2020
Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma
Middleton MR, McAlpine C, Woodcock VK, Corrie P, Infante JR, Steven NM, Evans TRJ, Anthoney A, Shoushtari AN, Hamid O, Gupta A, Vardeu A, Leach E, Naidoo R, Stanhope S, Lewis S, Hurst J, O’Kelly I, Sznol M. Tebentafusp, A TCR/Anti-CD3 Bispecific Fusion Protein Targeting gp100, Potently Activated Antitumor Immune Responses in Patients with Metastatic Melanoma. Clinical Cancer Research 2020, 26: 5869-5878. PMID: 32816891, PMCID: PMC9210997, DOI: 10.1158/1078-0432.ccr-20-1247.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAtaxia Telangiectasia Mutated ProteinsCD3 ComplexCD8-Positive T-LymphocytesCell ProliferationChemokine CXCL10Cytotoxicity, ImmunologicDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticGp100 Melanoma AntigenHumansImmunityInterferon-gammaMaleMelanomaMiddle AgedNeoplasm ProteinsReceptors, Antigen, T-CellReceptors, CXCR3Recombinant Fusion ProteinsTumor MicroenvironmentConceptsT cellsBispecific fusion proteinMetastatic melanomaT cell receptorSerum CXCL10Multicenter phase I/II trialPhase I/II trialTreatment-related adverse eventsHigh-affinity T-cell receptorsAppearance of rashMetastatic cutaneous melanomaAntitumor immune responseOverall survival rateMetastatic uveal melanomaCytotoxic T cellsPathway-related markersTumor biopsy samplesMechanism of actionII trialAdverse eventsAdvanced melanomaBroad therapeutic potentialPatient survivalPatient cohortCutaneous melanoma
2017
Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma
Sznol M, Ferrucci PF, Hogg D, Atkins MB, Wolter P, Guidoboni M, Lebbé C, Kirkwood JM, Schachter J, Daniels GA, Hassel J, Cebon J, Gerritsen W, Atkinson V, Thomas L, McCaffrey J, Power D, Walker D, Bhore R, Jiang J, Hodi FS, Wolchok JD. Pooled Analysis Safety Profile of Nivolumab and Ipilimumab Combination Therapy in Patients With Advanced Melanoma. Journal Of Clinical Oncology 2017, 35: jco.2016.72.116. PMID: 28915085, DOI: 10.1200/jco.2016.72.1167.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalClinical Trials, Phase I as TopicClinical Trials, Phase II as TopicClinical Trials, Phase III as TopicDisease-Free SurvivalDose-Response Relationship, DrugDrug Administration ScheduleDrug Therapy, CombinationFemaleHumansIpilimumabMaleMaximum Tolerated DoseMelanomaMiddle AgedNeoplasm InvasivenessNeoplasm StagingNivolumabPatient SafetyPrognosisRandomized Controlled Trials as TopicRetrospective StudiesSkin NeoplasmsSurvival AnalysisConceptsTreatment-related adverse eventsTreatment-related select adverse eventsSelect adverse eventsAdverse eventsImmune-modulating agentsAdvanced melanomaMedian timeSafety profileResolution rateGrade 3/4 treatment-related adverse eventsTreatment-related grade 3/4 adverse eventsGrade 3/4 adverse eventsDose of nivolumabIpilimumab combination therapyProgression-free survivalEndocrine adverse eventsAddition of nivolumabGrade 3/4AE managementMedian durationUnacceptable toxicityAntitumor responseCombination therapyStudy deathsDisease progressionNuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma
Smithy JW, Moore LM, Pelekanou V, Rehman J, Gaule P, Wong PF, Neumeister VM, Sznol M, Kluger HM, Rimm DL. Nuclear IRF-1 expression as a mechanism to assess “Capability” to express PD-L1 and response to PD-1 therapy in metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2017, 5: 25. PMID: 28331615, PMCID: PMC5359951, DOI: 10.1186/s40425-017-0229-2.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedB7-H1 AntigenBiomarkers, PharmacologicalDisease-Free SurvivalFemaleGene Expression Regulation, NeoplasticHumansImmunotherapyInterferon Regulatory Factor-1IpilimumabMaleMelanomaMiddle AgedNeoplasm MetastasisNeoplasms, Second PrimaryNivolumabProgrammed Cell Death 1 ReceptorConceptsProgression-free survivalObjective radiographic responsePD-L1 expressionPD-L1IRF-1 expressionMetastatic melanomaAnti-PD-1 therapyCombination ipilimumab/nivolumabHigh PD-L1 expressionAnti-PD-1 immunotherapyYale-New Haven HospitalIpilimumab/nivolumabPD-1 therapyPR/CRPre-treatment formalinRECIST v1.1 criteriaDeath ligand 1Valuable predictive biomarkerMajor unmet needNew Haven HospitalInterferon regulatory factor 1Combination ipilimumabProgressive diseaseRadiographic responseComplete response
2015
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma
Larkin J, Chiarion-Sileni V, Gonzalez R, Grob JJ, Cowey CL, Lao CD, Schadendorf D, Dummer R, Smylie M, Rutkowski P, Ferrucci PF, Hill A, Wagstaff J, Carlino MS, Haanen JB, Maio M, Marquez-Rodas I, McArthur GA, Ascierto PA, Long GV, Callahan MK, Postow MA, Grossmann K, Sznol M, Dreno B, Bastholt L, Yang A, Rollin LM, Horak C, Hodi FS, Wolchok JD. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma. New England Journal Of Medicine 2015, 373: 23-34. PMID: 26027431, PMCID: PMC5698905, DOI: 10.1056/nejmoa1504030.Peer-Reviewed Original ResearchConceptsProgression-free survivalMedian progression-free survivalIpilimumab groupMetastatic melanomaNivolumab groupUntreated patientsPD-L1Negative tumorsTreatment-related adverse eventsLonger progression-free survivalUnresectable stage IIICoprimary end pointsCTLA-4 blockadePhase 3 studyPD-1 ligandsCombined NivolumabAdverse eventsOverall survivalPD-1Combination therapyUntreated melanomaIpilimumabNivolumabGrade 3Stage IIISurvival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab
McDermott DF, Drake CG, Sznol M, Choueiri TK, Powderly JD, Smith DC, Brahmer JR, Carvajal RD, Hammers HJ, Puzanov I, Hodi FS, Kluger HM, Topalian SL, Pardoll DM, Wigginton JM, Kollia GD, Gupta A, McDonald D, Sankar V, Sosman JA, Atkins MB. Survival, Durable Response, and Long-Term Safety in Patients With Previously Treated Advanced Renal Cell Carcinoma Receiving Nivolumab. Journal Of Clinical Oncology 2015, 33: 2013-2020. PMID: 25800770, PMCID: PMC4517051, DOI: 10.1200/jco.2014.58.1041.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntineoplastic AgentsCarcinoma, Renal CellCohort StudiesDisease-Free SurvivalDose-Response Relationship, DrugFemaleHumansKidney NeoplasmsMaleMaximum Tolerated DoseMiddle AgedNivolumabPatient SafetyProgrammed Cell Death 1 ReceptorTime FactorsTreatment OutcomeConceptsAdvanced renal cell carcinomaRenal cell carcinomaLong-term safetyOverall survivalDurable responsesTreatment-refractory solid tumorsTreatment-related adverse eventsOngoing randomized clinical trialsImpact of nivolumabMedian overall survivalMedian response durationPortion of patientsDuration of responseRandomized clinical trialsDrug discontinuationIntravenous nivolumabStable diseaseExpansion cohortTreatment discontinuationAdverse eventsObjective responseAdditional patientsAntibody nivolumabCell surface moleculesCell carcinomaNivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial
Weber JS, D'Angelo SP, Minor D, Hodi FS, Gutzmer R, Neyns B, Hoeller C, Khushalani NI, Miller WH, Lao CD, Linette GP, Thomas L, Lorigan P, Grossmann KF, Hassel JC, Maio M, Sznol M, Ascierto PA, Mohr P, Chmielowski B, Bryce A, Svane IM, Grob JJ, Krackhardt AM, Horak C, Lambert A, Yang AS, Larkin J. Nivolumab versus chemotherapy in patients with advanced melanoma who progressed after anti-CTLA-4 treatment (CheckMate 037): a randomised, controlled, open-label, phase 3 trial. The Lancet Oncology 2015, 16: 375-384. PMID: 25795410, DOI: 10.1016/s1470-2045(15)70076-8.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntineoplastic Combined Chemotherapy ProtocolsCarboplatinCTLA-4 AntigenDisease-Free SurvivalDrug-Related Side Effects and Adverse ReactionsFemaleHumansIpilimumabMaleMelanomaMiddle AgedNeoplasm StagingNivolumabPaclitaxelProto-Oncogene Proteins B-rafConceptsPhase 3 trialObjective responseAdvanced melanomaBRAF inhibitorsPrimary endpointAdverse eventsGrade 3Human IgG4 PD-1 immune checkpoint inhibitor antibodyDrug-related serious adverse eventsICC groupImmune checkpoint inhibitor antibodyCheckpoint inhibitor antibodyDurable objective responsesLater-line treatmentNivolumab-treated patientsSafety of nivolumabTreatment-related deathsUnacceptable toxic effectsSerious adverse eventsProportion of patientsFirst interim analysisNew treatment optionsBest overall responseDose of treatmentHigh unmet need
2014
Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor
Johnson DB, Flaherty KT, Weber JS, Infante JR, Kim KB, Kefford RF, Hamid O, Schuchter L, Cebon J, Sharfman WH, McWilliams RR, Sznol M, Lawrence DP, Gibney GT, Burris HA, Falchook GS, Algazi A, Lewis K, Long GV, Patel K, Ibrahim N, Sun P, Little S, Cunningham E, Sosman JA, Daud A, Gonzalez R. Combined BRAF (Dabrafenib) and MEK Inhibition (Trametinib) in Patients With BRAFV600-Mutant Melanoma Experiencing Progression With Single-Agent BRAF Inhibitor. Journal Of Clinical Oncology 2014, 32: 3697-3704. PMID: 25287827, PMCID: PMC4226803, DOI: 10.1200/jco.2014.57.3535.Peer-Reviewed Original ResearchMeSH KeywordsAdolescentAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsDisease ProgressionDisease-Free SurvivalFemaleHumansImidazolesMaleMelanomaMiddle AgedMitogen-Activated Protein Kinase KinasesMutationOximesProtein Kinase InhibitorsProto-Oncogene Proteins B-rafPyridonesPyrimidinonesConceptsObjective response rateProgression-free survivalMedian progression-free survivalEfficacy of dabrafenibBRAF inhibitor treatmentBRAF inhibitorsOpen-label phase I/II studyInhibitor treatmentPhase I/II studySingle-agent BRAF inhibitorsMEK inhibitionBRAF inhibitor-resistant melanomaBRAF inhibitor monotherapyMedian overall survivalModest clinical efficacyBRAF inhibitor therapyEarly clinical studiesDabrafenib monotherapyInitial therapyStable diseaseII studyInhibitor monotherapyOverall survivalInhibitor therapyStudy enrollmentSurvival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab
Topalian SL, Sznol M, McDermott DF, Kluger HM, Carvajal RD, Sharfman WH, Brahmer JR, Lawrence DP, Atkins MB, Powderly JD, Leming PD, Lipson EJ, Puzanov I, Smith DC, Taube JM, Wigginton JM, Kollia GD, Gupta A, Pardoll DM, Sosman JA, Hodi FS. Survival, Durable Tumor Remission, and Long-Term Safety in Patients With Advanced Melanoma Receiving Nivolumab. Journal Of Clinical Oncology 2014, 32: 1020-1030. PMID: 24590637, PMCID: PMC4811023, DOI: 10.1200/jco.2013.53.0105.Peer-Reviewed Original ResearchConceptsLong-term safetyOverall survivalToxicity ratesTumor regressionResponse durationOngoing randomized clinical trialsDurable tumor remissionNivolumab-treated patientsMedian overall survivalMedian response durationPD-1 blockadeObjective tumor regressionMaintenance of responseCell death 1Randomized clinical trialsSimilar patient populationsActivated T cellsDrug discontinuationIntravenous nivolumabNivolumab therapyNivolumab treatmentTreatment discontinuationObjective responseAdvanced melanomaDeath-1
2012
Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival.
Knisely JP, Yu JB, Flanigan J, Sznol M, Kluger HM, Chiang VL. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. Journal Of Neurosurgery 2012, 117: 227-33. PMID: 22702482, PMCID: PMC6098938, DOI: 10.3171/2012.5.jns111929.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntineoplastic AgentsBrain NeoplasmsCombined Modality TherapyCompassionate Use TrialsDisease-Free SurvivalFemaleHumansIpilimumabMaleMelanomaMiddle AgedNeoplasm StagingPrognosisProportional Hazards ModelsRadiosurgeryRetreatmentRetrospective StudiesConceptsMelanoma brain metastasesBrain metastasesPerformance statusMedian survivalDiagnosis-Specific Graded Prognostic Assessment (DS-GPA) scoreInstitutional review board-approved chart reviewSurvival rateGraded Prognostic Assessment scoreBrain metastasis diagnosisPrognostic assessment scoreSurvival of patientsNumber of metastasesDS-GPA scoreRadiation therapy usePrimary disease locationBrain oligometastasesIpilimumab groupIpilimumab useSalvage WBRTChart reviewOverall survivalPatient ageSystemic therapyTherapy useClinical variables
2010
A phase 2 trial of dasatinib in advanced melanoma
Kluger HM, Dudek AZ, McCann C, Ritacco J, Southard N, Jilaveanu LB, Molinaro A, Sznol M. A phase 2 trial of dasatinib in advanced melanoma. Cancer 2010, 117: 2202-2208. PMID: 21523734, PMCID: PMC3116034, DOI: 10.1002/cncr.25766.Peer-Reviewed Original ResearchConceptsProgression-free survivalC-kit mutationsPhase 2 trialResponse ratePartial responseMedian progression-free survivalMelanoma cell proliferationDaily dasatinibMucosal primaryPFS ratesStarting dosageCommon toxicitiesUnresectable melanomaAdvanced melanomaPleural effusionMelanoma patientsPredictive biomarkersMinor responseCombination trialsTumor assessmentDose reductionPatientsPrespecified endpointsDasatinibMelanoma