2023
A Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1
Weiss S, Sznol M, Shaheen M, Berciano-Guerrero M, Couselo E, Rodríguez-Abreu D, Boni V, Schuchter L, Gonzalez-Cao M, Arance A, Wei W, Ganti A, Hauke R, Berrocal A, Iannotti N, Hsu F, Kluger H. A Phase II Trial of the CD40 Agonist Sotigalimab (APX005M) in Combination with Nivolumab in Subjects with Metastatic Melanoma with Disease Progression on Anti-PD-1. Clinical Cancer Research 2023, 30: 74-81. PMID: 37535056, PMCID: PMC10767304, DOI: 10.1158/1078-0432.ccr-23-0475.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntineoplastic Combined Chemotherapy ProtocolsDisease ProgressionHumansMelanomaNivolumabConceptsObjective response ratePhase II trialAdverse eventsPartial responseDisease progressionII trialGrade 3 adverse eventsAnti PD-1CD40 agonist antibodyElevated liver functionTreatment-related SAEsCommon adverse eventsActivation of CD40Subset of patientsFavorable safety profileAntigen presenting cellsStable diseaseMedian durationAdvanced melanomaAdditional patientsLiver functionSafety profileMetastatic melanomaPreclinical dataPresenting cells
2022
FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy
Choueiri T, Kluger H, George S, Tykodi S, Kuzel T, Perets R, Nair S, Procopio G, Carducci M, Castonguay V, Folefac E, Lee C, Hotte S, Miller W, Saggi S, Lee C, Desilva H, Bhagavatheeswaran P, Motzer R, Escudier B. FRACTION-RCC: nivolumab plus ipilimumab for advanced renal cell carcinoma after progression on immuno-oncology therapy. Journal For ImmunoTherapy Of Cancer 2022, 10: e005780. PMID: 36328377, PMCID: PMC9639138, DOI: 10.1136/jitc-2022-005780.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsB7-H1 AntigenCarcinoma, Renal CellHumansImmunotherapyIpilimumabKidney NeoplasmsNivolumabTreatment OutcomeConceptsAdvanced renal cell carcinomaObjective response rateDuration of responseIO therapyImmuno-oncology therapiesRenal cell carcinomaOverall survivalCell carcinomaAnti-PD-1/PD-L1 therapyImmune-mediated adverse eventsMedian DORProgression-free survival ratesTreatment-related deathsManageable safety profileMedian overall survivalPD-L1 therapyDurable clinical benefitKarnofsky performance statusPrimary outcome measureHigh unmet needExploratory endpointsIpilimumab armPFS ratesStable diseaseAdverse events
2020
Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02)
Diab A, Tannir NM, Bentebibel SE, Hwu P, Papadimitrakopoulou V, Haymaker C, Kluger HM, Gettinger SN, Sznol M, Tykodi SS, Curti BD, Tagliaferri MA, Zalevsky J, Hannah AL, Hoch U, Aung S, Fanton C, Rizwan A, Iacucci E, Liao Y, Bernatchez C, Hurwitz ME, Cho DC. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discovery 2020, 10: 1158-1173. PMID: 32439653, DOI: 10.1158/2159-8290.cd-19-1510.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Non-Small-Cell LungCarcinoma, Renal CellFemaleGene Expression Regulation, NeoplasticHumansImmune Checkpoint InhibitorsImmunotherapyInterleukin-2Kidney NeoplasmsLung NeoplasmsLymphocyte CountLymphocytes, Tumor-InfiltratingMaleMelanomaMiddle AgedNivolumabPolyethylene GlycolsProgrammed Cell Death 1 ReceptorTreatment OutcomeYoung AdultConceptsTreatment-related adverse eventsAdvanced solid tumorsPD-L1 statusSolid tumorsGrade 3/4 treatment-related adverse eventsPD-1/PD-L1 blockadeCommon treatment-related adverse eventsPhase I dose-escalation trialPoor prognostic risk factorsTotal objective response rateI dose-escalation studyI dose-escalation trialLongitudinal tumor biopsiesPD-L1 blockadeT-cell enhancementTreatment-related deathsObjective response ratePhase II doseDose-escalation studyDose-escalation trialDose-limiting toxicityFlu-like symptomsPrognostic risk factorsTumor-infiltrating lymphocytesCytotoxicity of CD8
2019
Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma
Regan MM, Werner L, Rao S, Gupte-Singh K, Hodi FS, Kirkwood JM, Kluger HM, Larkin J, Postow MA, Ritchings C, Sznol M, Tarhini AA, Wolchok JD, Atkins MB, McDermott DF. Treatment-Free Survival: A Novel Outcome Measure of the Effects of Immune Checkpoint Inhibition—A Pooled Analysis of Patients With Advanced Melanoma. Journal Of Clinical Oncology 2019, 37: 3350-3358. PMID: 31498030, PMCID: PMC6901280, DOI: 10.1200/jco.19.00345.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsDouble-Blind MethodFollow-Up StudiesHumansIpilimumabMelanomaNivolumabPrognosisSurvival RateConceptsTreatment-related adverse eventsTreatment-free survivalHigher treatment-related adverse eventsKaplan-Meier curvesTherapy initiationAdvanced melanomaICI therapyEnd pointGrade 3Outcome measuresLonger treatment-free survivalImmuno-oncology agentsSystemic therapy initiationThird end pointTreatment-free timeImmune checkpoint inhibitionSurvival end pointsEvent end pointsNovel outcome measuresCheckMate 067ICI cessationAdverse eventsTherapy cessationCheckpoint inhibitionPooled analysisPatterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma
Klemen ND, Wang M, Feingold PL, Cooper K, Pavri SN, Han D, Detterbeck FC, Boffa DJ, Khan SA, Olino K, Clune J, Ariyan S, Salem RR, Weiss SA, Kluger HM, Sznol M, Cha C. Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma. Journal For ImmunoTherapy Of Cancer 2019, 7: 196. PMID: 31340861, PMCID: PMC6657062, DOI: 10.1186/s40425-019-0672-3.Peer-Reviewed Original ResearchConceptsThree-year progression-free survivalProgression-free survivalDisease-specific survivalFive-year disease-specific survivalPatterns of failureDurable progression-free survivalLocal therapyStereotactic body radiotherapyMetastatic melanomaNew metastasesPatient selectionIndependent radiological reviewOngoing complete responseResultsFour hundred twentyEvidence of diseaseCNS metastasisCPI treatmentImmunotherapy failureCheckpoint inhibitorsMost patientsProgressive diseaseRadiological reviewComplete responsePD-1PD-L1
2018
Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management
Coleman E, Ko C, Dai F, Tomayko MM, Kluger H, Leventhal JS. Inflammatory eruptions associated with immune checkpoint inhibitor therapy: A single-institution retrospective analysis with stratification of reactions by toxicity and implications for management. Journal Of The American Academy Of Dermatology 2018, 80: 990-997. PMID: 30399387, PMCID: PMC6420863, DOI: 10.1016/j.jaad.2018.10.062.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Agents, ImmunologicalAntineoplastic Combined Chemotherapy ProtocolsDrug EruptionsExanthemaFemaleHumansIpilimumabLichenoid EruptionsMaleMiddle AgedNivolumabRetrospective StudiesSkin NeoplasmsStevens-Johnson SyndromeWithholding TreatmentConceptsInflammatory eruptionsCheckpoint inhibitorsTherapeutic responseImmune checkpoint inhibitor therapySingle tertiary care centerSingle-institution retrospective analysisYale-New Haven HospitalCheckpoint inhibitor therapyTertiary care centerMinority of patientsInpatient dermatology serviceDegree of severityMost rashesInhibitor therapyRetrospective studyTopical treatmentEarly recognitionMedical recordsCare centerInflammatory reactionRetrospective analysisDermatology servicesImmunotherapyMean latencyGrade 2
2017
Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study
Callahan MK, Kluger H, Postow MA, Segal NH, Lesokhin A, Atkins MB, Kirkwood JM, Krishnan S, Bhore R, Horak C, Wolchok JD, Sznol M. Nivolumab Plus Ipilimumab in Patients With Advanced Melanoma: Updated Survival, Response, and Safety Data in a Phase I Dose-Escalation Study. Journal Of Clinical Oncology 2017, 36: jco.2017.72.285. PMID: 29040030, PMCID: PMC5946731, DOI: 10.1200/jco.2017.72.2850.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsDrug Administration ScheduleFemaleHumansIpilimumabMaleMelanomaMiddle AgedNivolumabSkin NeoplasmsTime FactorsTreatment OutcomeYoung AdultConceptsPhase I dose-escalation studyTreatment-related adverse eventsI dose-escalation studyDose-escalation studyAdvanced melanomaOverall survivalAdverse eventsOS ratesClinical activityGrade 3Common grade 3Doses of nivolumabDurable clinical activityModified WHO criteriaNivolumab Plus IpilimumabTreatment-related deathsUntreated advanced melanomaImmune checkpoint inhibitorsMedian overall survivalObjective response rateLong-term followSubsequent clinical developmentConcurrent nivolumabCheckpoint inhibitorsExpansion cohortSarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma
Reddy SB, Possick JD, Kluger HM, Galan A, Han D. Sarcoidosis Following Anti-PD-1 and Anti-CTLA-4 Therapy for Metastatic Melanoma. Journal Of Immunotherapy 2017, 40: 307-311. PMID: 28737620, DOI: 10.1097/cji.0000000000000181.Peer-Reviewed Case Reports and Technical NotesMeSH KeywordsAdrenal Cortex HormonesAntibodies, MonoclonalAntineoplastic Combined Chemotherapy ProtocolsAutoimmunityCTLA-4 AntigenDrug-Related Side Effects and Adverse ReactionsFemaleHumansImmunotherapyIpilimumabLungMelanomaMiddle AgedNivolumabProgrammed Cell Death 1 ReceptorSarcoidosisSkinSkin NeoplasmsTreatment OutcomeConceptsAnti-PD-1 therapyImmune checkpoint inhibitorsStage IV melanomaCheckpoint inhibitorsOncologic responseSevere immune-related adverse effectsImmune checkpoint inhibitor therapyImmune-related adverse effectsAnti PD-1Severe pulmonary manifestationsCheckpoint inhibitor therapyPD-1 inhibitorsDevelopment of sarcoidosisAutoimmune tendencyCorticosteroid treatmentLast dosePulmonary manifestationsCutaneous sarcoidosisRare complicationInhibitor therapyRadiologic findingsPatient's symptomsMetastatic melanomaPotential complicationsSarcoidosis
2016
Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma
Li J, Kluger H, Devine L, Lee JJ, Kelly WK, Rink L, Saif MW. Phase I study of safety and tolerability of sunitinib in combination with sirolimus in patients with refractory solid malignancies and determination of VEGF (VEGF-A) and soluble VEGF-R2 (sVEGFR2) in plasma. Cancer Chemotherapy And Pharmacology 2016, 77: 1193-1200. PMID: 27103123, DOI: 10.1007/s00280-016-3033-7.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsDose-Response Relationship, DrugDrug Administration ScheduleFemaleHumansIndolesMaleMaximum Tolerated DoseMiddle AgedNeoplasmsPyrrolesSirolimusSunitinibTOR Serine-Threonine KinasesVascular Endothelial Growth Factor AVascular Endothelial Growth Factor Receptor-2Young AdultConceptsRenal cell carcinomaComplete responseFourth cohortVEGF productionOral small-molecule inhibitorApparent pharmacokinetic interactionMedian age 57Prior systemic therapyRefractory solid malignanciesResidual renal massTolerability of sunitinibHand-foot syndromeHalf of patientsLymph node dissectionCombination of sunitinibPhase 1 studyDose of sunitinibOral mTOR inhibitorDose/scheduleUnknown compensatory mechanismsCycle 1Multiple receptor tyrosine kinasesAnti-tumor activityEpithelial growth factor receptor (EGFR) signalingTumor cell proliferationCopy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma
Wilson MA, Zhao F, Khare S, Roszik J, Woodman SE, D'Andrea K, Wubbenhorst B, Rimm DL, Kirkwood JM, Kluger HM, Schuchter LM, Lee SJ, Flaherty KT, Nathanson KL. Copy Number Changes Are Associated with Response to Treatment with Carboplatin, Paclitaxel, and Sorafenib in Melanoma. Clinical Cancer Research 2016, 22: 374-382. PMID: 26307133, PMCID: PMC4821426, DOI: 10.1158/1078-0432.ccr-15-1162.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsCarboplatinDisease-Free SurvivalDNA Copy Number VariationsDNA Mutational AnalysisDouble-Blind MethodGenes, rasHumansMelanomaMutationNeoplasm StagingNiacinamidePaclitaxelPhenylurea CompoundsProto-Oncogene Proteins B-rafProto-Oncogene Proteins c-metSorafenibTreatment OutcomeConceptsProgression-free survivalGene copy gainOverall survivalImproved progression-free survivalCopy gainImproved overall survivalGenomic alterationsCancer Genome Atlas (TCGA) datasetImproved treatment responseClinical outcomesMET amplificationV600KCCND1 amplificationTreatment responseMelanoma pathogenesisV600E mutationCurrent FDAPretreatment samplesBRAF geneTumor samplesPatientsSorafenibTherapyTumorsAtlas dataset
2015
Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo
Das R, Verma R, Sznol M, Boddupalli CS, Gettinger SN, Kluger H, Callahan M, Wolchok JD, Halaban R, Dhodapkar MV, Dhodapkar KM. Combination Therapy with Anti–CTLA-4 and Anti–PD-1 Leads to Distinct Immunologic Changes In Vivo. The Journal Of Immunology 2015, 194: 950-959. PMID: 25539810, PMCID: PMC4380504, DOI: 10.4049/jimmunol.1401686.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntigens, SurfaceAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenCytokinesGene Expression ProfilingGene Expression Regulation, NeoplasticHumansImmunophenotypingIpilimumabLymphocytes, Tumor-InfiltratingNeoplasmsNivolumabProgrammed Cell Death 1 ReceptorSignal TransductionT-Lymphocyte SubsetsConceptsPD-1T cellsCTLA-4Checkpoint blockadeCombination therapyReceptor occupancyCombination immune checkpoint blockadeCTLA-4 immune checkpointsPD-1 receptor occupancyTransitional memory T cellsAnti-PD-1 therapyAnti CTLA-4Immune-based combinationsPD-1 blockadeSoluble IL-2RImmune checkpoint blockadeNK cell functionMemory T cellsTherapy-induced changesT cell activationTumor T cellsHuman T cellsRemarkable antitumor effectImmunologic changesImmunologic effects
2014
Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib
Wilson MA, Zhao F, Letrero R, D'Andrea K, Rimm DL, Kirkwood JM, Kluger HM, Lee SJ, Schuchter LM, Flaherty KT, Nathanson KL. Correlation of Somatic Mutations and Clinical Outcome in Melanoma Patients Treated with Carboplatin, Paclitaxel, and Sorafenib. Clinical Cancer Research 2014, 20: 3328-3337. PMID: 24714776, PMCID: PMC4058354, DOI: 10.1158/1078-0432.ccr-14-0093.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinDouble-Blind MethodFemaleFollow-Up StudiesGenotypeGTP PhosphohydrolasesHumansMaleMelanomaMembrane ProteinsMiddle AgedMutationNeoplasm StagingNiacinamidePaclitaxelPhenylurea CompoundsPrognosisProto-Oncogene Proteins B-rafSkin NeoplasmsSorafenibSurvival RateConceptsProgression-free survivalNRAS-mutant melanomaPlatelet-derived growth factor receptorPerformance statusClinical outcomesNRAS mutationsCox proportional hazards modelVEGF receptorsSomatic mutationsWorse performance statusGood performance statusImproved clinical responseKaplan-Meier methodClinical trial populationsPretreatment tumor samplesSite of diseaseProportional hazards modelEffect of sorafenibBRAF-mutant melanomaFisher's exact testGrowth factor receptorClinical responseOverall survivalClinicopathologic featuresMelanoma patients
2013
Nivolumab plus Ipilimumab in Advanced Melanoma
Wolchok JD, Kluger H, Callahan MK, Postow MA, Rizvi NA, Lesokhin AM, Segal NH, Ariyan CE, Gordon RA, Reed K, Burke MM, Caldwell A, Kronenberg SA, Agunwamba BU, Zhang X, Lowy I, Inzunza HD, Feely W, Horak CE, Hong Q, Korman AJ, Wigginton JM, Gupta A, Sznol M. Nivolumab plus Ipilimumab in Advanced Melanoma. New England Journal Of Medicine 2013, 369: 122-133. PMID: 23724867, PMCID: PMC5698004, DOI: 10.1056/nejmoa1302369.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntineoplastic AgentsAntineoplastic Combined Chemotherapy ProtocolsCTLA-4 AntigenFemaleHumansInfusions, IntravenousIpilimumabMaleMelanomaMiddle AgedNeoplasm StagingNivolumabProgrammed Cell Death 1 ReceptorSkin NeoplasmsYoung AdultConceptsObjective response ratePhase 1 trialAdverse eventsConcurrent therapyAdvanced melanomaTumor regressionClinical activityGrade 3Distinct immunologic mechanismsManageable safety profileProlongs overall survivalDurable tumor regressionSupportive preclinical dataRegimen groupImmunologic mechanismsObjective responseOverall survivalIntravenous dosesSafety profileTumor reductionPreclinical dataIpilimumabNivolumabPatientsMaximum doses
2009
Chemotherapy and biologic therapies for melanoma: do they work?
Jilaveanu LB, Aziz SA, Kluger HM. Chemotherapy and biologic therapies for melanoma: do they work? Clinics In Dermatology 2009, 27: 614-625. PMID: 19880049, DOI: 10.1016/j.clindermatol.2008.09.020.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiological ProductsBiological TherapyDrug Therapy, CombinationFemaleHumansMaleMelanomaNeoplasm InvasivenessNeoplasm StagingPrognosisRisk AssessmentSkin NeoplasmsSurvival AnalysisTreatment OutcomeConceptsResponse rateMinority of patientsSubset of patientsInterleukin-2 (IL-2) resultsImproved response ratesIncidence of melanomaIdentification of predictorsCombination of agentsUnresectable diseaseBiologic therapyOlder regimensOverall survivalStandard chemotherapyTherapeutic optionsClinical trialsNew agentsSmall molecule inhibitorsSingle agentImmune systemMonoclonal antibodiesDeath rateMelanomaMalignant melanocytesChemotherapyMolecule inhibitorsExpression of Sorafenib Targets in Melanoma Patients Treated with Carboplatin, Paclitaxel and Sorafenib
Jilaveanu L, Zito C, Lee SJ, Nathanson KL, Camp RL, Rimm DL, Flaherty KT, Kluger HM. Expression of Sorafenib Targets in Melanoma Patients Treated with Carboplatin, Paclitaxel and Sorafenib. Clinical Cancer Research 2009, 15: 1076-1085. PMID: 19188183, PMCID: PMC4263281, DOI: 10.1158/1078-0432.ccr-08-2280.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBenzenesulfonatesCarboplatinCell Line, TumorDisease-Free SurvivalDrug Delivery SystemsHumansMelanomaMitogen-Activated Protein Kinase 3NiacinamidePaclitaxelPhenylurea CompoundsPyridinesReceptors, Vascular Endothelial Growth FactorSkin NeoplasmsSorafenibTreatment OutcomeConceptsSerine/threonine-protein kinase 1Mitogen-activated protein kinase pathwayHigher ERK1/2Protein kinase 1Fibroblast growth factor receptor 1Protein kinase pathwayReceptor tyrosine kinasesPlatelet-derived growth factor receptor betaGrowth factor receptor betaVEGF-R2 expressionSorafenib targetsB-RAF V600E mutationGrowth factor receptor 1C-RafKinase pathwayVascular endothelial growth factor receptor 2B-RafKinase 1Kinase 1/2Tyrosine kinaseEndothelial growth factor receptor 2Factor receptor 1ERK1/2Kinase inhibitorsMultitarget kinase inhibitor
2006
Metastatic myoepithelial carcinoma of the vulva treated with carboplatin and paclitaxel
Noronha V, Cooper DL, Higgins SA, Murren JR, Kluger HM. Metastatic myoepithelial carcinoma of the vulva treated with carboplatin and paclitaxel. The Lancet Oncology 2006, 7: 270-271. PMID: 16510337, DOI: 10.1016/s1470-2045(06)70619-2.Peer-Reviewed Original ResearchAdultAntineoplastic Combined Chemotherapy ProtocolsCarboplatinCarcinomaFemaleHumansLymphatic MetastasisMyoepitheliomaPaclitaxelTreatment OutcomeVulvar Neoplasms