alignment of tmb measured on clinical samples: phase 2b of ...apr 28, 2020 · consistently in...
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Diana Merino Vega, PhDFriends of Cancer Research
@d2merino
AACR Virtual Annual Meeting
April 28, 2020#AACR20 @CancerResrch
Alignment of TMB measured on clinical samples: Phase 2B of the Friends of Cancer Research TMB
Harmonization Project
Disclosure of Relevant Financial Relationships
Ihavenorelevantfinancialrelationshipstodisclose
Tumor Mutational Burden (TMB)
• Ameasureofthenumberofsomaticmutationsperareaofthetumor’sgenome(mut/Mb)
• HighTMBoccursinnumeroustumortypesandevidenceisgrowingfortheassociationofTMBwithneoantigenload1
• TMBisapredictivebiomarkerandhasbeenshowntocorrelatewithclinicalbenefitfromcancerimmunotherapies1,2
• MethodsofTMBestimationandreportingvarywidelyacrossclinicalstudies3
1.ChanTA,etal.AnnOncol.2019.2.ChalmersZR,etal.GenomeMed.2017.3.StenzingerA,AllenJD,etal.GenesChromosomesCancer.2019.4.YarchoanM,etal.NEnglJMed.2017.
CorrelationbetweenTMBandORRwithanti-PD-L1/PD-1therapyin27tumortypes4
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Friends of Cancer Research TMB Harmonization Project
Multi-stakeholderworkinggrouptoalignonandpublishuniversalbestpracticesfordefiningTMB,andanalyticvalidationapproachesincludingalignmentagainstreferencestandards.
www.focr.org/tmbMerinoetal.JImmunotherapyCancer,2020
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Clinical Samples
Clinical samples NGS panel
Panel TMB score
Lab TMB algorithm
Clinical samplesWES
Clinical samples WES-
TMB score
Consortium agreed TMB
algorithm
Phase 2B: Empirical Analysis- Clinical Samples
25 tumor-normal matched FFPE clinical samples
DNA extracted in reference lab
Different cancer types (lung, bladder, gastric)
Assessing empirical variability in WES
TMB vs. panel TMB
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1
Clinical Samples
Clinical samples NGS panel
Panel TMB score
Lab TMB algorithm
Clinical samplesWES
Clinical samples WES-
TMB score
Consortium agreed TMB
algorithm
Phase 2B: Empirical Analysis- Clinical Samples
Assessing empirical variability in WES
TMB vs. panel TMB
Clinical Samples NGS panel
All TCGA WES vs. panel
Stratum 1 TCGA WES vs. panel
Cell lineWES vs. panel
Apply calibration approaches to align across NGS panels
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2
25 tumor-normal matched FFPE clinical samples
DNA extracted in reference lab
Different cancer types (lung, bladder, gastric) 3calibrationmethods
1
LinearRegressionforClinicalSamples(N=25)
Variability in estimated association between panel TMB and WES TMB across participating laboratories
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CellLineSamples(N=10)
Variability in estimated association between panel TMB and WES TMB across
participating laboratories
Stratum1TCGASamples(N=1563)AllTCGASamples(N=4065)
Calibration approaches using TCGA & cell lines as reference standards
WES TMB (mut/Mb)
P
anel
TM
B (m
ut/M
b)
0
1
0
2
0
30
40
50
6
0
0 10 20 30 40 50 60
95%predictionlimits
𝘺0=observed panelTMB
𝓍0=estimatedWESTMBcalculatedfromcalibrationcurveatobserved𝘺0 (CLL95(𝘺0),CUL95(𝘺0))=intervalofuncertaintyaround𝓍0
𝘺0
𝓍0
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Calibration approaches using TCGA & cell lines as reference standards
WES TMB (mut/Mb)
P
anel
TM
B (m
ut/M
b)
0
1
0
2
0
30
40
50
6
0
0 10 20 30 40 50 60
95%predictionlimits
𝘺0=observed panelTMB
𝘺0
𝓍0
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𝓍0=estimatedWESTMBcalculatedfromcalibrationcurveatobserved𝘺0 (CLL95(𝘺0),CUL95(𝘺0))=intervalofuncertaintyaround𝓍0
Application of Three Calibration Approaches to Lung Clinical Samples (N=10)
Uncalibrated clinical samples Calibration with ALL TCGA Calibration with Stratum 1 TCGA Calibration with cell lines
Uncalibrated clinical samples Calibration with ALL TCGA Calibration with Stratum 1 TCGA Calibration with cell lines
Application of Three Calibration Approaches to Lung Clinical Samples (N=10)
Phase 2B: Summary of Findings
• VariabilityintheassociationbetweenpanelTMBandWESTMBacrossparticipatinglaboratorieswhentestingFFPE-derivedtumorsampleswassimilartothatobservedinTCGAsamplesandcelllines.
• CalibrationapproachesusingTCGAdataweremorerobustthanthoseusingarelativelysmallnumberofcelllinesamples,minimizingthespreadinpanelTMBvaluesforclinicalsamples
• CalibrationmethodsusingTCGAmaybeaviableapproachtoalignacrosspanelTMBscores
• OngoingworkwillexplorewhetherTCGAcalibrationmethodsperformconsistentlyinadditionaltumorsamples,includingTMB-highsamples
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Friends TMB Harmonization Project Catalyzing Change Through Collaboration
➢Conveningstakeholdersearlyinthedevelopmentofcomplexdiagnosticswillhelpidentifykeychallengesandstreamlinemeasurestosolvethem
➢CollaborativeapproachisnecessarytoimproveconsistencyandreliabilityofpanelTMBestimatestobeusedintheclinic
➢Scientificandregulatoryapproachesarenecessaryforalignmentonoptimalperformancethresholdsandstandardsdevelopment
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TMBHarmonizationConsortium
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Government: National Cancer Institute (NCI), U.S. Food and Drug Administration (FDA) Academia: Brigham & Women’s Hospital, College of American Pathologists
(CAP), Columbia University, EORTC, Genomic Testing Cooperative, Hartwig Medical Foundation, Johns Hopkins University, Massachusetts General Hospital, MD Anderson Cancer Center, Memorial Sloan Kettering Cancer Center, Quality in
Pathology (QuIP), University of Heidelberg Diagnostics: ACT Genomics, Biodesix, Caris Life Sciences, Foundation Medicine, Inc., Guardant Health, Inc., Illumina, Inc.,
Intermountain Precision Genomics, NeoGenomics Laboratories, Inc., OmniSeq, Personal Genome Diagnostics (PGDx), Q2 Solutions, QIAGEN, Inc., Quest
Diagnostics, RocheDx, Thermo Fisher Scientific, Thrive Industry: AstraZeneca, Bristol-Myers Squibb Company, EMD Serono, Inc., Genentech, Merck & Co., Inc., Pfizer, Inc., Regeneron Pharmaceuticals Operational: precisionFDA, SeraCare
Thank you!
Formoreinformationandupdates,visitfocr.org/tmb
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