2023
Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy
Martinez-Morilla S, Moutafi M, Fernandez A, Jessel S, Divakar P, Wong P, Garcia-Milian R, Schalper K, Kluger H, Rimm D. Digital spatial profiling of melanoma shows CD95 expression in immune cells is associated with resistance to immunotherapy. OncoImmunology 2023, 12: 2260618. PMID: 37781235, PMCID: PMC10540659, DOI: 10.1080/2162402x.2023.2260618.Peer-Reviewed Original ResearchConceptsDigital spatial profilingImmune checkpoint inhibitor therapyShorter progression-free survivalQuantitative immunofluorescenceCheckpoint inhibitor therapyProgression-free survivalMetastatic melanoma patientsPre-treatment specimensIndependent validation cohortMetastatic melanoma casesAdjuvant settingNanoString GeoMxMultivariable adjustmentAdverse eventsImmunotherapy cohortInhibitor therapyPD-L1Immune markersMelanoma patientsUnivariable analysisValidation cohortImmune cellsMelanoma casesMultiplex immunofluorescenceCD95 expressionScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis
Mann J, Lucca L, Austin M, Merkin R, Robert M, Al Bawardy B, Raddassi K, Aizenbud L, Joshi N, Hafler D, Abraham C, Herold K, Kluger H. ScRNA-seq defines dynamic T-cell subsets in longitudinal colon and peripheral blood samples in immune checkpoint inhibitor-induced colitis. Journal For ImmunoTherapy Of Cancer 2023, 11: e007358. PMID: 37586769, PMCID: PMC10432652, DOI: 10.1136/jitc-2023-007358.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsT cell subsetsCheckpoint inhibitorsImmune environmentImmune checkpoint inhibitor-induced colitisCheckpoint inhibitor-induced colitisPeripheral immune environmentsStages of colitisTreatment of colitisMerkel cell carcinomaT cell populationsPeripheral blood samplesCourse of progressionT cell receptorMultiple tumor typesAlternative cancer therapyCommon toxicitiesICI colitisTreatment discontinuationAdverse eventsBiologic therapyImmune suppressionCell carcinomaColitisBlood samplesA 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 ResearchConceptsObjective 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 cellsPeripheral blood immune cell and cytokine profiling of patients receiving corticosteroids for immune checkpoint inhibitor-related adverse events: Steroid dose and duration.
Merkin R, Schoenfeld D, Djureinovic D, Austin M, Wang M, Qu R, Zhang L, Mann J, Wei W, Sun L, Aizenbud L, Destina J, Kluger H. Peripheral blood immune cell and cytokine profiling of patients receiving corticosteroids for immune checkpoint inhibitor-related adverse events: Steroid dose and duration. Journal Of Clinical Oncology 2023, 41: e14694-e14694. DOI: 10.1200/jco.2023.41.16_suppl.e14694.Peer-Reviewed Original ResearchImmune-related adverse eventsImmune checkpoint inhibitorsSevere immune-related adverse eventsPeripheral blood immune cellsBlood immune cellsSteroid therapyDose levelsSteroid taperAdverse eventsIL-6Immune cellsImmune checkpoint inhibitor-related adverse eventsSeverity of irAEsMultiple immune-related adverse eventsAnti-PD-1 therapyT effector memory cellsPeripheral blood mononuclear cellsYale Cancer CenterSerum cytokine concentrationsEffector memory cellsPathogenic T cellsBlood mononuclear cellsConcentrations of TNFαBiomarkers of responseT cell subtypesGermline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors
Caulfield J, Aizenbud L, Perdigoto A, Meffre E, Jilaveanu L, Michalek D, Rich S, Aizenbud Y, Adeniran A, Herold K, Austin M, Kluger H. Germline genetic variants are associated with development of insulin-dependent diabetes in cancer patients treated with immune checkpoint inhibitors. Journal For ImmunoTherapy Of Cancer 2023, 11: e006570. PMID: 36898736, PMCID: PMC10008335, DOI: 10.1136/jitc-2022-006570.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsInsulin-dependent diabetesImmune checkpoint inhibitorsType 1 diabetesCheckpoint inhibitorsControl patientsSevere immune-related adverse eventsImmunotherapy-treated patientsCheckpoint inhibitor therapyIslet cell destructionPotential predictive biomarkersIslet cell functionWhole-exome sequencingICI exposureAdverse eventsGermline genetic variantsInhibitor therapyPatient selectionTreatment regimensCancer patientsPredictive biomarkersGeneral populationPatientsDiabetesSame drugOutcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma
Dizman N, Austin M, Considine B, Jessel S, Schoenfeld D, Merl M, Hurwitz M, Sznol M, Kluger H. Outcomes With Combination Pembrolizumab and Axitinib in Second and Further Line Treatment of Metastatic Renal Cell Carcinoma. Clinical Genitourinary Cancer 2023, 21: 221-229. PMID: 36681606, DOI: 10.1016/j.clgc.2023.01.002.Peer-Reviewed Original ResearchConceptsMetastatic renal cell carcinomaPembrolizumab/axitinibObjective response rateProgression-free survivalImmune checkpoint inhibitorsMedian progression-free survivalAdverse eventsRenal cell carcinomaCell carcinomaClear cell metastatic renal cell carcinomaVascular endothelial growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsCombination immune checkpoint inhibitorsGrade 5 adverse eventsPrior immune checkpoint inhibitorsSuperior progression-free survivalReceptor tyrosine kinase inhibitorsYale-New Haven HospitalFurther-line treatmentNivolumab/ipilimumabRECIST 1.1 criteriaResponse-evaluable patientsDisease control rateSecond-line therapyFirst-line treatment
2022
Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab
Dey A, Austin M, Kluger H, Trunova N, Mann H, Shire N, Morgan C, Zhou D, Mugundu G. Association between immune-mediated adverse events and efficacy in metastatic non-small-cell lung cancer patients treated with durvalumab and tremelimumab. Frontiers In Immunology 2022, 13: 1026964. PMID: 36405729, PMCID: PMC9670978, DOI: 10.3389/fimmu.2022.1026964.Peer-Reviewed Original ResearchConceptsCell lung cancer patientsLung cancer patientsAdverse eventsBaseline characteristicsOverall survivalCancer patientsMultivariate Cox proportional hazards modelImmune-mediated adverse eventsCox proportional hazards modelIndividual patient-level dataImmune checkpoint inhibitorsImproved overall survivalEfficacy of immunotherapyPatient demographic featuresOptimal clinical benefitPatient-level dataProportional hazards modelCheckpoint inhibitorsCombination armLaboratory featuresSteroid treatmentClinical benefitPatient survivalPatient populationHigher oddsFRACTION-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 ResearchConceptsAdvanced 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 eventsClinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting.
Kahn A, Perry C, Etts K, Kluger H, Sznol M. Clinical predictors of longer survival in patients with BRAFV600-mutated metastatic melanoma receiving immunotherapy prior to BRAF/MEK inhibition in the metastatic setting. Journal Of Clinical Oncology 2022, 40: 9555-9555. DOI: 10.1200/jco.2022.40.16_suppl.9555.Peer-Reviewed Original ResearchBRAF/MEKiFirst-line immunotherapyBRAF/MEK inhibitionBRAF V600Metastatic melanomaLonger survivalAdverse eventsMedian durationMost patientsBone metastasesClinical predictorsDisease progressionMEK inhibitionAdvanced BRAF V600ECOG PS 0Median ECOG PSFirst-line settingKaplan-Meier methodMost common sitePredictors of survivalECOG PSMedian LDHData cutoffMetastatic settingMedian survivalAutoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review
Heng JS, Kim JM, Jones DK, Stoessel KM, Weiss SA, Sznol M, Kluger HM, Walter SD, Silverstein NA, Pointdujour-Lim R. Autoimmune retinopathy with associated anti-retinal antibodies as a potential immune-related adverse event associated with immunotherapy in patients with advanced cutaneous melanoma: case series and systematic review. BMJ Open Ophthalmology 2022, 7: e000889. PMID: 35047671, PMCID: PMC8724805, DOI: 10.1136/bmjophth-2021-000889.Peer-Reviewed Original ResearchConceptsAdvanced cutaneous melanomaAnti-retinal antibodiesImmune-related adverse eventsAutoimmune retinopathyCutaneous melanomaNivolumab immunotherapySystematic reviewAdverse eventsMucosal melanomaAcute exudative polymorphous vitelliform maculopathyPotential immune-related adverse eventsBilateral visual field lossNew visual symptomsImmune checkpoint inhibitionRetrospective chart reviewCutaneous melanoma patientsVaried clinical manifestationsVisual field lossComplete ophthalmic examinationScreening of patientsMeta-Analyses (PRISMA) guidelinesPreferred Reporting ItemsVitelliform maculopathyChart reviewFunduscopic changes
2021
A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1
Weiss SA, Djureinovic D, Jessel S, Krykbaeva I, Zhang L, Jilaveanu L, Ralabate A, Johnson B, Levit NS, Anderson G, Zelterman D, Wei W, Mahajan A, Trifan O, Bosenberg M, Kaech SM, Perry CJ, Damsky W, Gettinger S, Sznol M, Hurwitz M, Kluger HM. A Phase I Study of APX005M and Cabiralizumab with or without Nivolumab in Patients with Melanoma, Kidney Cancer, or Non–Small Cell Lung Cancer Resistant to Anti-PD-1/PD-L1. Clinical Cancer Research 2021, 27: 4757-4767. PMID: 34140403, PMCID: PMC9236708, DOI: 10.1158/1078-0432.ccr-21-0903.Peer-Reviewed Original ResearchConceptsAnti-PD-1/PD-L1Non-small cell lung cancerCell lung cancerRenal cell carcinomaPD-L1Lung cancerDisease progressionCommon treatment-related adverse eventsPD-1/PD-L1 inhibitorsTreatment-related adverse eventsPhase 2 doseSubstantial clinical challengeUnconfirmed partial responseDose-limiting toxicityPD-L1 inhibitorsPhase I trialDose-escalation designPro-inflammatory cytokinesMultiple tumor typesAsymptomatic elevationStable diseaseIntolerable toxicityAdverse eventsMedian durationPartial responseA phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO).
Dumbrava E, Dougan M, Gupta S, Cappelli L, Katsumoto T, Rahma O, Painter J, Wang Y, Suarez-Almazor M, Reid P, Wesley S, Hafler D, Bingham C, Warner B, Chung L, Ott P, Kluger H, Khosroshahi A, Tawbi H, Sharon E. A phase 1b study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO). Journal Of Clinical Oncology 2021, 39: tps2676-tps2676. DOI: 10.1200/jco.2021.39.15_suppl.tps2676.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsDisease-specific cohortsAutoimmune disordersAdverse eventsAdvanced malignanciesAnti-PD-1/PD-L1 antibodiesPre-existing autoimmune disordersAnti-PD1 monoclonal antibodiesImpact of nivolumabPhase 1b studyKey secondary endpointPhase Ib studySerious adverse eventsDose-limiting toxicityInflammatory bowel diseasePD-L1 antibodiesSeverity IndexSystemic lupus erythematosusDysfunctional immune systemClinical Trials NetworkTissue-based biomarkersSpecific eligibility criteriaICI therapyPrimary endpointSecondary endpointsLifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma
Sarnaik AA, Hamid O, Khushalani NI, Lewis KD, Medina T, Kluger HM, Thomas SS, Domingo-Musibay E, Pavlick AC, Whitman ED, Martin-Algarra S, Corrie P, Curti BD, Oláh J, Lutzky J, Weber JS, Larkin JMG, Shi W, Takamura T, Jagasia M, Qin H, Wu X, Chartier C, Finckenstein F, Fardis M, Kirkwood JM, Chesney JA. Lifileucel, a Tumor-Infiltrating Lymphocyte Therapy, in Metastatic Melanoma. Journal Of Clinical Oncology 2021, 39: 2656-2666. PMID: 33979178, PMCID: PMC8376325, DOI: 10.1200/jco.21.00612.Peer-Reviewed Original ResearchConceptsObjective response rateDisease control rateAdvanced melanomaPrimary refractoryControl rateMetastatic melanomaTreatment optionsInterleukin-2Investigator-assessed objective response rateHigh-dose interleukin-2Tumor-Infiltrating Lymphocyte TherapyImmune checkpoint inhibitorsPrimary end pointTumor-infiltrating lymphocytesEffective treatment optionLimited treatment optionsAdoptive cell therapyMajor unmet needLymphodepletion regimenPrior therapyCheckpoint inhibitorsAdverse eventsDurable responsesMedian durationPartial responseImmune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis
Tarhini AA, Kang N, Lee SJ, Hodi FS, Cohen GI, Hamid O, Hutchins LF, Sosman JA, Kluger HM, Eroglu Z, Koon HB, Lawrence DP, Kendra KL, Minor DR, Lee CB, Albertini MR, Flaherty LE, Petrella TM, Streicher H, Sondak VK, Kirkwood JM. Immune adverse events (irAEs) with adjuvant ipilimumab in melanoma, use of immunosuppressants and association with outcome: ECOG-ACRIN E1609 study analysis. Journal For ImmunoTherapy Of Cancer 2021, 9: e002535. PMID: 33963015, PMCID: PMC8108687, DOI: 10.1136/jitc-2021-002535.Peer-Reviewed Original ResearchConceptsImmune-related adverse eventsRelapse-free survivalUse of immunosuppressantsAdjuvant ipilimumabGrade 3Grade 1Significant associationAdverse eventsPrognostic factorsSpecific immune-related adverse eventsTerms of RFSEndocrine immune-related adverse eventsBetter relapse-free survivalHigh-dose corticosteroidsImmune adverse eventsHigh-risk melanomaIndependent prognostic factorOverall survival outcomesDose corticosteroidsImmunosuppressant useRFS benefitsImproved OSBetter prognosisAdjuvant useSurvival outcomesAdverse events induced by immune checkpoint inhibitors
Perdigoto AL, Kluger H, Herold KC. Adverse events induced by immune checkpoint inhibitors. Current Opinion In Immunology 2021, 69: 29-38. PMID: 33640598, PMCID: PMC8122053, DOI: 10.1016/j.coi.2021.02.002.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityCytotoxicity, ImmunologicDrug-Related Side Effects and Adverse ReactionsGene-Environment InteractionGenetic Predisposition to DiseaseHumansImmune Checkpoint InhibitorsImmunotherapyLymphocyte ActivationNeoplasmsT-LymphocytesConceptsImmune checkpoint inhibitorsCheckpoint inhibitorsAdverse eventsT cellsImmune related adverse eventsEmergence of autoantibodiesRelated adverse eventsAnti-tumor responseAutoreactive T cellsActivated T cellsAutoimmune mechanismsTreatment of cancerAutoimmune diseasesInflammatory responsePredictive valueHost factorsToxic effectsInhibitorsDirect effectOngoing investigationAutoantibodiesCellsAutoimmunityPathogenesisCancerMycophenolate as Primary Treatment for Immune Checkpoint Inhibitor Induced Acute Kidney Injury in a Patient with Concurrent Immunotherapy-Associated Diabetes: A Case Report.
Jessel S, Austin M, Kluger HM. Mycophenolate as Primary Treatment for Immune Checkpoint Inhibitor Induced Acute Kidney Injury in a Patient with Concurrent Immunotherapy-Associated Diabetes: A Case Report. Clinical Oncology Case Reports 2021, 4 PMID: 33763663, PMCID: PMC7985664.Peer-Reviewed Original ResearchAcute kidney injuryImmune checkpoint inhibitorsKidney injuryCheckpoint inhibitorsT cellsImmune-related adverse eventsCycles of nivolumabEffective frontline therapyAggressive fluid resuscitationSteroid-sparing agentRegulatory T cellsInitiation of insulinT cell responsesCytotoxic T cellsMycophenolate mofetilAdverse eventsFrontline therapyRenal functionComplete responseFluid resuscitationKidney functionCase reportMetastatic melanomaPrimary treatmentTumor types
2020
Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors.
Perdigoto AL, Tran T, Patel N, Clark P, Patell K, Stamatouli AM, Reddy V, Clune J, Herold KC, Robert ME, Kluger HM. Elective Colectomy in a Patient with Active Ulcerative Colitis and Metastatic Melanoma Enabling Successful Treatment with Immune Checkpoint Inhibitors. Clinical Oncology Case Reports 2020, 3 PMID: 33778814, PMCID: PMC7993656.Peer-Reviewed Original ResearchCheckpoint inhibitor therapyElective colectomyUlcerative colitisInhibitor therapyMetastatic melanomaImmune-related adverse eventsExcellent tumor responseImmune checkpoint inhibitorsSevere ulcerative colitisActive ulcerative colitisCheckpoint inhibitor immunotherapyCheckpoint inhibitor treatmentInflammatory bowel diseaseEffective treatment optionBenefits of treatmentImmune system activationTumor cell destructionCheckpoint inhibitorsAdvanced malignanciesAdverse eventsSelect patientsBowel diseaseAutoimmune diseasesTreatment optionsTumor responseFRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC).
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, Gold D, Motzer R, Escudier B. FRACTION-RCC: Innovative, high-throughput assessment of nivolumab + ipilimumab for treatment-refractory advanced renal cell carcinoma (aRCC). Journal Of Clinical Oncology 2020, 38: 5007-5007. DOI: 10.1200/jco.2020.38.15_suppl.5007.Peer-Reviewed Original ResearchAdvanced renal cell carcinomaDuration of responseTreatment-related adverse eventsAdverse eventsPartial responsePrior linesGrade treatment-related adverse eventsImmune-mediated adverse eventsProgression-free survival probabilityDurable partial responseTreatment-related deathsCheckpoint inhibitor therapyObjective response rateCheckpoint inhibitor treatmentRenal cell carcinomaCombination nivolumabInvestigational combinationPrior TKICheckpoint inhibitorsPrimary endpointWeek 24Complete responseInhibitor therapyTKI therapyPrior progressionA phase Ib study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO).
Ileana Dumbrava E, Suarez-Almazor M, Painter J, Johanns T, Dougan M, Cappelli L, Bingham C, Wang Y, Gupta S, Warner B, Rahma O, Naidoo J, Ott P, Hafler D, Kluger H, Khosroshahi A, Katsumoto T, Kummar S, Sharon E, Tawbi H. A phase Ib study of nivolumab in patients with autoimmune disorders and advanced malignancies (AIM-NIVO). Journal Of Clinical Oncology 2020, 38: tps3158-tps3158. DOI: 10.1200/jco.2020.38.15_suppl.tps3158.Peer-Reviewed Original ResearchImmune checkpoint inhibitorsAnti-PD-1/PD-L1 antibodiesPhase Ib studyPD-L1 antibodiesAutoimmune disordersAdvanced malignanciesDisease-specific cohortsAdverse eventsIb studyPre-existing autoimmune disordersImpact of nivolumabRisk of flareKey secondary endpointSerious adverse eventsBest objective responseDose-limiting toxicityInflammatory bowel diseaseSeverity IndexSystemic lupus erythematosusAnti-PD1 antibodyClinical Trials NetworkTissue-based biomarkersSpecific eligibility criteriaICI therapyCheckpoint inhibitorsPembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial
Goldberg SB, Schalper KA, Gettinger SN, Mahajan A, Herbst RS, Chiang AC, Lilenbaum R, Wilson FH, Omay SB, Yu JB, Jilaveanu L, Tran T, Pavlik K, Rowen E, Gerrish H, Komlo A, Gupta R, Wyatt H, Ribeiro M, Kluger Y, Zhou G, Wei W, Chiang VL, Kluger HM. Pembrolizumab for management of patients with NSCLC and brain metastases: long-term results and biomarker analysis from a non-randomised, open-label, phase 2 trial. The Lancet Oncology 2020, 21: 655-663. PMID: 32251621, PMCID: PMC7380514, DOI: 10.1016/s1470-2045(20)30111-x.Peer-Reviewed Original ResearchConceptsBrain metastasis responseYale Cancer CenterPD-L1 expressionPhase 2 trialUntreated brain metastasesBrain metastasesAdrenal insufficiencyAdverse eventsMetastasis responseCNS diseaseCancer CenterCohort 2Cohort 1Eastern Cooperative Oncology Group performance statusTreatment-related serious adverse eventsModified Response Evaluation CriteriaStage IV NSCLCTreatment-related deathsAcute kidney injuryPD-1 blockadeSerious adverse eventsSolid Tumors criteriaPhase 2 studyProportion of patientsResponse Evaluation Criteria