2024
First-line Systemic Therapy Following Adjuvant Immunotherapy in Renal Cell Carcinoma: An International Multicenter Study
El Zarif T, Semaan K, Xie W, Eid M, Zarba M, Issa W, Zhang T, Nguyen C, Alva A, Fahey C, Beckermann K, Karam J, Campbell M, Procopio G, Stellato M, Buti S, Zemankova A, Melichar B, Massari F, Mollica V, Venugopal B, Ebrahimi H, de Velasco G, Gurney H, De Giorgi U, Parikh O, Winquist E, Master V, Garcia A, Cutuli H, Ferguson T, Gross-Goupil M, Baca S, Pal S, Braun D, McKay R, Heng D, Choueiri T. First-line Systemic Therapy Following Adjuvant Immunotherapy in Renal Cell Carcinoma: An International Multicenter Study. European Urology 2024 PMID: 39147674, DOI: 10.1016/j.eururo.2024.07.016.Peer-Reviewed Original ResearchRenal cell carcinomaProgression-free survivalInternational Metastatic RCC Database ConsortiumRecurrent renal cell carcinomaTreatment-related adverse eventsSystemic therapyAdjuvant pembrolizumabOverall survivalCell carcinomaClinical outcomesIO therapyAdjuvant immunotherapyAdverse eventsVascular endothelial growth factor-targeted therapyDetect occult metastatic diseaseOutcomes of first-lineFirst-line systemic therapyFavorable-risk diseaseIO-based regimensOccult metastatic diseaseMedian follow-upKaplan-Meier methodShort follow-up periodFollow-up periodInternational multicenter study22 Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs)
Saad E, Mehrabad E, Labaki C, Saliby R, Semaan K, Eid M, Machaalani M, Chehade R, Nawfal R, Sun M, Sharon E, Shah P, Vemula S, Gupta S, Braun D, Van Allen E, Gusev A, Choueiri T. 22 Association of a germline single nucleotide polymorphism (SNP) in the interleukin-7 (IL7) gene with immune-related adverse events (irAEs). The Oncologist 2024, 29: s1-s2. PMCID: PMC11301885, DOI: 10.1093/oncolo/oyae181.003.Peer-Reviewed Original ResearchImmune-related adverse eventsMetastatic non-small cell lung cancerMetastatic renal cell carcinomaImmune checkpoint inhibitorsProgression-free survivalWhole-exome sequencingRecurrent grade 2Overall survivalGrade 2Interleukin-7Single nucleotide polymorphismsNivolumab armPembrolizumab armSomatic alterationsAdverse eventsTreatment armsPrediction of immune-related adverse eventsCumulative rates of adverse eventsTumor whole-exome sequencingRates of grade 2Non-small cell lung cancerGermline single nucleotide polymorphismsClinical trials of patientsAssociated with significantly higher ratesPD-1 inhibitorsExpression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial.
Nabil Laimon Y, Paul M, Ghandour F, El Ahmar N, Matar S, Denize T, Bagheri Sheshdeh A, Savla V, Mohanna R, Sun M, Saliby R, Saad E, Machaalani M, Braun D, Aftab D, Xie W, CHOUEIRI T, Signoretti S. Expression of the receptor tyrosine kinase AXL and clinical outcomes to cabozantinib and everolimus in patients with metastatic renal cell carcinoma enrolled in the METEOR trial. Journal Of Clinical Oncology 2024, 42: 4543-4543. DOI: 10.1200/jco.2024.42.16_suppl.4543.Peer-Reviewed Original ResearchProgression-free survivalAssociated with progression-free survivalReceptor tyrosine kinase AXLTyrosine kinase inhibitorsRenal cell carcinomaImmune cellsMETEOR trialTyrosine kinase AXLAxl expressionTumor cellsCell carcinomaAssociated with shorter progression-free survivalMetastatic clear cell renal cell carcinomaAnti-PD-1 therapyLevels of AXL expressionMetastatic renal cell carcinomaMultitargeted tyrosine kinase inhibitorPresence of bone metastasesShorter progression-free survivalClear cell renal cell carcinomaIMDC risk groupsPretreatment tumor tissueVEGFR-TKI treatmentCell renal cell carcinomaDouble immunohistochemistry stainingAdvanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Serzan M, Jegede O, Alter R, Bilen M, Braun D, Einstein D, Haas N, Herchenhorn D, King J, Runcie K, Sosman J, Sternberg C, Yang Y, Signoretti S, CHOUEIRI T, Atkins M. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). Journal Of Clinical Oncology 2024, 42: tps4614-tps4614. DOI: 10.1200/jco.2024.42.16_suppl.tps4614.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsArm BArm APrimary endpointRate of immune-related adverse eventsMetastatic clear cell renal cell carcinomaImmune-related adverse eventsMolecular predictors of responseVEGF receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsEnhance T cell primingOne-sided significance levelClear cell renal cell carcinomaAnti-PD1 inhibitorsIMDC risk groupsTreatment free intervalProgression-free survivalT cell primingTreatment-free survivalCell renal cell carcinomaSubpopulations of TregsFirst-line treatmentRenal cell carcinomaPredictors of responseAssociated with increased presenceIntratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial.
Matar S, Jegede O, Denize T, Ghandour F, Nabil Laimon Y, El Ahmar N, Bagheri Sheshdeh A, Savla V, Mohanna R, Catalano P, Braun D, Sun M, Gupta S, Vemula S, Freeman G, Motzer R, Atkins M, McDermott D, CHOUEIRI T, Signoretti S. Intratumoral T-cell infiltration and response to nivolumab plus ipilimumab in patients with metastatic clear cell renal cell carcinoma from the CheckMate-214 trial. Journal Of Clinical Oncology 2024, 42: 4536-4536. DOI: 10.1200/jco.2024.42.16_suppl.4536.Peer-Reviewed Original ResearchProgression-free survivalAssociated with progression-free survivalMultiplex immunofluorescenceClinical trialsClinical outcomesMetastatic clear cell renal cell carcinomaIntratumoral T cell infiltrationTreated with nivolumab monotherapyMetastatic clear cell RCCClear cell renal cell carcinomaResponse to nivolumabT cell infiltrationCell renal cell carcinomaPoor-risk patientsRenal cell carcinomaClear cell RCCFormalin fixed paraffinContinuous variablesNivolumab monotherapyCox proportional hazardsAntigen-experiencedCell RCCCell carcinomaLogistic regression modelsPositive associationCharacterizing genomic alterations in patients with metastatic urothelial carcinoma (mUC) treated with enfortumab-vedotin (EV) with a focus on 1q23.3.
Saliby R, Semaan K, Epstein I, Liria S, Dall C, Saad E, Eid M, Canniff J, Kwak L, Berg S, Mantia C, McGregor B, Braun D, CHOUEIRI T, Bellmunt J. Characterizing genomic alterations in patients with metastatic urothelial carcinoma (mUC) treated with enfortumab-vedotin (EV) with a focus on 1q23.3. Journal Of Clinical Oncology 2024, 42: e16570-e16570. DOI: 10.1200/jco.2024.42.16_suppl.e16570.Peer-Reviewed Original ResearchMetastatic urothelial carcinomaToxicity-free survivalProgression-free survivalEnfortumab vedotinOverall survivalProgressive diseaseTwo-copy deletionGenomic alterationsClinical outcomesAssociation of genomic alterationsNumerically longer OSDana-Farber Cancer InstituteLog-rank testFisher's exact testUnivariate Cox regressionAdvanced UCLonger OSUrothelial carcinomaSomatic alterationsDana-FarberExact testCox regressionEV efficacyPatientsImprove outcomesMolecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC).
Zaemes J, Hugaboom M, Shah V, Haas N, McDermott D, Jegede O, Bilen M, Stein M, Sosman J, Alter R, Plimack E, Hurwitz M, Wu C, Einstein D, Hammers H, Signoretti S, West D, Denize T, Atkins M, Braun D. Molecular analysis of the HCRN GU16-260-Cohort A phase II study of first-line (1L) nivolumab (nivo) and salvage nivo + ipilimumab (ipi) in patients (pts) with advanced clear cell renal cell carcinoma (accRCC). Journal Of Clinical Oncology 2024, 42: 4546-4546. DOI: 10.1200/jco.2024.42.16_suppl.4546.Peer-Reviewed Original ResearchObjective response rateImmune checkpoint blockadeProgression-free survivalProgressive diseaseAnti-VEGFOverall survivalAssociated with higher progression-free survivalTumor samplesAdvanced clear cell renal cell carcinomaCombined immune checkpoint blockadeHigher progression-free survivalIncreased PFSImmune checkpoint blockade therapyShorter progression-free survivalClear cell renal cell carcinomaAnti-VEGF therapyCell renal cell carcinomaWeeks of therapyRenal cell carcinomaBiomarkers of efficacyFFPE tumor samplesNIVO monotherapyCheckpoint blockadeDecreased OSProspective trialsTumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial.
El Ahmar N, Matar S, Jegede O, Nabil Laimon Y, Savla V, Bagheri Sheshdeh A, Denize T, Mohanna R, Choueiri T, Catalano P, Braun D, Haas N, Hammers H, Bilen M, Stein M, Sosman J, Wu C, McDermott D, Atkins M, Signoretti S. Tumor-infiltrating CD163-positive macrophages and clinical outcomes to first-line nivolumab therapy in patients with advanced clear cell renal cell carcinoma (ccRCC) enrolled in the HCRN GU16-260 trial. Journal Of Clinical Oncology 2024, 42: 448-448. DOI: 10.1200/jco.2024.42.4_suppl.448.Peer-Reviewed Original ResearchClear cell renal cell carcinomaProgression-free survivalCD163-positive macrophagesTumor areaNivolumab therapyDensity of CD163-positive cellsCD8+ T cell infiltrationAssociated with progression-free survivalResponse to immune checkpoint inhibitorsAdvanced clear cell renal cell carcinomaAnti-PD-1 therapyTumor-infiltrating myeloid cellsProgression-free survival endpointAssociated with poor outcomesFirst-line nivolumabImmune checkpoint inhibitorsMyeloid cell infiltrationT cell infiltrationCell renal cell carcinomaRenal cell carcinomaPrimary tumor tissuesCD163-positive cellsCheckpoint inhibitorsCox proportional hazardsCell carcinomaAdvanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587).
Serzan M, Jegede O, Bilen M, Braun D, Einstein D, Haas N, Hammers H, King J, Runcie K, Sosman J, Sternberg C, Yang Y, Choueiri T, Signoretti S, Atkins M. Advanced renal cell cancer combination immunotherapy clinical trial (ARCITECT; HCRN GU 22-587). Journal Of Clinical Oncology 2024, 42: tps492-tps492. DOI: 10.1200/jco.2024.42.4_suppl.tps492.Peer-Reviewed Original ResearchTyrosine kinase inhibitorsArm BArm APrimary endpointRate of immune-related adverse eventsMetastatic clear cell renal cell carcinomaImmune-related adverse eventsMolecular predictors of responseVEGF receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsEnhance T cell primingOne-sided significance levelClear cell renal cell carcinomaAnti-PD1 inhibitorsIMDC risk groupsTreatment free intervalProgression-free survivalT cell primingTreatment-free survivalCell renal cell carcinomaSubpopulations of TregsFirst-line treatmentRenal cell carcinomaPredictors of responseAnti-tumor activityPD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients.
Denize T, Jegede O, Matar S, El Ahmar N, West D, Walton E, Bagheri A, Savla V, Nabil Laimon Y, Gupta S, Vemula S, Braun D, Burke K, Catalano P, Freeman G, Motzer R, Atkins M, McDermott D, Sharpe A, Choueiri T, Signoretti S. PD-1 Expression on Intratumoral Regulatory T Cells Is Associated with Lack of Benefit from Anti-PD-1 Therapy in Metastatic Clear-Cell Renal Cell Carcinoma Patients. Clinical Cancer Research 2024, 30: 803-813. PMID: 38060202, PMCID: PMC10922154, DOI: 10.1158/1078-0432.ccr-23-2274.Peer-Reviewed Original ResearchPD-1 expressionObjective response rateProgression-free survivalLow objective response rateShorter progression-free survivalPD-1 blockadeRegulatory T cellsShorter overall survivalOverall survivalPD-1Nivolumab armT cellsMetastatic clear-cell renal cell carcinoma patientsMetastatic clear cell renal cell carcinomaAnti-PD-1 therapyIntratumoral regulatory T cellsClear cell renal cell carcinoma patientsRenal cell carcinoma patientsClear cell renal cell carcinomaPD-1 inhibitorsPD-1 inhibitionCell carcinoma patientsCell renal cell carcinomaExpression of CD8Tumor-infiltrating Tregs
2023
Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma
Choueiri T, Donahue A, Braun D, Rini B, Powles T, Haanen J, Larkin J, Mu X, Pu J, Teresi R, di Pietro A, Robbins P, Motzer R. Integrative Analyses of Tumor and Peripheral Biomarkers in the Treatment of Advanced Renal Cell Carcinoma. Cancer Discovery 2023, 14: of1-of18. PMID: 38385846, PMCID: PMC10905671, DOI: 10.1158/2159-8290.cd-23-0680.Peer-Reviewed Original ResearchProlonged progression-free survivalT cellsTreatment of advanced renal cell carcinomaImmunomodulatory mechanismsAdvanced renal cell carcinomaBaseline tumor tissuePD-L1 inhibitorsProgression-free survivalContribution of tumor biologyT cell numbersTumors harboring mutationsTumor molecular subtypeLongitudinal blood samplesRenal cell carcinomaCell-mediated mechanismsAnalysis of tumorsInnate immune subsetsJAVELIN RenalSunitinib armPD-L1Immune subsetsCell carcinomaMolecular subtypesTumor biologyTreatment regimensA Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma
McKay R, Leucht K, Xie W, Jegede O, Braun D, Atkins M, Grimm M, Choueiri T. A Pooled Analysis of 3 Phase II Trials of Salvage Nivolumab/Ipilimumab After Nivolumab in Renal Cell Carcinoma. The Oncologist 2023, 29: 324-331. PMID: 37950901, PMCID: PMC10994246, DOI: 10.1093/oncolo/oyad298.Peer-Reviewed Original ResearchObjective response rateClear cell renal cell carcinomaRenal cell carcinomaProgression-free survivalCell renal cell carcinomaAdvanced clear cell renal cell carcinomaOverall survivalCell carcinomaPooled analysisSix-month progression-free survivalBest objective response rateActivity of nivolumabInitiation of nivolumabNivolumab/ipilimumabPoor-risk diseasePhase II trialEligible patientsII trialObjective responsePrior immunotherapyImproved survivalRisk diseaseClinical trialsIpilimumabNivolumabCirculating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma
Saliby R, Zarif T, Bakouny Z, Shah V, Xie W, Flippot R, Denize T, Kane M, Madsen K, Ficial M, Hirsch L, Wei X, Steinharter J, Harshman L, Vaishampayan U, Severgnini M, McDermott D, Lee G, Xu W, Van Allen E, McGregor B, Signoretti S, Choueiri T, McKay R, Braun D. Circulating and Intratumoral Immune Determinants of Response to Atezolizumab plus Bevacizumab in Patients with Variant Histology or Sarcomatoid Renal Cell Carcinoma. Cancer Immunology Research 2023, 11: 1114-1124. PMID: 37279009, PMCID: PMC10526700, DOI: 10.1158/2326-6066.cir-22-0996.Peer-Reviewed Original ResearchConceptsRenal cell carcinomaT cellsWorse PFSImmunotherapy responseCell carcinomaPeripheral immune cell populationsWorse progression-free survivalSarcomatoid renal cell carcinomaPhase II clinical trialImmunotherapy-based combinationsValue of tumourPoor-risk patientsProgression-free survivalImmune cell populationsVascular endothelial growth factorKidney cancer diagnosisEndothelial growth factorFuture biomarker studiesLack of responseInflammatory modulesExhausted CD8Variant histologyOverall survivalPD-L1Sarcomatoid differentiationPhase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B)
Atkins M, Jegede O, Haas N, McDermott D, Bilen M, Stein M, Sosman J, Alter R, Plimack E, Ornstein M, Hurwitz M, Peace D, Signoretti S, Denize T, Cimadamore A, Wu C, Braun D, Einstein D, Catalano P, Hammers H. Phase II study of nivolumab and salvage nivolumab/ipilimumab in treatment-naïve patients with advanced non-clear cell renal cell carcinoma (HCRN GU16-260-Cohort B). Journal For ImmunoTherapy Of Cancer 2023, 11: e004780. PMID: 36948504, PMCID: PMC10040058, DOI: 10.1136/jitc-2022-004780.Peer-Reviewed Original ResearchConceptsNivolumab/ipilimumabObjective response rateNon-clear cell renal cell carcinomaTreatment-naïve patientsCell renal cell carcinomaProgressive diseaseRenal cell carcinomaNivolumab monotherapyStable diseaseCell carcinomaAdvanced non-clear cell renal cell carcinomaMedian progression-free survivalTreatment-related adverse eventsDeath ligand 1 (PD-L1) expressionLigand 1 expressionPhase II studyProgression-free survivalWeeks of treatmentSymptomatic disease progressionEligible patientsSalvage therapyB patientsII studySalvage treatmentSarcomatoid features
2022
Transcriptomic Correlates of Tumor Cell PD-L1 Expression and Response to Nivolumab Monotherapy in Metastatic Clear Cell Renal Cell Carcinoma.
Denize T, Hou Y, Pignon J, Walton E, West D, Freeman G, Braun D, Wu C, Gupta S, Motzer R, Atkins M, McDermott D, Choueiri T, Shukla S, Signoretti S. Transcriptomic Correlates of Tumor Cell PD-L1 Expression and Response to Nivolumab Monotherapy in Metastatic Clear Cell Renal Cell Carcinoma. Clinical Cancer Research 2022, 28: 4045-4055. PMID: 35802667, PMCID: PMC9481706, DOI: 10.1158/1078-0432.ccr-22-0923.Peer-Reviewed Original ResearchConceptsTC PD-L1 expressionClear cell renal cell carcinomaPD-L1 expressionMetastatic clear cell renal cell carcinomaCell renal cell carcinomaRenal cell carcinomaProliferation-related pathwaysCell proliferation-related pathwaysClinical outcomesTumor cellsCell carcinomaTumor cell PD-L1 expressionAnti-PD-1 monotherapyPD-L1 positive tumorsHigher objective response rateLonger progression-free survivalTumor-infiltrating immune cellsTC PD-L1Objective response ratePD-L1 statusProgression-free survivalT-cell activation signaturesCheckMate 025 trialNivolumab monotherapyPD-L1