Supplementary Tables - The Precision Medicine Approach

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Supplementary tables: the precision medicine approach to cancer therapy, part 1 — solid tumoursTable 1: Biomarkers important in breast cancer, the precision medicine (PM) agents used in this disease, andthe companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedERAnastrozole(Arimidex)Examples of companiondiagnostic testsImmunohistochemistryNHS(IHC)Use of test resultsEndoPredict geneexpression profiling assay(Myriad Genetics) nNHSIdentifies ER ve tumours. Notcost effective for NHSOncotype DX (GenomicHealth Inc)NHSAssesses whether a patient islikely to benefit fromchemotherapy66EndoPredict GeneExpression Profiling Assay(Myriad Genetics)nNHSIdentifies PgR ve tumours. Notconsidered to be cost effectivefor NHSOncotype DX (GenomicHealth Inc)nNHSAssesses whether a patient islikely to benefit fromchemotherapy66. Notconsidered to be cost effectivefor NHSExemestane(Aromasin)Everolimus(Afinitor)IHC is assessed as intensity (1–3)and proportion of cells stained(0–5) to provide a score of 0–8(known as the Allred score)Letrozole lbociclib (Ibrance)Ribociclib reston)1

TrastuzumabEmtansine (Kadcyla)ImmunohistochemistryNHSScore of 3 defined as positive,2 equivocalHER2 IQFISH PharmDXassayNHS (Dako Omnis)Used for direct confirmation ofHER2 status, for example tocheck for amplification of HER2 antigen in breast tumour cellsafter an equivocal HER2 IHCresult of 2 Used to select patients fortreatment with trastuzumaband pertuzumabHercepTest (DakoPharmDx) — asemiquantitative IHCassayNHSPertuzumab(Perjeta)Mutated BRCA1 and Olaparib*BRCA2(Lynparza)BRCA Analysis CDx(Myriad Genetics Inc)NHS68,69Identifies ovarian cancerpatients carrying germline BRCAmutations who may benefitfrom treatment with olaparib ortalazoparib70None-Talazoparib**(BMN-673)CDK4 and CDK6Abemaciclib(Verzenio)Palbociclib (Ibrance)PIK3CARibociclib (Kisqali)Alpelisib** (Piqray)Qiagen’s TherascreenPIK3CA RGQ PCR KitUsed to detect mutations inPIK3CA found in breast cancerpatients* agents that are likely to be approved by National Institute for Health and Care Excellence (NICE) in the nearfuture, but may not necessarily be used in the NHS40,71** agents that are unlicensed in the UK at the time of writing*** agents that have been removed from NICE guidance or rejected by NICENHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73nNHScompanion diagnostic tests which are not used in the NHS based on cost/benefit ratio72,732

Table 2: Biomarkers important in lung cancer, the precision medicine (PM) agents used in this disease, andthe companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedEpidermal growthfactor receptortyrosine kinase(EGFR-TK)EGFR1/Humanepidermal growthfactor receptor 1(HER1)EGFR/Erb-B familyGefitinib (Iressa)†Erlotinib (Tarceva)†Necitumumab***(Portrazza)EGFR (sensitivityAfatinib (Giotrif)§toward T790Mmutation) and withExon 19 deletions orExon 21 risso)ΔEGFR and HER2(Exon 20 insertionmutation in EGFR)Poziotinib** (alsoknown asNOV120101 orHM781-36B)96Anaplasticlymphoma kinase(ALK)Ceritinib (Zykadia)Examples ofcompaniondiagnostic testsThe Cobas EGFRMutation Test v2NHS(Roche MolecularSystems, Inc)‡Use of test resultsThermo FisherOncomineDx TargetTestNHS (ThermoFisher Scientific)OncomineDx Target is a 23-gene testused to identify the best respondersto agents working through the genesidentified (i.e. EGFR, BRAF, ALK, ROS1, KRAS and NRAS). It can also be usedto monitor the presence or absence ofvariants in other genes91–93Both EGFR tests are used to guide theselection of patients who may benefitfrom treatment with afatinibEGFR Pharm Dx test(Dako Inc)NHS andthe TherascreenEGFR RGQ PCR test(Qiagen)NHS,94Therascreen EGFRRGQ PCR Kit(Qiagen)NHS,95The Cobas EGFR V2testNHS (RocheMolecular Systems,Inc)Thermo FisherOncomineDx TargetTestNHS (ThermoFisher Scientific)Ventana ALK (D5F3)AssayNHS (Novartisin collaborationwith Roche)3Used to select patients with non-smallcell lung cancer (NSCLC) who maybenefit from gefitinib and erlotinibThis test detects exon deletions andinsertions in the EGFR gene95The V2 test is used to select NSCLCpatients who may benefit fromtreatment with osimertinibOncomineDx Target is a 23-gene testused to identify best responders toagents working through the genesidentified (i.e. EGFR, BRAF, ALK, ROS1, KRAS and NRAS). It can also be usedto monitor the presence or absence ofvariants of other genes91–93Results from this test at the time ofdiagnosis can help determine whetherpatients may benefit from treatmentwith ceritinib and/or alectinib

Alectinib (Alecensa)Brigatinib (Alunbrig)HTG EdgeSeqALKPlus Assay EUNHS(HTG MolecularDiagnostics)HTG EdgeSeq ALKPlus is anin vitro next-generation sequencingassay used to test for ALK status inNSCLC patients. It works inconjunction with the HTG EdgeSeqAnalyser97Thermo FisherOncomineDx TargetTestNHS (ThermoFisher Scientific)OncomineDx Target is a 23-gene testthat can be used to identify potentialbest responders to crizotinib, and isalso used to monitor for the presenceor absence of variants of othergenes91–93NexCourseComplete/SolidTestnNHS (GenoptixInc)This test is used only to detect themutation and not for drug selectionThermo FisherOncomineDx TargetTestNHS (ThermoFisher Scientific)OncomineDx Target is a 23-gene testthat can be used to identify bestresponders to the genes identified (i.e.EGFR, BRAF, ALK, ROS-1, KRAS andNRAS), and also to detect thepresence or absence of variants ofother genes91–93Crizotinib (Xalkori)ROS-1Crizotinib (Xalkori)Lorlatinib (PF6463922)Vascular endothelialgrowth factor(VEGFR), plateletderived growthfactor (PDGFR) andfibroblast growthfactor *(Cyramza)Dabrafenib***(Tafinlar)4

MEKTrametinib***(Mekinist)PD-L1 Pembrolizumab(Keytruda)PD-L1 IHC L1 IHC d in the selection of patients whomay benefit from treatment withpembrolizumabDurvalumab(Imfinzi)The Ventana PD-L1(SP263) Assay NHSusing the VentanaBenchMark UltraInstrument(Ventana MedicalSystems Inc)Used to select patients who maybenefit from treatment cusInc)98The FoundationOne CDx profiles 324genes as well as microsatelliteinstability and TMB, and is used toidentify potential best responders to15 FDA-approved treatmentsAlthough it is not yet an approvedcompanion diagnostic assay for TMB,it is being used experimentally toinform the clinical management ofpatients with respect to thisbiomarker87,99Nivolumab (Opdivo)TMB (not currentlyused in practice)Used in the selection of patients whomay benefit from treatment withnivolumab*agents that are likely to be approved by National Institute for Health and Care Excellence (NICE) in the near5

future, but may not necessarily be used in the NHS40,71** agents that are unlicensed in the UK at the time of writing*** agents that have been removed from NICE guidance or rejected by NICENHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73nNHScompanion diagnostic tests which are not used in the NHS based on cost/benefit ratio72,73†Both gefitinib and erlotinib are first-generation TKIs‡The IdyllaTM EGFR Mutation Assay is used only for research and not for diagnostic purposes§Afatinib is considered a second-generation inhibitorΔOsimertinib is considered a third-generation inhibitor. The decision by NICE to disallow the use of osimertinibfor end-of-life consideration in this cancer type is being appealed by AstraZeneca (100) The PD-L1 assays described in this section can be used with more than one type of PD-L1 inhibitorTable 3: Biomarkers important in metastatic colorectal cancer (mCRC), the precision medicine (PM) agentsused in this disease and the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedNRAS/KRASPanitumumab(Vectibix)Examples ofcompaniondiagnostic testsIdylla NRAS-BRAFMutation TestNHS(Biocartis/Amgen)116Use of test resultsCobas KRASMutation TestNHS(Roche MolecularSystems Inc)Used to help identifymCRC patients who maybenefit from treatmentwith cetuximab orpanitumumab based on alack of mutationsTherascreen KRASRGQ PCR TestNHS(Quiagen Ltd)6Used to help identifymCRC patients eligible fortreatment withpanitumumab based on alack of mutations

Cetuximab (Erbitux)Idylla ctKRASMutation TestnNHS(Biocartis/Merck)117Detects 21 mutations inthe KRAS gene. The firstliquid biopsy test toimprove the selection ofpatients who may benefitfrom anti-EGFR therapiessuch as cetuximab117. Notconsidered to be costeffective by the NHSHER3Panitumumab(Vectibix)Idylla NRAS-BRAFMutation TestnNHS(Biocartis/Amgen)116Used to help identifymCRC patients suitable fortreatment withpanitumumab. Notconsidered to be costeffective for the za)None-None-Regorafenib(Stivarga)Irinotecan (Campto)None-UGT1A1 MolecularAssaynNHS (Pfizer)The presence of thepolymorph UGT1A1*28 isassociated with poormetabolism of theirinotecan metabolite (SN38), and the need for alower starting dose (oravoidance of treatment)due to potentially severehematological toxicityVEGFR2VEGFR2-TIE2UGT1A17

PD-L1(some of the PD-L1 testsdescribed can be used inassociation with different PD-L1inhibitors)Pembrolizumab*(Keytruda)See entry forpembrolizumab inTable 2See entry forpembrolizumab in Table 2Nivolumab*(Opdivo)See entry fornivolumab in Table 2See entry for nivolumab inTable FocusInc)98Atezolizumab**(Tecentriq)NoneThe FoundationOne CDxtest profiles 324 genesand is used to helpidentify potential bestresponders to 15 FDAapproved treatments.Although it is not formallyrecognised as acompanion diagnostic kitfor MSI-H and dMMR, itcan be used to inform theclinical management ofpatients with respect tothese biomarkers87-* agents that are likely to be approved by National Institute for Health and Care Excellence (NICE) in the nearfuture, but may not necessarily be used in the NHS40,71** agents that are unlicensed in the UK at the time of writing*** agents that have been removed from NICE guidance or rejected by NICENHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73nNHScompanion diagnostic tests which are not used in the NHS based on cost/benefit ratio72,738

Table 4: Biomarkers important in metastatic melanoma, the precision medicine (PM) agents used in thisdisease and the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedBRAFV600Vemurafenib(Zelboraf)Examples ofcompaniondiagnostic testsCobas 4800 BRAFV600 Mutation TestNHS(RocheMolecular Systems,Inc)Use of test resultsThermo FisherOncomine Dx TargetTestnNHS (ThermoFisher Scientific)Identifies those patients who mightbest respond to BRAF inhibitors basedon the profiling of 23 genes includingEGFR, BRAF, ALK, ROS-1, KRAS andNRAS (91-93). Not considered to becost-effective for the NHSDetects V600E/E2/D and V600K/R/Mmutations in codon 600 of the BRAFgene, and is used to help identifypatients who may benefit from BRAFinhibitors127. Not considered to becost effective for the NHSIndicates the presence of V600E andV600K mutations in patients withunresectable or metastatic melanomato select those who may benefit fromtreatment with dabrafenib andtrametinib (or cobimetinib)Idylla BRAFMutation TestnNHS(Biocartis, ekinist)THxID-BRAF CDxTest#,NHS(BioMérieux Inc)Indicates the presence of the BRAFV600mutation identifying patients suitablefor treatment with mab(Keytruda)Nivolumab (Opdivo)See entry forpembrolizumab inTable 2.See entry fornivolumab in Table2.9See entry for pembrolizumab in Table2See entry for nivolumab in Table 2

CTLA-4Ipilimumab (Yervoy)None-*** agents that have been removed from National Institute for Health and Care Excellence (NICE) guidance orrejected by NICENHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73nNHScompanion diagnostic tests which are not used in the NHS based on cost/benefit ratio72,73#In 2013 the FDA approved the use of dabrafenib and trametinib in combination alongside the THxID BRAF testfrom BioMérieux. It is the second companion diagnostic approved by the FDA for BRAF mutation detectionfollowing approval of Roche’s Cobas 4800 BRAF V600 Mutation Test in 2011Table 5: Biomarkers important in ovarian cancer, the precision medicine (PM) agents used in this diseaseand the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedMutated BRCA1 and Niraparib (Zejula)BRCA2Olaparib (Lynparza)Examples ofcompaniondiagnostic testsBRACAnalysis CDxNHS(Myriad GeneticsInc)Use of test resultsBRCA Analysis CDx(Myriad GeneticsInc)NHS,68,69Identifies ovarian cancer patientscarrying germline BRCA mutationswho may benefit from treatment witholaparib70Identifies advanced ovarian cancerpatients with mutations in theirBRCA1 and BRCA2 genes who arelikely to benefit from treatment withrucaparibRucaparib (Rubraca) FoundationFocusCDxBRAC NHS(FoundationMedicine Inc)VEGFR1 andVEGFR2CA125 and CA125 IIBevacizumab(Avastin)NoneNoneIdentifies ovarian cancer patientscarrying germline BRCA mutationswho should respond to niraparib-Test kits, based onCA125 and CA125 II are diagnosticELISA, are underbiomarkers for ovarian cancerdevelopment incollaborationbetweenMorphotek Inc andFujirebioDiagnosticsNHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,7310

Table 6: Biomarkers important in prostate cancer, the precision medicine (PM) agents used in this diseaseand the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedAR 1 olutamide**(Nubeqa)Olaparib**(Lynparza)Examples ofcompaniondiagnostic testsNumerouscommercial test kitsavailable.Use of test results-N/A-N/A-N/AThere is currently no screening program forprostate cancer in the UK, as benefits have notbeen proven to outweigh the risks147See Table 5 forBRACA1/2 analysis has been usedexamples ofexperimentally to identify prostate cancercompanionpatients who are likely to respond to PARPdiagnostic testsinhibitors such as olaparibavailable for BRCA1and BRCA2* agents that are likely to be approved by National Institute for Health and Care Excellence (NICE) in the nearfuture, but may not necessarily be used in the NHS40,71** agents that are unlicensed in the UK at the time of writingTable 7: Biomarkers important in renal cancer, the precision medicine (PM) agents used in this disease andthe companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedVEGFR 1–3 andPDGFRα/βPazopanib(Votrient)Sunitinib (Sutent)Examples ofcompaniondiagnostic testsNexCourse nNHSComplete/SolidGenoptix-A(Novartis Inc)Use of test resultsLC-MS/MSNHSWithin the NHS, plasma levels of theactive metabolite of Sunitinib (i.e. N-11Over-expression of VEGFR 1–3 isdetected and allows the selection ofpatients for treatment with Pazopanib

VEGFR 1-3PD-L1Lenvatinib(Lenvima)Tivozanib (Fotivda)Nonedesmethylsunitin-ib) are measured toassess adherence and optimisetreatment-None-Sorafenib s(Torisel)None-Axitinib umab*(Keytruda)See entry forpembrolizumab inTable 2See entry fornivolumab inTable 2NoneSee entry for pembrolizumabin Table 2Nivolumab (Opdivo)See entry for nivolumabin Table 2Atezolizumab**(Tecentriq)* agents that are likely to be approved by National Institute for Health and Care Excellence (NICE) in the nearfuture, but may not necessarily be used in the NHS40,71** agents that are unlicensed in the UK at the time of writingNHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73nNHScompanion diagnostic tests which are not used in the NHS based on cost/benefit ratio72,73Table 8: Biomarkers important in hepatocellular carcinoma, the precision medicine (PM) agents used in thisdisease, and the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedVEGFR and PDGFRSorafenib (Nexavar)Examples ofcompaniondiagnostic testsSorafenib by LCMS/MSNHS12Use of test resultsMeasures the active metabolite ofSorafenib (Sorafenib N-oxide) inplasma to assess adherence, monitortoxicity and optimise treatment

VEGFRPD-L1Lenvatinib ne-None-None-See entry forSee entry for nivolumab in Table 2nivolumab inTable 2** agents that are unlicensed in the UK at the time of writingNHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73Table 9: Biomarkers used in medullary and papillary thyroid cancers, the precision medicine (PM) agentsused in this disease, and the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents usedVEGFR and PDGFRSorafenib (Nexavar)Lenvatinib Tafinlar)Examples ofcompaniondiagnostic testsSee entry forSorafenib in Table 8NoneUse of test resultsNone-None-None-See entry forDabrafenib andTrametinib inTable 4See entry for Dabrafenib andTrametinib in Table 4Trametinib**(Mekinist)** agents that are unlicensed in the UK at the time of writing13See entry for Sorafenib in Table 8-

Table 10: Biomarkers used in pancreatic neuroendocrine tumours (PNTs), the precision medicine (PM)agents used in this disease, and the companion diagnostic (CDx) tests used to select patients most likely torespondBiomarkersAgents usedVEGFEverolimus (Afinitor )VEGFR, VEGFR2 andPDGFRα/βSunitinib (Sutent)Vandetanib**(Caprelsa)Erlotinib** (Tarceva)UGT1A1Examples ofcompaniondiagnostic testsTandem massspectrometric(LC-MS/MS) assayfor measuringeverolimusNHSSee entry forSunitinib in Table 7NoneUse of test resultsNone-Due to a narrow therapeutic index,plasma concentrations of everolimusmust be routinely monitored, usuallyon a pre-dose (trough) sampleSee entry for Sunitinib in Table 7-Nano-LiposomalIrinotecan***(Onivyde)Olaparib* (Lynparza)See entry forSee entry for Irinotecan in Table 3Irinotecan in Table3BRCA1 and BRCA2See Table 5 forSee Table 5 for examples ofexamples ofcompanion diagnostic tests availablecompanionfor BRCA1 and BRCA2diagnostic testsavailable forBRCA1 and BRCA2** agents that are unlicensed in the UK at the time of writing*** agents that have been removed from National Institute for Health and Care Excellence (NICE) guidance orrejected by NICENHScompanion diagnostic tests which are used in the NHS based on cost/benefit ratio72,73Table 11: The main biomarker used in bladder cancer, the precision medicine (PM) agents used in thisdisease, and the companion diagnostic (CDx) tests used to select patients most likely to respondBiomarkersAgents triq)Examples ofcompaniondiagnostic testsSee entry forDurvalumab inTable 2None14Use of test resultsSee entry for Durvalumab in Table 2-

e-Therascreen FGFRThis testing kit is used to identifynNHSRGQ RT-PCR Kitpatients who may benefit from(Qiagen)erdafitinib** agents that are unlicensed in the UK at the time of writingnNHScompanion diagnostic tests which are not used in the NHS based on cost/benefit ratio72,73Table 12: The main biomarker relevant to basal cell carcinoma, and the small moleculeinhibitors associated with itBiomarkerAgents usedExamples ofcompaniondiagnostic testsNoneHedgehog signaling ** agents that are unlicensed in the UK at the time of writingUse of test results-Table 13: The main biomarkers relevant to gastrointestinal stromal tumours, the precision medicine (PM)agents used in this disease, and the companion diagnostic (CDx) tests used to select patients most likely torespondBiomarkersAgents usedC-Kit (also known asCD117) or DOG1Imatinib (Glivec)PDGFRAExamples of companiondiagnostic testsNoneUse of test resultsSunitinib (Sutent)See entry for Sunitinib inTable 7See entry for Sunitinib inTable 7Regorafenib (Stivarga)None-Sunitinib (Sutent)See entry for Sunitinib inTable 7NoneSee entry for Sunitinib inTable 7-Regorafenib (Stivarga)15-

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Cobas 4800 BRAF V600 Mutation Test NHS (Roche Molecular Systems, Inc) Indicates the presence of the BRAFV600 mutation identifying patients suitable for treatment with vemura