2015
Objective Measurement and Clinical Significance of TILs in Non–Small Cell Lung Cancer
Schalper KA, Brown J, Carvajal-Hausdorf D, McLaughlin J, Velcheti V, Syrigos KN, Herbst RS, Rimm DL. Objective Measurement and Clinical Significance of TILs in Non–Small Cell Lung Cancer. Journal Of The National Cancer Institute 2015, 107: dju435. PMID: 25650315, PMCID: PMC4565530, DOI: 10.1093/jnci/dju435.Peer-Reviewed Original ResearchMeSH KeywordsAntigens, CD20Carcinoma, Non-Small-Cell LungCD3 ComplexCD8 AntigensConfounding Factors, EpidemiologicFluorescent DyesHumansIndolesKaplan-Meier EstimateLung NeoplasmsLymphocytes, Tumor-InfiltratingMicroscopy, FluorescencePredictive Value of TestsRetrospective StudiesT-Lymphocytes, CytotoxicConceptsTumor-infiltrating lymphocytesLevels of CD3TIL subtypesMultivariable analysisTumor sizeLonger survivalAssociation of TILsLevel of TILsNon-small cell lung cancerNon-small cell lung cancer samplesLocal immune effectsClinico-pathologic characteristicsImmune checkpoint inhibitorsCell lung cancerCell lung cancer samplesLung cancer samplesDifferent tumor compartmentsObjective measurementsElevated CD3High CD20TIL markersTIL subpopulationsCheckpoint inhibitorsSmoking historyHistology type
2012
Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC): Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study)
Morgensztern D, Herbst RS. Multitargeted Tyrosine Kinase Inhibitors in Unselected Patients With Advanced Non–Small-Cell Lung Cancer (NSCLC): Impressions From MONET (the Motesanib NSCLC Efficacy and Tolerability Study). Journal Of Clinical Oncology 2012, 30: 2805-2808. PMID: 22753916, DOI: 10.1200/jco.2012.42.7260.Peer-Reviewed Original Research
2008
Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer
Oh Y, Herbst RS, Burris H, Cleverly A, Musib L, Lahn M, Bepler G. Enzastaurin, an Oral Serine/Threonine Kinase Inhibitor, As Second- or Third-Line Therapy of Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2008, 26: 1135-1141. PMID: 18309949, DOI: 10.1200/jco.2007.14.3685.Peer-Reviewed Original ResearchConceptsOral serine/threonine kinase inhibitorCell lung cancerPFS ratesMetastatic NSCLCOverall survivalLung cancerEastern Cooperative Oncology Group performance statusSix-month PFS rateProgression-free survival ratesEpidermal growth factor inhibitorsSerine/threonine kinase inhibitorProtein kinase CKinase inhibitorsPrior systemic regimensMedian overall survivalPrimary end pointThird-line therapyPhase II trialGrowth factor inhibitorsTumor cell apoptosisMedian PFSStable diseaseCommon toxicitiesPrior therapySystemic regimens
2007
Enzastaurin, a Protein Kinase Cβ–Selective Inhibitor, and Its Potential Application as an Anticancer Agent in Lung Cancer
Herbst RS, Oh Y, Wagle A, Lahn M. Enzastaurin, a Protein Kinase Cβ–Selective Inhibitor, and Its Potential Application as an Anticancer Agent in Lung Cancer. Clinical Cancer Research 2007, 13: 4641s-4646s. PMID: 17671157, DOI: 10.1158/1078-0432.ccr-07-0538.Peer-Reviewed Original ResearchConceptsSerine/threonine kinase inhibitorLung cancerOral serine/threonine kinase inhibitorProtein kinase CFavorable safety profileCurrent phase IKinase CTumor cell apoptosisAkt pathwayClinical findingsSafety profilePKC inhibitorTumor-induced angiogenesisPreclinical experienceCell apoptosisEnzastaurinKinase inhibitorsPhase ICancerSafety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors
Rosen LS, Kurzrock R, Mulay M, Van Vugt A, Purdom M, Ng C, Silverman J, Koutsoukos A, Sun YN, Bass MB, Xu RY, Polverino A, Wiezorek JS, Chang DD, Benjamin R, Herbst RS. Safety, Pharmacokinetics, and Efficacy of AMG 706, an Oral Multikinase Inhibitor, in Patients With Advanced Solid Tumors. Journal Of Clinical Oncology 2007, 25: 2369-2376. PMID: 17557949, DOI: 10.1200/jco.2006.07.8170.Peer-Reviewed Original ResearchConceptsMaximum-tolerated doseAMG 706Advanced solid tumorsSolid tumorsAdvanced refractory solid tumorsRefractory advanced solid tumorsVascular endothelial growth factor receptor 1Frequent adverse eventsRefractory solid tumorsDose-proportional mannerFactor receptorDose-finding studyOral multikinase inhibitorStudy of patientsPlacental growth factorGrowth factor receptor 1Platelet-derived growth factor receptorFactor receptor 1Stem cell factor receptorGrowth factor receptorStable diseaseKinase domain receptorAdverse eventsPartial responseProgressive disease
2006
Toxicities of Antiangiogenic Therapy in Non–Small-Cell Lung Cancer
Herbst RS. Toxicities of Antiangiogenic Therapy in Non–Small-Cell Lung Cancer. Clinical Lung Cancer 2006, 8: s23-s30. PMID: 17239287, DOI: 10.3816/clc.2006.s.010.Peer-Reviewed Original ResearchMeSH KeywordsAngiogenesis InhibitorsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBenzenesulfonatesBevacizumabCarcinoma, Non-Small-Cell LungCarcinoma, Squamous CellHumansIndolesLung NeoplasmsNiacinamidePhenylurea CompoundsPiperidinesPyridinesPyrrolesQuinazolinesSorafenibSunitinibVascular Endothelial Growth FactorsConceptsAnti-VEGF antibodyCell lung cancerVascular endothelial growth factorAntiangiogenic agentsOverall survivalLung cancerPhase III pivotal trialsClass-effect toxicitiesFirst-line chemotherapyAdverse event profileSquamous cell histologyChemotherapy-associated toxicityVEGFR tyrosine kinaseTyrosine kinase inhibitorsEndothelial growth factorMetastatic NSCLCThromboembolic eventsCell histologyPivotal trialsEvent profileRisk factorsVEGF receptor activityAntiangiogenic therapySmall molecule inhibitorsTumor typesPhase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer
Carducci MA, Musib L, Kies MS, Pili R, Truong M, Brahmer JR, Cole P, Sullivan R, Riddle J, Schmidt J, Enas N, Sinha V, Thornton DE, Herbst RS. Phase I Dose Escalation and Pharmacokinetic Study of Enzastaurin, an Oral Protein Kinase C Beta Inhibitor, in Patients With Advanced Cancer. Journal Of Clinical Oncology 2006, 24: 4092-4099. PMID: 16943527, DOI: 10.1200/jco.2005.05.3447.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAntineoplastic AgentsDose-Response Relationship, DrugDrug Administration ScheduleFemaleFlow CytometryGene Expression Regulation, EnzymologicGene Expression Regulation, NeoplasticHumansIndolesMaleMiddle AgedNeoplasmsProtein Kinase CProtein Kinase C betaProtein Kinase InhibitorsConceptsMaximum-tolerated doseProtein kinase C beta inhibitorStable diseaseAdvanced cancerEastern Cooperative Oncology Group performance statusSignificant grade 3/4 toxicityBeta inhibitorGrade 3/4 toxicitiesPhase II dosePhase II trialDose-limiting toxicityYears of ageExpansion cohortGI toxicityII trialStarting dosePerformance statusDose escalationAdditional patientsNeck cancerPrevalent malignancySafety dataPatientsSecondary objectiveEnzastaurinDevelopment and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-β Inhibitor
Green LJ, Marder P, Ray C, Cook CA, Jaken S, Musib LC, Herbst RS, Carducci M, Britten CD, Basche M, Eckhardt SG, Thornton D. Development and Validation of a Drug Activity Biomarker that Shows Target Inhibition in Cancer Patients Receiving Enzastaurin, a Novel Protein Kinase C-β Inhibitor. Clinical Cancer Research 2006, 12: 3408-3415. PMID: 16740765, DOI: 10.1158/1078-0432.ccr-05-2231.Peer-Reviewed Original ResearchMeSH KeywordsAntineoplastic Combined Chemotherapy ProtocolsBiomarkersCapecitabineCell Line, TumorClinical Trials, Phase I as TopicDeoxycytidineEnzyme ActivatorsEnzyme InhibitorsFlow CytometryFluorouracilFollow-Up StudiesHumansIndolesLeukocytes, MononuclearMonocytesNeoplasmsProtein Kinase CProtein Kinase C betaReproducibility of ResultsSensitivity and SpecificitySignal TransductionStructure-Activity RelationshipTreatment OutcomeConceptsPeripheral blood mononuclear cellsDaily oral dosesBlood mononuclear cellsCancer patientsOral dosesMononuclear cellsFlow cytometryDrug activity biomarkerPKC activityTarget cellsActivity biomarkersPhorbol esterNormal donorsPatientsActivity of PKCU937 cell lineTarget inhibitionEnzastaurinKinase inhibitorsΒ inhibitorSignificant decreaseCell linesU937 cellsIntracellular phosphoproteinsProtein kinase C
2005
Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668
Davis DW, Takamori R, Raut CP, Xiong HQ, Herbst RS, Stadler WM, Heymach JV, Demetri GD, Rashid A, Shen Y, Wen S, Abbruzzese JL, McConkey DJ. Pharmacodynamic Analysis of Target Inhibition and Endothelial Cell Death in Tumors Treated with the Vascular Endothelial Growth Factor Receptor Antagonists SU5416 or SU6668. Clinical Cancer Research 2005, 11: 678-689. PMID: 15701856, DOI: 10.1158/1078-0432.678.11.2.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAnimalsApoptosisDose-Response Relationship, DrugEndothelium, VascularFemaleHumansIndolesMaleMiceMice, NudeMiddle AgedNeovascularization, PathologicOxindolesPancreatic NeoplasmsPhosphorylationPropionatesPyrrolesReceptor, Platelet-Derived Growth Factor betaTransplantation, HeterologousVascular Endothelial Growth Factor Receptor-2ConceptsPlatelet-derived growth factor receptorTumor microvessel densityGrowth factor receptorMicrovessel densityCell apoptosisVascular endothelial growth factor receptorAdvanced solid malignanciesFactor receptorEndothelial growth factor receptorPrimary patient tumorsG core biopsyDose-dependent effectPhosphorylated VEGFR-2Primary human tumorsEndothelial cell deathCell deathEndothelial cell apoptosisTumor cell apoptosisTumor cell deathPost therapyCore biopsyPharmacodynamic analysisSolid malignanciesVessel sizeClinical trials
2004
A phase I surrogate endpoint study of SU6668 in patients with solid tumors
Xiong HQ, Herbst R, Faria SC, Scholz C, Davis D, Jackson EF, Madden T, McConkey D, Hicks M, Hess K, Charnsangavej C, Abbruzzese JL. A phase I surrogate endpoint study of SU6668 in patients with solid tumors. Investigational New Drugs 2004, 22: 459-466. PMID: 15292716, DOI: 10.1023/b:drug.0000036688.96453.8d.Peer-Reviewed Original ResearchConceptsCore needle biopsyBiologic effectsNeedle biopsyDay 1Solid tumorsMean apparent oral clearanceContrast-enhanced magnetic resonance imagingApparent oral clearanceDynamic contrast-enhanced magnetic resonance imagingCorrelative studiesHigh-performance liquid chromatography assayMagnetic resonance imagingDCE-MRI resultsEligible patientsOral clearanceLiquid chromatography assayEndpoint studiesAntiangiogenic agentsFunctional CTBlood flowTumor specimensPatientsTissue biopsiesDay 22PK studies