2022
Immune-checkpoint inhibitors for glioblastoma: what have we learned?
Omuro A. Immune-checkpoint inhibitors for glioblastoma: what have we learned? Arquivos De Neuro-Psiquiatria 2022, 80: 266-269. PMID: 35976319, PMCID: PMC9491432, DOI: 10.1590/0004-282x-anp-2022-s129.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsRecurrent glioblastomaBrain tumorsRandomized phase 3 trialCommon malignant primary brain tumorPost-treatment tumor samplesMalignant primary brain tumorSuccessful immunotherapeutic approachesPhase 3 trialPhase 1 studySelection of patientsT cell dysfunctionNew safety concernsHigh mutational burdenPrimary brain tumorsCheckpoint inhibitorsRadiographic responseImmunotherapeutic approachesPD-L1Survival improvementImmunologic responseTherapeutic optionsClinical trialsCNS microenvironmentCell dysfunctionPhase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance)
Galanis E, Anderson SK, Twohy E, Butowski NA, Hormigo A, Schiff D, Omuro A, Jaeckle KA, Kumar S, Kaufmann TJ, Geyer S, Kumthekar PU, Campian J, Giannini C, Buckner JC, Wen PY. Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance). Neuro-Oncology Advances 2022, 4: vdac041. PMID: 35664553, PMCID: PMC9154335, DOI: 10.1093/noajnl/vdac041.Peer-Reviewed Original ResearchProgression-free survivalRandomized phase II trialPhase II trialBevacizumab monotherapyRecurrent glioblastomaII trialTreatment armsMedian progression-free survivalLimited effective treatment optionsPhase IQuestionable survival benefitEarly clinical dataEffective treatment optionPhase IIQuality of lifeCombination armPrimary endpointAdverse eventsSurvival benefitLife scoresPoor prognosisTreatment optionsMechanisms of resistanceBevacizumabClinical data
2020
Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma
Reardon DA, Brandes AA, Omuro A, Mulholland P, Lim M, Wick A, Baehring J, Ahluwalia MS, Roth P, Bähr O, Phuphanich S, Sepulveda JM, De Souza P, Sahebjam S, Carleton M, Tatsuoka K, Taitt C, Zwirtes R, Sampson J, Weller M. Effect of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma. JAMA Oncology 2020, 6: 1003-1010. PMID: 32437507, PMCID: PMC7243167, DOI: 10.1001/jamaoncol.2020.1024.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAngiogenesis InhibitorsAntineoplastic Agents, ImmunologicalBevacizumabBrain NeoplasmsDNA Modification MethylasesDNA Repair EnzymesFemaleGlioblastomaHumansImmune Checkpoint InhibitorsMaleMiddle AgedNeoplasm Recurrence, LocalNivolumabProgrammed Cell Death 1 ReceptorTemozolomideTreatment OutcomeTumor Suppressor ProteinsYoung AdultConceptsTreatment-related adverse eventsPhase 3 clinical trialsPrimary end pointOverall survivalRecurrent glioblastomaClinical trialsMedian OSGrade 3/4 treatment-related adverse eventsRandomized phase 3 clinical trialSingle-agent PD-1 blockadeEnd pointEffects of nivolumabUnacceptable toxic effectsMedian overall survivalObjective response ratePD-1 blockadeOverall patient populationImmune checkpoint blockadeData cutoffAdverse eventsCheckpoint blockadeFirst recurrenceInhibitor therapyClinical outcomesSafety profile
2019
ATIM-47. NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE
Weller M, Reardon D, Brandes A, Sampson J, Mulholland P, Wick A, Baehring J, Ahluwalia M, Roth P, Bähr O, Phuphanich S, Sepulveda J, de Souza P, Sahebjam S, Potter V, Tatsuoka K, Taitt C, Zwirtes R, Omuro A, Lim M. ATIM-47. NIVOLUMAB VS BEVACIZUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: EXPLORATORY ANALYSIS OF MGMT METHYLATION STATUS AND BASELINE CORTICOSTEROID USE. Neuro-Oncology 2019, 21: vi12-vi12. PMCID: PMC6847600, DOI: 10.1093/neuonc/noz175.045.Peer-Reviewed Original ResearchMedian overall survivalBaseline corticosteroid useCorticosteroid useBaseline corticosteroidsMGMT methylation statusRecurrent glioblastomaUnmethylated tumorsMultivariable Cox proportional hazards model analysisCox proportional hazards model analysisLonger median overall survivalProportional hazards model analysisBevacizumab-treated patientsLimited survival benefitNivolumab-treated patientsSubgroup of patientsExploratory subgroup analysisHazards model analysisMethyltransferase promoter methylation statusDNA methyltransferase promoter methylation statusMethylation statusMGMT promoter statusTemozolomide chemoradiotherapyFirst recurrencePrimary endpointOverall survivalBuparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial
Wen PY, Touat M, Alexander BM, Mellinghoff IK, Ramkissoon S, McCluskey CS, Pelton K, Haidar S, Basu SS, Gaffey SC, Brown LE, Martinez-Ledesma JE, Wu S, Kim J, Wei W, Park MA, Huse JT, Kuhn JG, Rinne ML, Colman H, Agar NYR, Omuro AM, DeAngelis LM, Gilbert MR, de Groot JF, Cloughesy TF, S. A, Roberts TM, Zhao JJ, Lee EQ, Nayak L, Heath JR, Horky LL, Batchelor TT, Beroukhim R, Chang SM, Ligon AH, Dunn IF, Koul D, Young GS, Prados MD, Reardon DA, Yung WKA, Ligon KL. Buparlisib in Patients With Recurrent Glioblastoma Harboring Phosphatidylinositol 3-Kinase Pathway Activation: An Open-Label, Multicenter, Multi-Arm, Phase II Trial. Journal Of Clinical Oncology 2019, 37: jco.18.01207. PMID: 30715997, PMCID: PMC6553812, DOI: 10.1200/jco.18.01207.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAminopyridinesAntineoplastic AgentsBrain NeoplasmsChemotherapy, AdjuvantDisease ProgressionEnzyme ActivationFemaleGlioblastomaHumansMaleMiddle AgedMorpholinesNeoadjuvant TherapyNeoplasm Recurrence, LocalPhosphatidylinositol 3-KinasePhosphoinositide-3 Kinase InhibitorsProgression-Free SurvivalTime FactorsConceptsPhase II trialCohort 2Cohort 1PI3K pathwayTumor tissueII trialRecurrent glioblastomaBrain penetrationPan-PI3K inhibitor buparlisibPathway inhibitionPathway activationCommon grade 3K pathwayPrimary end pointGreater adverse eventsProgression-free survivalPI3K pathway inhibitionPI3K pathway activationPlasma drug levelsSingle-agent efficacySignificant brain penetrationPI3K inhibitorsMedian PFSOpen labelAdverse events
2017
Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143
Omuro A, Vlahovic G, Lim M, Sahebjam S, Baehring J, Cloughesy T, Voloschin A, Ramkissoon SH, Ligon KL, Latek R, Zwirtes R, Strauss L, Paliwal P, Harbison CT, Reardon DA, Sampson JH. Nivolumab with or without ipilimumab in patients with recurrent glioblastoma: results from exploratory phase I cohorts of CheckMate 143. Neuro-Oncology 2017, 20: 674-686. PMID: 29106665, PMCID: PMC5892140, DOI: 10.1093/neuonc/nox208.Peer-Reviewed Original ResearchConceptsAdverse eventsRecurrent glioblastomaCommon treatment-related adverse eventsTreatment-related adverse eventsDeath ligand 1 (PD-L1) expressionEffects of nivolumabExploratory efficacy outcomesSafety/tolerabilityFindings merit further investigationLigand 1 expressionCheckMate 143Ipilimumab doseNivolumab monotherapyStable diseaseAlternative regimenEfficacy outcomesRadiographic progressionMost patientsPartial responseNivolumabIpilimumabMerit further investigationPatientsI cohortFurther evaluationNCCTG N1174: Phase I/comparative randomized phase (Ph) II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma (GBM) (Alliance).
Galanis E, Anderson S, Butowski N, Hormigo A, Schiff D, Tran D, Omuro A, Jaeckle K, Kumar S, Kaufmann T, Buckner J, Twohy E, Giannini C, Wen P. NCCTG N1174: Phase I/comparative randomized phase (Ph) II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma (GBM) (Alliance). Journal Of Clinical Oncology 2017, 35: 2023-2023. DOI: 10.1200/jco.2017.35.15_suppl.2023.Peer-Reviewed Original ResearchProgression-free survivalII trialMedian progression-free survivalRandomized phase II trialPhase II trialGlioma stem cellsOverall survivalOverall incidenceRecurrent glioblastomaMultiple time pointsVEGF inhibitionGrade 3GBM patientsPositive subsetSingle agentI cohortResponse rateHumanized antibodyFlow cytometryEndothelial cellsTime pointsTGFβ receptorsGlioblastomaBevacizumabCD105OS10.3 Randomized Phase 3 Study Evaluating the Efficacy and Safety of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: CheckMate 143
Reardon D, Omuro A, Brandes A, Rieger J, Wick A, Sepulveda J, Phuphanich S, de Souza P, Ahluwalia M, Lim M, Vlahovic G, Sampson J. OS10.3 Randomized Phase 3 Study Evaluating the Efficacy and Safety of Nivolumab vs Bevacizumab in Patients With Recurrent Glioblastoma: CheckMate 143. Neuro-Oncology 2017, 19: iii21-iii21. PMCID: PMC5463583, DOI: 10.1093/neuonc/nox036.071.Peer-Reviewed Original ResearchObjective response rateTreatment-related AEsProgression-free survivalOverall survivalRecurrent glioblastomaSerious AEsMeasurable diseaseOS ratesInvestigator-assessed progression-free survivalCommon treatment-related AEsHuman IgG4 monoclonal antibodyOnly serious AESafety of nivolumabMedian overall survivalNeuro-Oncology criteriaSecond-line settingDeath-1 receptorSingle-agent therapyAvailable treatment optionsMalignant neoplasm progressionIgG4 monoclonal antibodyMultiple cancer typesCheckMate 143Evaluable ptsImproved OS
2016
Multicenter Phase IB trial of carboxyamidotriazole orotate (CTO) combined with temozolomide (TMZ) for recurrent glioblastoma (GBM) and other malignant gliomas (MG).
Lin X, Kaley T, Pentsova E, DeAngelis L, Daras M, Gavrilovic I, Mellinghoff I, McKeown A, Manne M, Hansen J, Bavisotto L, Gorman G, Lamson M, Karmali R, Omuro A. Multicenter Phase IB trial of carboxyamidotriazole orotate (CTO) combined with temozolomide (TMZ) for recurrent glioblastoma (GBM) and other malignant gliomas (MG). Journal Of Clinical Oncology 2016, 34: 2064-2064. DOI: 10.1200/jco.2016.34.15_suppl.2064.Peer-Reviewed Original ResearchSafety and activity of nivolumab (nivo) monotherapy and nivo in combination with ipilimumab (ipi) in recurrent glioblastoma (GBM): Updated results from checkmate-143.
Reardon D, Sampson J, Sahebjam S, Lim M, Baehring J, Vlahovic G, Cloughesy T, Strauss L, Latek R, Paliwal P, Harbison C, Voloschin A, Omuro A. Safety and activity of nivolumab (nivo) monotherapy and nivo in combination with ipilimumab (ipi) in recurrent glioblastoma (GBM): Updated results from checkmate-143. Journal Of Clinical Oncology 2016, 34: 2014-2014. DOI: 10.1200/jco.2016.34.15_suppl.2014.Peer-Reviewed Original Research
2015
NIMG-18EVALUATING TUMOR PROGRESSION AND IMMUNOLOGIC REACTIONS DURING IMMUNOTHERAPY: NEUROIMAGING OBSERVATIONS FROM A MULTICENTER STUDY OF NIVOLUMAB MONOTHERAPY AND NIVOLUMAB IN COMBINATION WITH IPILIMUMAB IN RECURRENT GLIOBLASTOMA (CHECKMATE-143)
Omuro A, Baehring J, Sahebjam S, Vlahovic G, Voloschin A, Young R, Hayes W, Latek R, Coric V, Cloughesy T, Lim M, Sampson J, Reardon D. NIMG-18EVALUATING TUMOR PROGRESSION AND IMMUNOLOGIC REACTIONS DURING IMMUNOTHERAPY: NEUROIMAGING OBSERVATIONS FROM A MULTICENTER STUDY OF NIVOLUMAB MONOTHERAPY AND NIVOLUMAB IN COMBINATION WITH IPILIMUMAB IN RECURRENT GLIOBLASTOMA (CHECKMATE-143). Neuro-Oncology 2015, 17: v157-v157. PMCID: PMC4639041, DOI: 10.1093/neuonc/nov225.18.Peer-Reviewed Original ResearchQOL-07DESCRIPTION OF CLINICAL AND PATIENT REPORTED OUTCOMES ASSESSMENTS FROM A PHASE 3, MULTICENTER, RANDOMIZED TRIAL EVALUATING NIVOLUMAB MONOTHERAPY VERSUS BEVACIZUMAB IN RECURRENT GLIOBLASTOMA: CHECKMATE-143
Nayak L, Brandes A, Omuro A, Rieger J, Wick A, Phuphanich S, Sumrall A, Sahebjam S, Ahluwalia M, de Souza P, Sepulveda J, Maio M, Grauer O, Vlahovic G, Baehring J, Dastani H, Latek R, Coric V, Reardon D. QOL-07DESCRIPTION OF CLINICAL AND PATIENT REPORTED OUTCOMES ASSESSMENTS FROM A PHASE 3, MULTICENTER, RANDOMIZED TRIAL EVALUATING NIVOLUMAB MONOTHERAPY VERSUS BEVACIZUMAB IN RECURRENT GLIOBLASTOMA: CHECKMATE-143. Neuro-Oncology 2015, 17: v189-v189. PMCID: PMC4639164, DOI: 10.1093/neuonc/nov230.07.Peer-Reviewed Original ResearchCBM-06IMMUNE BIOMARKER RESULTS FROM A TRIAL OF NIVOLUMAB ± IPILIMUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: CHECKMATE-143
Lowther D, Weinhold K, Reap E, Vlahovic G, Omuro A, Sahebjam S, Baehring J, Voloschin A, Cloughesy T, Lim M, Coric V, Latek R, Simon J, Lerner B, Raddassi K, Hafler D, Sampson J. CBM-06IMMUNE BIOMARKER RESULTS FROM A TRIAL OF NIVOLUMAB ± IPILIMUMAB IN PATIENTS WITH RECURRENT GLIOBLASTOMA: CHECKMATE-143. Neuro-Oncology 2015, 17: v70-v70. PMCID: PMC4638710, DOI: 10.1093/neuonc/nov211.06.Peer-Reviewed Original ResearchOrally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study
Butowski N, Colman H, De Groot JF, Omuro AM, Nayak L, Wen PY, Cloughesy TF, Marimuthu A, Haidar S, Perry A, Huse J, Phillips J, West BL, Nolop KB, Hsu HH, Ligon KL, Molinaro AM, Prados M. Orally administered colony stimulating factor 1 receptor inhibitor PLX3397 in recurrent glioblastoma: an Ivy Foundation Early Phase Clinical Trials Consortium phase II study. Neuro-Oncology 2015, 18: 557-564. PMID: 26449250, PMCID: PMC4799682, DOI: 10.1093/neuonc/nov245.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAminopyridinesBiomarkers, TumorBlood-Brain BarrierBrain NeoplasmsCohort StudiesFemaleFollow-Up StudiesGlioblastomaHumansImmunoenzyme TechniquesMaleMiddle AgedNeoplasm Recurrence, LocalNeoplasm StagingPrognosisPyrrolesReceptors, Granulocyte-Macrophage Colony-Stimulating FactorTissue DistributionTumor BurdenConceptsPhase II studyII studyRecurrent glioblastomaTumor tissueMedian drug levelsPrimary efficacy endpointProgression-free survivalBlood-brain barrierPretreatment baseline valuesBlood-tumor barrierExploratory endpointsInhibitor PLX3397Efficacy endpointPrimary endpointSecondary endpointsObjective responseSurgical resectionOral dosePharmacodynamic changesPharmacodynamic measuresTumor burdenDrug exposureTissue pharmacokineticsDrug levelsStem cell factorPreliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143.
Sampson J, Vlahovic G, Sahebjam S, Omuro A, Baehring J, Hafler D, Voloschin A, Paliwal P, Grosso J, Coric V, Cloughesy T, Lim M, Reardon D. Preliminary safety and activity of nivolumab and its combination with ipilimumab in recurrent glioblastoma (GBM): CHECKMATE-143. Journal Of Clinical Oncology 2015, 33: 3010-3010. DOI: 10.1200/jco.2015.33.15_suppl.3010.Peer-Reviewed Original Research
2014
Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor buparlisib (BKM120) in recurrent glioblastoma.
Wen P, Yung W, Mellinghoff I, Ramkissoon S, Alexander B, Rinne M, Colman H, Omuro A, DeAngelis L, Gilbert M, De Groot J, Cloughesy T, Chi A, Lee E, Nayak L, Batchelor T, Chang S, Prados M, Reardon D, Ligon K. Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor buparlisib (BKM120) in recurrent glioblastoma. Journal Of Clinical Oncology 2014, 32: 2019-2019. DOI: 10.1200/jco.2014.32.15_suppl.2019.Peer-Reviewed Original Research
2013
Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study.
Cloughesy T, Mischel P, Omuro A, Prados M, Wen P, Wu B, Rockich K, Xu Y, Lager J, Mellinghoff I. Tumor pharmacokinetics (PK) and pharmacodynamics (PD) of SAR245409 (XL765) and SAR245408 (XL147) administered as single agents to patients with recurrent glioblastoma (GBM): An Ivy Foundation early-phase clinical trials consortium study. Journal Of Clinical Oncology 2013, 31: 2012-2012. DOI: 10.1200/jco.2013.31.15_suppl.2012.Peer-Reviewed Original ResearchPan-PI3K inhibitorCohort 1Cohort 2Frozen tumor tissueTumor tissueTumor samplesK inhibitorsArchived tumor samplesPK/PD analysisPI3K/mTOR pathwayPD analysisTreatment of glioblastomaInhibition of proliferationPI3K inhibitorsPharmacodynamic impactEarly surgeryLast doseSurgical resectionCNS tumorsMean tumorRecurrent glioblastomaTumor resectionFFPE tumor samplesPK analysisCohort 3Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM).
Wen P, Yung W, Mellinghoff I, Lamborn K, Ramkissoon S, Cloughesy T, Rinne M, Omuro A, DeAngelis L, Gilbert M, Chi A, Batchelor T, Colman H, Chang S, Massacesi C, DiTomaso E, Prados M, Reardon D, Ligon K. Phase II trial of the phosphatidyinositol-3 kinase (PI3K) inhibitor BKM120 in recurrent glioblastoma (GBM). Journal Of Clinical Oncology 2013, 31: 2015-2015. DOI: 10.1200/jco.2013.31.15_suppl.2015.Peer-Reviewed Original ResearchPI3K pathwayRecurrent glioblastomaK pathwayPan-class I PI3K inhibitorMajor grade 3/4 toxicitiesEnzyme-inducing antiepileptic drugsAdequate bone marrowGrade 3/4 toxicitiesPhase II studyPhase II trialProgression-free survivalClinical Trials ConsortiumRecurrent GBM patientsAdditional eligibility criteriaPotential therapeutic targetReduction of pAKTWhole-exome sequencingPI3K inhibitorsAnalysis of tumorsRadiologic progressionUnresectable glioblastomaII trialPrimary endpointRecurrent diseaseII study
2011
A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression
Mason WP, Belanger K, Nicholas G, Vallières I, Mathieu D, Kavan P, Desjardins A, Omuro A, Reymond D. A phase II study of the Ras-MAPK signaling pathway inhibitor TLN-4601 in patients with glioblastoma at first progression. Journal Of Neuro-Oncology 2011, 107: 343-349. PMID: 22048878, DOI: 10.1007/s11060-011-0747-6.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic AgentsBrain NeoplasmsChromatography, LiquidDibenzazepinesErbB ReceptorsFemaleFollow-Up StudiesGene Expression Regulation, NeoplasticGlioblastomaHumansInfusions, IntraventricularKaplan-Meier EstimateMagnetic Resonance ImagingMaleMiddle AgedPTEN PhosphohydrolaseTandem Mass SpectrometryConceptsPharmacokinetic evaluationProgressive glioblastomaFirst progressionM2/dayPhase II studyMR scansPhase II trialContinuous intravenous administrationBlood-brain barrierLack of efficacyPeripheral benzodiazepine receptorEvaluable patientsStable diseaseII trialRadiographic progressionAdverse eventsII studyRecurrent glioblastomaDisease progressionDrug levelsIntravenous administrationBiomarker assessmentPatientsAnimal modelsBenzodiazepine receptors