2019
A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors
Bentebibel SE, Hurwitz ME, Bernatchez C, Haymaker C, Hudgens CW, Kluger HM, Tetzlaff MT, Tagliaferri MA, Zalevsky J, Hoch U, Fanton C, Aung S, Hwu P, Curti BD, Tannir NM, Sznol M, Diab A. A First-in-Human Study and Biomarker Analysis of NKTR-214, a Novel IL2Rβγ-Biased Cytokine, in Patients with Advanced or Metastatic Solid Tumors. Cancer Discovery 2019, 9: 711-721. PMID: 30988166, DOI: 10.1158/2159-8290.cd-18-1495.Peer-Reviewed Original ResearchConceptsNKTR-214Tumor biopsiesDurable disease stabilizationImmuno-oncology agentsMulticenter phase IPathway-targeted agentsTreatment tumor biopsiesPhase II doseActivation of CD8Metastatic solid tumorsNatural killer cellsOutpatient regimenCheckpoint inhibitorsDisease stabilizationRegulatory cellsEffector phenotypeKiller cellsTreatment algorithmImmune activationTumor shrinkagePharmacodynamic markersImmune cellsClinical activityIL2 receptorHuman studies
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 ResearchConceptsPhase 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 cohortPhase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma
Daud A, Kluger HM, Kurzrock R, Schimmoller F, Weitzman AL, Samuel TA, Moussa AH, Gordon MS, Shapiro GI. Phase II randomised discontinuation trial of the MET/VEGF receptor inhibitor cabozantinib in metastatic melanoma. British Journal Of Cancer 2017, 116: 432-440. PMID: 28103611, PMCID: PMC5318966, DOI: 10.1038/bjc.2016.419.Peer-Reviewed Original ResearchConceptsObjective response rateStable diseaseWeek 12Metastatic melanomaEvaluable patientsDiscontinuation trialUveal melanomaCommon grade 3/4 adverse eventsGrade 3/4 adverse eventsTreatment-related deathsMedian overall survivalProgression-free survivalResponse Evaluation CriteriaCohort of patientsStudy days 1Further clinical investigationPhase IIAbdominal painDiverticular perforationPrimary endpointAdverse eventsOverall survivalTarget lesionsClinical activityClinical investigation
2016
Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma
Choueiri TK, Fishman MN, Escudier B, McDermott DF, Drake CG, Kluger H, Stadler WM, Perez-Gracia JL, McNeel DG, Curti B, Harrison MR, Plimack ER, Appleman L, Fong L, Albiges L, Cohen L, Young TC, Chasalow SD, Ross-Macdonald P, Srivastava S, Jure-Kunkel M, Kurland JF, Simon JS, Sznol M. Immunomodulatory Activity of Nivolumab in Metastatic Renal Cell Carcinoma. Clinical Cancer Research 2016, 22: 5461-5471. PMID: 27169994, PMCID: PMC5106340, DOI: 10.1158/1078-0432.ccr-15-2839.Peer-Reviewed Original ResearchConceptsMetastatic renal cell carcinomaTreatment-naïve patientsPD-L1 expressionTumor-associated lymphocytesTreatment biopsiesOverall survivalAnti-PD-1 immune checkpoint inhibitorImmune checkpoint inhibitorsMedian overall survivalNew safety signalsPD-1 inhibitionPhase 3 trialMedian percent changeRenal cell carcinomaUpregulation of IFNγTumor gene expressionNivolumab dosesSerum chemokinesCheckpoint inhibitorsChemokine levelsBaseline biopsiesCell carcinomaImmunomodulatory effectsPeripheral bloodClinical activity
2014
Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL).
Sznol M, Kluger H, Callahan M, Postow M, Gordon R, Segal N, Rizvi N, Lesokhin A, Atkins M, Kirkwood J, Burke M, Ralabate A, Rivera A, Kronenberg S, Agunwamba B, Feely W, Hong Q, Krishnan S, Gupta A, Wolchok J. Survival, response duration, and activity by BRAF mutation (MT) status of nivolumab (NIVO, anti-PD-1, BMS-936558, ONO-4538) and ipilimumab (IPI) concurrent therapy in advanced melanoma (MEL). Journal Of Clinical Oncology 2014, 32: lba9003-lba9003. DOI: 10.1200/jco.2014.32.18_suppl.lba9003.Peer-Reviewed Original ResearchClinical activityTreatment-related adverse eventsMT statusManageable safety profilePrior systemic therapyPhase I trialMajority of ptsBRAF mutation statusBRAF MTIPI therapyStage M1cPrior therapyMedian durationObjective responseSystemic therapyAdvanced melanomaAdverse eventsConcurrent therapyI trialOS ratesSafety profileTumor reductionTumor responseGrade 3Wk 24
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 ResearchConceptsObjective 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 dosesSafety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL).
Wolchok J, Kluger H, Callahan M, Postow M, Gordon R, Segal N, Rizvi N, Lesokhin A, Reed K, Burke M, Caldwell A, Kronenberg S, Agunwamba B, Feely W, Hong Q, Horak C, Korman A, Wigginton J, Gupta A, Sznol M. Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL). Journal Of Clinical Oncology 2013, 31: 9012-9012. DOI: 10.1200/jco.2013.31.15_suppl.9012.Peer-Reviewed Original ResearchObjective response rateRelated adverse eventsPhase III trialsConcurrent therapyIII trialsPD-1Clinical activityCTLA-4/PDIpilimumab combination therapyCTLA-4 blockadeManageable safety profilePhase 1 studyPhase I trialImmune checkpoint receptorsIpilimumab therapyMonotherapy dataPrior therapySymptom resolutionAdverse eventsI trialAdvanced melanomaDurable CRCheckpoint receptorsSafety profileCombination therapy