-iUPD Non-iCR/Non-iUPD iUPD

New Lesions NA NA NA NA

Overall Response

NA iUPD iUPD iCPD

Explanation AsSOD≥PDthresholdNTL unchanged ThisisinitialPDperRECIST1.1andiUPDper iRECIST

SODdecreasedbutstillabovePDthresholdNTL stable ANDThere is no other driver of iCPD (no new cause of PDorworseningofexistingcause)Hence,thisisiUPD

SOD decreased further.NTLs show unequivocal progression. New cause of PD in subject with iUPD.

InForm Guidance:

Lesion eCRF: Enter TL measurements, NTL statusResponse eCRF: Enter SOD,OverallResponse=iUPD



Baseline Visit 1 Visit 2 Visit 3

25

iRECISTExample 5


Example 5

Timepoint Baseline Visit 1 Visit 2 SOD 100 130 95 TL Response NA iUPD iSD NTL Response NA Non-iCR/non-iUPD Non-iCR/non-iUPD New NA none 24 mm + NT Overall response NA iUPD iCPD Explanation TL SOD >= PD threshold (20 % from nadir and

+5 mm in SOD) NTL stable This is initial PD per RECIST 1.1 and iUPD per iRECIST

TL SOD has decreased <= PD threshold, but does not meet PR threshold, Hence TL response = iSD NTL stable (Non-iCR/non-iUPD) However, there are new TL + NTL Another cause of PD has appeared

InForm Guidance:

LNRIR: Enter measurements of TL , details of NTL ORIR: Enter SOD, overall response = iUPD Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL Enter details of NTL Enter measurements of new TL + assessments of the new NTL ORIR: Enter SOD of TL, overall response = iCPD Complete Discontinuation Visit (DV) per protocol/DEGs

24 mm

21 mm

32 mm

23 mm

30 mm

32 mm

23 mm

45 mm

20 mm

20 mm

32 mm

23 mm

24 mm



NTL Response NA Non-iCR/non-iUPD Non-iCR/non-iUPD

New Lesions NA none 24mm+NT

Overall Response

NA iUPD iCPD

Explanation TLSOD≥PDthresholdNTL stable ThisisinitialPDperRECIST1.1andiUPDperiRECIST

TLSODhasdecreased≤PDthreshold,butdoesnotmeetPRthreshold,HenceTLresponse=iSDNTLstable(Non-iCR/non-iUPD)However,therearenewTL+NTLAnother cause of PD has appeared

InForm Guidance:

Lesion eCRF: Enter measurements of TL , details of NTL Response eCRF: Enter SOD,OverallResponse=iUPD

Lesion eCRF: Enter measurements of TLEnter details of NTLEntermeasurementsofnewTL+assessmentsofthenewNTLResponse eCRF: Enter SOD of TL,OverallResponse=iCPD


26

iRECISTExample 6

Merck Imaging Tip Sheet v10.0 RECIST 1.1 and iRECIST Example 6

Timepoint Baseline Visit 1 Visit 2 SOD 100 130 110 TL Response NA iUPD iSD NTL response NA Non-iCR/Non-iUPD Non-iCR/Non-iUPD New NA 14 mm TL 20 mm TL Overall Response NA iUPD iCPD Explanation TL SOD = 100 mm

NTL appear to be stable

TL SOD >= PD threshold (20 % from nadir and +5 mm in SOD) NTL stable New TL appears This is initial PD per RECIST 1.1 and iUPD per iRECIST

TL SOD decreases to below PD threshold NTL stable New lesion SOD increases ≥5 mm Original cause of PD has worsened

InForm Guidance:

LNRIR: Enter measurements of TL , details of NTL + new lesion ORIR: Enter SOD, SOD of NL-T overall response = iUPD Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL Enter details of NTL Enter measurements of new TL ORIR: Enter SOD of TL, SOD of NL-T overall response = iCPD Complete Discontinuation Visit (DV) per protocol/DEGs

24 mm

21 mm

32 mm

23 mm

30 mm

32 mm

23 mm

14 mm

45 mm

32 mm

23 mm

20 mm

30 mm

25 mm



NTL Response NA Non-iCR/Non-iUPD Non-iCR/Non-iUPD

New Lesions NA 14 mm TL 20 mm TL

Overall Response

NA iUPD iCPD

Explanation TLSOD=100mmNTL appear to be stable

TLSOD≥PDthresholdNTL stable New TL appearsThisisinitialPDperRECIST1.1andiUPDperiRECIST

TL SOD decreases to below PD thresholdNTL stableNewlesionSODincreases≥5mmOriginal cause of PD has worsened

InForm Guidance: Lesion eCRF: Enter measurements of TL , details of NTL +newlesionResponse eCRF: Enter SOD, SOD of NL-TOverallResponse=iUPD

Lesion eCRF: Enter measurements of TLEnter details of NTLEnter measurements of new TL Response eCRF: Enter SOD of TL, SOD of NL-TOverallResponse=iCPD


27

iRECISTExample 7

Merck Imaging Tip Sheet v10.0 RECIST 1.1 and iRECIST Example 7

Timepoint Baseline Visit 1 Visit 2 SOD 100 130 60 TL Response NA iUPD iPR NTL Response NA Non-iCR/Non-iPD Non-iCR/Non-iPD New NA 14 mm 12 mm Overall Response NA iUPD iPR Explanation Tl SOD = 100 mm TL SOD >= PD threshold (20 % from

nadir and +5 mm in SOD) NTL stable New TL appears (new lesion 1) This is initial PD per RECIST 1.1 and iUPD per iRECIST

TL SOD decreases, meets PR threshold, hence TL response = iPR new nadir = 60 NTL stable (Non-iCR/Non-iUPD) AND There is no other driver of iCPD

InForm Guidance LNRIR: Enter measurements of TL , details of NTL + new lesion ORIR: Enter SOD, NL-SOD overall response = iUPD if subj is clinically stable, Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL , details of NTL + new lesion ORIR: Enter SOD, NL-SOD overall response = iPR if subj is clinically stable, Complete form for Treatment Beyond Radiographic Disease Progression

24 mm

21 mm

32 mm

23 mm

30 mm

32 mm

23 mm

14 mm

45 mm9 mm

11 mm

24 mm

16 mm

12 mm


TL Response NA iUPD iPR

NTL Response NA Non-iCR/Non-iPD Non-iCR/Non-iPD

New Lesions NA 14 mm 12 mm

Overall Response

NA iUPD iPR

Explanation TlSOD=100mm TLSOD≥PDthresholdNTL stable New TL appears (new lesion 1)ThisisinitialPDperRECIST1.1andiUPDperiRECIST

TLSODdecreases,meetsPRthreshold,henceTLresponse=iPRnewnadir=60mm(forfuturevisits)NTLstable(Non-iCR/Non-iUPD)ANDThere is no other driver of iCPD

InForm Guidance: Lesion eCRF: Enter measurements of TL , details of NTL +newlesionResponse eCRF: Enter SOD, NL-SODOverallResponse=iUPD

LesioneCRF:EntermeasurementsofTL,detailsofNTL+newlesionResponse eCRF: Enter SOD, NL-SODOverallResponse=iPR


28


Merck Imaging Tip Sheet v10.0 RECIST 1.1 and iRECIST Example 7 (cont’d)

Timepoint Visit 3 Visit 4 Visit 5 SOD 71 75 78 TL Response iSD iUPD iUPD NTL Response Non-iCR/Non-iPD Non-iCR/Non-iPD Non-iCR/Non-iPD New 10 mm 14 mm, 1 new NTL 14 mm, new NTL is stable + additional NTL Overall Response

iSD iUPD iCPD

Explanation TL SOD increases, does not meet PD threshold, hence TL response = iSD NTL stable (Non-iCR/Non-iUPD) New lesion 1 has decreased 2mm AND Overall response = iSD

TL SOD increases, meets PD threshold TL response = iUPD NTL appear to remain stable from previous timepoint hence NTL response = Non-iCR/Non-iUPD New lesion 1 has increased + 4mm from previous timepoint Additional new NTL lesion (new lesion # 2) Hence, overall response = iUPD

TL SOD increases + 3 mm (not enough to drive iCPD); TL response = iUPD NTL stable (Non-iCR/Non-iUPD) new lesion # 1= same size as before new lesion # 2= has not worsened Additional new lesion, i.e. new lesion # 3 As another cause of PD has appeared,

InForm Guidance

LNRIR: Enter measurements of TL , details of NTL + new lesion ORIR: Enter SOD, NL-SOD overall response = iPR if subj is clinically stable, Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL , details of NTL + new lesion ORIR: Enter SOD, NL-SOD overall response = iUPD if subj is clinically stable, Complete form for Treatment Beyond Radiographic Disease Progression

LNRIR: Enter measurements of TL , details of NTL + new lesions ORIR: Enter SOD, NL-SOD overall response = iCPD Complete Discontinuation Visit (DV) per protocol/DEGs

20 mm

11 mm

24 mm

16 mm

10 mm

20 mm

15 mm

24 mm

16 mm

14 mm23 mm

15 mm

24 mm

16 mm

14 mm

Timepoint Visit 3 Visit 4 Visit 5SOD 71 75 78TL Response iSD iUPD iUPDNTL Response Non-iCR/Non-iPD Non-iCR/Non-iPD Non-iCR/Non-iPD

New Lesions 10 mm 14 mm, 1 new NTL 14mm,newNTLisstable+additionalNTLOverall Response

iSD iUPD iCPD

Explanation TL SOD increases, does not meet PD threshold,henceTLresponse=iSDNTLstable(Non-iCR/Non-iUPD)New lesion 1 has decreased 2mmAND OverallResponse=iSD

TL SOD increases, meets PD thresholdTLresponse=iUPDNTL appear to remain stable from previous timepointhenceNTLresponse=Non-iCR/Non-iUPDNewlesion1hasincreased+4mmfromprevioustimepointAdditionalnewNTLlesion(newlesion#2)Hence,OverallResponse=iUPD

TLSODincreases+3mm(notenoughtodriveiCPD);TLresponse=iUPDNTLstable(Non-iCR/Non-iUPD)newlesion#1=samesizeasbeforenewlesion#2=hasnotworsenedAdditionalnewlesion,i.e.newlesion#3As another cause of PD has appeared,

InForm Guidance: Lesion eCRF: Enter measurements of TL , detailsofNTL+newlesionResponse eCRF: Enter SOD, NL-SODOverallResponse=iPR

Lesion eCRF: Enter measurements of TL , details of NTL+newlesionResponse eCRF: Enter SOD, NL-SODOerallResponse=iUPD

Lesion eCRF: Enter measurements of TL , detailsofNTL+newlesionsResponse eCRF: Enter SOD, NL-SODOverallResponse=iCPD


29

iRECISTExample 8

Timepoint Baseline Visit 1 Visit 2SOD 100 130 60 (new nadir)TL Response NA iUPD iPRNTL Response NA Non-iCR/Non-iUPD Non-iCR/Non-iUPD

New Lesions NA 14 mm TL 12mmTL,noadditionalnewlesionsOverall Response

NA iUPD iPR

Explanation TLSOD=100mm AsSOD≥PDthresholdNTL StableNew TL appears (new lesion 1)InitialPDperRECIST1.1andiUPDperiRECIST

TL SOD decreases, meets PR threshold, henceTLresponse=iPRnewnadir=60There is no other driver of iCPD

InForm Guidance: Enter measurements of TL Lesion eCRF: Enter measurements of TL , details of NTL+newlesionResponse eCRF: Enter SOD, NL-SODOverallResponse=iUPD

Lesion eCRF: Enter measurements of TL , detailsofNTL+newlesion1Response eCRF: Enter SOD, NL-SODOverallResponse=iPR


30


Timepoint Visit 3 Visit 4 Visit 5SOD 71 (18% increase) 71 78(≥5mmincreaseinSOD)TL Response iSD iSD iUPDNTL Response Non-iCR/Non-iUPD Non-iCR/Non-iUPD Non-iCR/Non-iUPD

New Lesions 18mmTL(≥5mmincrease) 17mmTL(still≥5mmabovenadir) 17mmTL,+additionalnewNTlesionOverall Response

iUPD iUPD iCPD

Explanation TL SOD increases, does not meet PD threshold,henceTLresponse=iSDNTLstable(Non-iCR/Non-iUPD)New lesion 1 has increased 6mmHenceOverallResponse=iUPD

TL SOD stableTLresponse=iSDNTLstable(Non-iCR/Non-iUPD)Newlesion1hasdecreased1mm,butstill≥5mmabove nadir Hence,OverallResponse=iUPD

TLSOD=78(≥5mmincrease)TLresponse=iUPDAnother cause of PD has appeared,Hence,OverallResponse=iCPD

InForm Guidance: Lesion eCRF: Enter measurements of TL , detailsofNTL+newlesion1Response eCRF: Enter SOD, NL-SODOverallResponse=iUPD

Lesion eCRF: Enter measurements of TL , details of NTL+newlesion1Response eCRF: Enter SOD, NL-SODOverallResponse=iUPD

Lesion eCRF: Enter measurements of TL , detailsofNTL+newlesionsResponse eCRF: Enter SOD, NL-SODOverallResponse=iCPD


31

iRECISTExample 9

Timepoint Baseline Visit 1 Visit 2SOD 100 100 100TL Response NA iSD iSDNTL Response NA iUPD Non-iCR/Non-iUPD

New Lesions NA NA NAOverall Response

NA iUPD iSD

Explanation TLSOD=100mm TL SOD stable NTL worseningInitialPDperRECIST1.1andiUPDperiRECIST

TL SOD stable, NTLimprove(Non-iCR/Non-iUPD)AND There is no other driver of iCPD

InForm Guidance: Enter measurements of TL Lesion eCRF: Enter measurements of TL , details of NTL Response eCRF: Enter SOD, NL-SODOverallResponse=iUPD

Lesion eCRF: Enter measurements of TL , details of NTLResponse eCRF: Enter SOD, NL-SODOverallResponse=iSD


32


Timepoint Visit 3 Visit 4SOD 100 100TL Response iSD iSDNTL Response iUPD iCPD

New Lesions NA NAOverall Response

iUPD iCPD

Explanation TL SOD stable, TLresponse=iSDNTLqualitativelyworsensHenceOverallResponse=iUPD

TL SOD stableTLresponse=iSDNTLshowsadditionalgrowthHenceNTLresponse=iCPDAndOverallResponse=iCPD

InForm Guidance: Lesion eCRF: Enter measurements of TL , details of NTLResponse eCRF: Enter SOD, NL-SODOverallResponse=iUPD

Lesion eCRF: Enter measurements of TL , details of NTLResponse eCRF: Enter SOD, NL-SODOverallResponse=iCPD

Visit 3 Visit 4

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