2018
ADAURA: Phase III, Double-blind, Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection
Wu YL, Herbst R, Mann H, Rukazenkov Y, Marotti M, Tsuboi M. ADAURA: Phase III, Double-blind, Randomized Study of Osimertinib Versus Placebo in EGFR Mutation-positive Early-stage NSCLC After Complete Surgical Resection. Clinical Lung Cancer 2018, 19: e533-e536. PMID: 29789220, DOI: 10.1016/j.cllc.2018.04.004.Peer-Reviewed Original ResearchConceptsCell lung cancerDisease recurrenceLung cancerMutation statusSurvival rateEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsComplete surgical tumor resectionDisease-free survival ratesT790M mutation statusReceptor tyrosine kinase inhibitorsMaximum treatment durationStage IB-IIIAPlacebo-controlled studyDisease-free survivalEarly-stage NSCLCComplete surgical resectionOverall survival rateHealth-related qualityHealth resource useSurgical tumor resectionEGFR mutation statusTyrosine kinase inhibitorsCentral confirmationVersus Placebo
2010
Phase II Selection Design Trial of Concurrent Chemotherapy and Cetuximab Versus Chemotherapy Followed by Cetuximab in Advanced-Stage Non–Small-Cell Lung Cancer: Southwest Oncology Group Study S0342
Herbst RS, Kelly K, Chansky K, Mack PC, Franklin WA, Hirsch FR, Atkins JN, Dakhil SR, Albain KS, Kim ES, Redman M, Crowley JJ, Gandara DR. Phase II Selection Design Trial of Concurrent Chemotherapy and Cetuximab Versus Chemotherapy Followed by Cetuximab in Advanced-Stage Non–Small-Cell Lung Cancer: Southwest Oncology Group Study S0342. Journal Of Clinical Oncology 2010, 28: 4747-4754. PMID: 20921467, PMCID: PMC3020704, DOI: 10.1200/jco.2009.27.9356.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorCarboplatinCarcinoma, Non-Small-Cell LungCetuximabDisease-Free SurvivalDrug Administration ScheduleErbB ReceptorsErlotinib HydrochlorideFemaleHumansKaplan-Meier EstimateLung NeoplasmsMaleMiddle AgedMutationNeoplasm StagingPaclitaxelPatient SelectionProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsResearch DesignSouthwestern United StatesTreatment OutcomeConceptsCell lung cancerConcurrent chemotherapyLung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsProgression-free survival timeRandomized phase II trialReceptor tyrosine kinase inhibitorsMedian overall survivalPaclitaxel/carboplatinTreatment-naive patientsGrade 3 rashPhase II trialAdvanced-stage NSCLCPhase III evaluationTyrosine kinase inhibitorsEnhanced antitumor activityConcurrent regimenMaintenance cetuximabMedian followVersus ChemotherapyChemotherapy regimenII trialSequential therapyConcurrent therapy
2008
BATTLE: Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination
Hong W, Herbst R, Mao L, Kim E. BATTLE: Biomarker-Based Approaches of Targeted Therapy for Lung Cancer Elimination. 2008 DOI: 10.21236/ada485729.Peer-Reviewed Original ResearchNonsmall cell lung cancerLung cancerTargeted therapyAdvanced nonsmall cell lung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsReceptor tyrosine kinase inhibitorsLung Cancer EliminationTumor response rateCell lung cancerLung cancer patientsCancer-related deathTyrosine kinase inhibitorsCancer patientsCancer eliminationEGFR mutationsTherapeutic approachesResponse rateCancerCancer typesPatientsKinase inhibitorsTherapyInitial successChemotherapy
2007
Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer
Herbst RS, O'Neill VJ, Fehrenbacher L, Belani CP, Bonomi PD, Hart L, Melnyk O, Ramies D, Lin M, Sandler A. Phase II Study of Efficacy and Safety of Bevacizumab in Combination With Chemotherapy or Erlotinib Compared With Chemotherapy Alone for Treatment of Recurrent or Refractory Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2007, 25: 4743-4750. PMID: 17909199, DOI: 10.1200/jco.2007.12.3026.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinomaAdenocarcinoma, Bronchiolo-AlveolarAdultAgedAged, 80 and overAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBevacizumabCarcinoma, Large CellCarcinoma, Non-Small-Cell LungDisease-Free SurvivalDocetaxelErlotinib HydrochlorideFemaleGlutamatesGuanineHumansLung NeoplasmsMaleMiddle AgedNeoplasm Recurrence, LocalNeoplasm StagingPemetrexedQuinazolinesSurvival RateTaxoidsTreatment OutcomeConceptsProgression-free survivalAdverse eventsLung cancerHumanized anti-vascular endothelial growth factor monoclonal antibodyRefractory non-small cell lung cancerAnti-vascular endothelial growth factor monoclonal antibodyEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsNon-small cell lung cancerSingle-arm phase IRandomized phase II trialOne-year survival rateReceptor tyrosine kinase inhibitorsFatal pulmonary hemorrhagePlatinum-based regimenSafety of bevacizumabStudies of bevacizumabUnexpected safety signalsPhase II studySecond-line settingPhase II trialTreatment of recurrentCell lung cancerFactor monoclonal antibodyFavorable safety profileA phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342
Herbst R, Chansky K, Kelly K, Atkins J, Davies A, Dakhil S, Albain K, Kim E, Crowley J, Gandara D. A phase II randomized selection trial evaluating concurrent chemotherapy plus cetuximab or chemotherapy followed by cetuximab in patients with advanced non-small cell lung cancer (NSCLC): Final report of SWOG 0342. Journal Of Clinical Oncology 2007, 25: 7545-7545. DOI: 10.1200/jco.2007.25.18_suppl.7545.Peer-Reviewed Original ResearchNon-small cell lung cancerSmall-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitorAdvanced non-small cell lung cancerAdvanced stage non-small cell lung cancerMetastatic non-small cell lung cancerStage non-small cell lung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsReceptor tyrosine kinase inhibitorsAdequate organ functionPhase III settingSuperior median survivalPhase II trialPhase III trialsCell lung cancerRandomized clinical trialsMolecular correlative studiesTyrosine kinase inhibitorsAnti-tumor activityPhase II selection trialTrue hazard ratioConcurrent chemotherapyConcurrent regimenEligible patientsEligible ptsKRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer
Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, Bekele BN, Herbst RS, Wistuba II. KRAS Mutation Is an Important Predictor of Resistance to Therapy with Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Non–Small-Cell Lung Cancer. Clinical Cancer Research 2007, 13: 2890-2896. PMID: 17504988, DOI: 10.1158/1078-0432.ccr-06-3043.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, Non-Small-Cell LungDisease ProgressionDrug Resistance, NeoplasmErbB ReceptorsErlotinib HydrochlorideFemaleGefitinibGene DosageHumansLung NeoplasmsMaleMiddle AgedMutationPrognosisProtein Kinase InhibitorsProto-Oncogene ProteinsProto-Oncogene Proteins p21(ras)QuinazolinesRas ProteinsTreatment OutcomeConceptsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsReceptor tyrosine kinase inhibitorsCell lung cancerKRAS mutationsTyrosine kinase inhibitorsEGFR-TKIEGFR copy numberEGFR mutationsLung cancerFavorable responseKinase inhibitorsShorter median timeArchival tissue specimensEGFR gene mutationsPanel of markersAdvanced NSCLCObjective responseProgressive diseaseSurvival benefitMedian timePoor responseSuch therapyDisease progressionPatients
2006
Combining Targeted Agents: Blocking the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways
Sandler A, Herbst R. Combining Targeted Agents: Blocking the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways. Clinical Cancer Research 2006, 12: 4421s-4425s. PMID: 16857821, DOI: 10.1158/1078-0432.ccr-06-0796.Peer-Reviewed Original ResearchMeSH KeywordsAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBevacizumabCarcinoma, Non-Small-Cell LungClinical Trials, Phase I as TopicClinical Trials, Phase II as TopicDrug SynergismEpidermal Growth FactorErlotinib HydrochlorideFemaleHumansLung NeoplasmsMaleQuinazolinesVascular Endothelial Growth Factor AConceptsNon-small cell lung cancerPhase II doseStage IIIB/IV non-small cell lung cancerAdvanced non-small cell lung cancerPhase I/II studyEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsRandomized phase II trialVascular endothelial growth factor (VEGF) pathwaySelective epidermal growth factor receptor tyrosine kinase inhibitorEndothelial growth factor pathwayReceptor tyrosine kinase inhibitorsGrowth factorCommon adverse eventsMedian overall survivalPhase II trialPhase III trialsProgression-free survivalSafety of erlotinibCell lung cancerHumanized monoclonal antibodyVascular endothelial growth factorTyrosine kinase inhibitorsEndothelial growth factorGrowth factor pathways
2005
TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer
Herbst RS, Prager D, Hermann R, Fehrenbacher L, Johnson BE, Sandler A, Kris MG, Tran HT, Klein P, Li X, Ramies D, Johnson DH, Miller VA. TRIBUTE: A Phase III Trial of Erlotinib Hydrochloride (OSI-774) Combined With Carboplatin and Paclitaxel Chemotherapy in Advanced Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2005, 23: 5892-5899. PMID: 16043829, DOI: 10.1200/jco.2005.02.840.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsCarboplatinCarcinoma, Non-Small-Cell LungDisease ProgressionErbB ReceptorsErlotinib HydrochlorideFemaleHumansLung NeoplasmsMaleMiddle AgedPaclitaxelPlacebosProtein Kinase InhibitorsQuinazolinesSurvival AnalysisConceptsUntreated advanced NSCLCOverall survivalAdvanced NSCLCObjective responseLung cancerAdvanced non-small cell lung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsNon-small cell lung cancerEnd pointReceptor tyrosine kinase inhibitorsCycles of carboplatinGood performance statusImproved overall survivalOutcomes of patientsPrimary end pointSecondary end pointsPhase III trialsSingle-agent activityCell lung cancerDuration of responseTyrosine kinase inhibitorsAssessable patientsConcurrent carboplatinErlotinib armPhase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer
Herbst RS, Johnson DH, Mininberg E, Carbone DP, Henderson T, Kim ES, Blumenschein G, Lee JJ, Liu DD, Truong MT, Hong WK, Tran H, Tsao A, Xie D, Ramies DA, Mass R, Seshagiri S, Eberhard DA, Kelley SK, Sandler A. Phase I/II Trial Evaluating the Anti-Vascular Endothelial Growth Factor Monoclonal Antibody Bevacizumab in Combination With the HER-1/Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Erlotinib for Patients With Recurrent Non–Small-Cell Lung Cancer. Journal Of Clinical Oncology 2005, 23: 2544-2555. PMID: 15753462, DOI: 10.1200/jco.2005.02.477.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedAntineoplastic Combined Chemotherapy ProtocolsBevacizumabCarcinoma, Non-Small-Cell LungDose-Response Relationship, DrugDrug InteractionsErlotinib HydrochlorideFemaleHumansInfusions, IntravenousLung NeoplasmsMaleMiddle AgedProtein Kinase InhibitorsQuinazolinesSurvival AnalysisTreatment OutcomeConceptsPhase II doseCell lung cancerLung cancerHumanized anti-vascular endothelial growth factor monoclonal antibodyVascular endothelial growth factor monoclonal antibody bevacizumabAnti-vascular endothelial growth factor monoclonal antibodyPhase I/II studyPhase I/II trialStage IIIB/IV NSCLCEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsEpidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinibTyrosine kinase inhibitor erlotinibReceptor tyrosine kinase inhibitorsCommon adverse eventsMedian overall survivalProgression-free survivalDose-limiting toxicityFactor monoclonal antibodyMonoclonal antibody bevacizumabKinase inhibitor erlotinibTyrosine kinase inhibitorsAdenocarcinoma histologyModerate rashPrior chemotherapy
2004
Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Does Not Improve Paclitaxel Effect in an Orthotopic Mouse Model of Lung Cancer
Onn A, Isobe T, Wu W, Itasaka S, Shintani T, Shibuya K, Kenji Y, O’Reilly M, Fidler IJ, Herbst RS. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Does Not Improve Paclitaxel Effect in an Orthotopic Mouse Model of Lung Cancer. Clinical Cancer Research 2004, 10: 8613-8619. PMID: 15623645, DOI: 10.1158/1078-0432.ccr-04-1241.Peer-Reviewed Original ResearchMeSH KeywordsAdenocarcinoma, Bronchiolo-AlveolarAnimalsAntineoplastic Agents, PhytogenicCarcinoma, Non-Small-Cell LungDrug Therapy, CombinationEnzyme ActivationEnzyme InhibitorsErbB ReceptorsFibroblast Growth Factor 2HumansLung NeoplasmsMaleMiceMice, NudeMitogen-Activated Protein KinasesModels, AnimalPaclitaxelPhosphorylationPyrimidinesPyrrolesSurvival RateConceptsEGFR tyrosine kinase inhibitorsTumor implantationLung cancerKinase inhibitorsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsReceptor tyrosine kinase inhibitorsBasic fibroblast growth factor expressionCombination of paclitaxelFibroblast growth factor expressionGroups of miceLungs of miceOrthotopic mouse modelHuman lung cancerTyrosine kinase inhibitorsGrowth factor expressionMaximal therapeutic effectHuman lung adenocarcinoma cellsLung adenocarcinoma cellsPaclitaxel 100Phosphorylation of EGFRConcurrent administrationEGFR-TKITherapeutic effectEpidermal growth factor receptor (EGFR) activationGefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Phase III Trial—INTACT 2
Herbst RS, Giaccone G, Schiller JH, Natale RB, Miller V, Manegold C, Scagliotti G, Rosell R, Oliff I, Reeves JA, Wolf MK, Krebs AD, Averbuch SD, Ochs JS, Grous J, Fandi A, Johnson DH. Gefitinib in Combination With Paclitaxel and Carboplatin in Advanced Non–Small-Cell Lung Cancer: A Phase III Trial—INTACT 2. Journal Of Clinical Oncology 2004, 22: 785-794. PMID: 14990633, DOI: 10.1200/jco.2004.07.215.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsCarboplatinCarcinoma, Non-Small-Cell LungDose-Response Relationship, DrugDrug Administration ScheduleFemaleGefitinibHumansInfusions, IntravenousLung NeoplasmsMaleMaximum Tolerated DoseMiddle AgedMultivariate AnalysisNeoplasm StagingPaclitaxelPredictive Value of TestsPrognosisQuinazolinesReference ValuesRisk AssessmentSurvival AnalysisTreatment OutcomeConceptsResponse rateOverall survivalLung cancerActive epidermal growth factor receptor tyrosine kinase inhibitorAdvanced non-small cell lung cancerEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsNon-small cell lung cancerReceptor tyrosine kinase inhibitorsDose-related diarrheaSignificant prolonged survivalUnexpected safety findingsChemotherapy-naive patientsDouble-blind trialPlacebo-controlled trialPhase II trialBaseline demographic characteristicsPhase I trialCell lung cancerConcentration/time curveTyrosine kinase inhibitorsCarboplatin areaDaily gefitinibGefitinib monotherapyMonotherapy trials
2003
Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors.
LoRusso PM, Herbst RS, Rischin D, Ranson M, Calvert H, Raymond E, Kieback D, Kaye S, Gianni L, Harris A, Bjork T, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Feyereislova A, Heyes A, Averbuch SD, Ochs J, Baselga J. Improvements in quality of life and disease-related symptoms in phase I trials of the selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 in non-small cell lung cancer and other solid tumors. Clinical Cancer Research 2003, 9: 2040-8. PMID: 12796366.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerPhase I clinical trialCell lung cancerDisease-related symptomsQuality of lifeAdvanced cancerLung cancerClinical changesClinical trialsOvarian cancerEpidermal growth factor receptor tyrosine kinase inhibitor ZD1839Tumor typesEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsTyrosine kinase inhibitor ZD1839Receptor tyrosine kinase inhibitorsCancer Therapy questionnaireLung Cancer SubscaleMultiple-dose safetyPhase I trialUnited States trialsTyrosine kinase inhibitorsFact QuestionnairePrior therapyTOI scoresDose-comparative monotherapy trials of ZD1839 in previously treated non–small cell lung cancer patients
Herbst RS. Dose-comparative monotherapy trials of ZD1839 in previously treated non–small cell lung cancer patients. Seminars In Oncology 2003, 30: 30-38. PMID: 12644982, DOI: 10.1053/sonc.2003.50030.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerAdvanced non-small cell lung cancerSymptom improvement rateTumor response rateDay groupSolid tumorsChemotherapy regimensIDEAL-2Ideal 1Lung cancerClinical trialsStage IIIResponse rateNon-small cell lung cancer patientsEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsAdvanced unresectable stage IIIMedian progression-free survivalObjective tumor response rateCell lung cancer patientsImprovement rateSelective epidermal growth factor receptor tyrosine kinase inhibitorReceptor tyrosine kinase inhibitorsPhase I clinical trialIressa Dose Evaluation
2002
Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial.
Herbst RS, Maddox AM, Rothenberg ML, Small EJ, Rubin EH, Baselga J, Rojo F, Hong WK, Swaisland H, Averbuch SD, Ochs J, LoRusso PM. Selective oral epidermal growth factor receptor tyrosine kinase inhibitor ZD1839 is generally well-tolerated and has activity in non-small-cell lung cancer and other solid tumors: results of a phase I trial. Journal Of Clinical Oncology 2002, 20: 3815-25. PMID: 12228201, DOI: 10.1200/jco.2002.03.038.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAgedAged, 80 and overAntineoplastic AgentsCarcinoma, Non-Small-Cell LungDose-Response Relationship, DrugDrug Administration ScheduleEnzyme InhibitorsFemaleGastrointestinal DiseasesGefitinibHead and Neck NeoplasmsHumansLung NeoplasmsMaleMaximum Tolerated DoseMiddle AgedNeoplasm StagingNeoplasmsProtein-Tyrosine KinasesQuinazolinesSkin DiseasesConceptsDose-limiting toxicityPharmacokinetic analysisEpidermal growth factor receptor tyrosine kinase inhibitor ZD1839Epidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsGrade 1/2 adverse eventsTyrosine kinase inhibitor ZD1839Primary dose-limiting toxicityReceptor tyrosine kinase inhibitorsPrior cancer therapyAntitumor activityDaily oral dosingPhase I trialCell lung cancerTyrosine kinase inhibitorsSolid tumor typesVariability of exposureStable diseaseAdverse eventsPartial responseUndue toxicityI trialTolerability trialCell lungFollicular rashZD1839: targeting the epidermal growth factor receptor in cancer therapy
Herbst RS. ZD1839: targeting the epidermal growth factor receptor in cancer therapy. Expert Opinion On Investigational Drugs 2002, 11: 837-849. PMID: 12036427, DOI: 10.1517/13543784.11.6.837.Peer-Reviewed Original ResearchConceptsNon-small cell lung cancerEpidermal growth factor receptorCell lung cancerGrowth factor receptorFactor receptorLung cancerSmall-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitorTumor typesEpidermal growth factor receptor tyrosine kinase inhibitorsGrowth factor receptor tyrosine kinase inhibitorsAntitumour activityReceptor tyrosine kinase inhibitorsMeaningful antitumour activityAcceptable tolerability profilePaclitaxel/carboplatinPhase II studyThird-line treatmentFirst-line treatmentPhase III trialsGemcitabine/cisplatinClinical trial programPromising clinical activityCancer cell growthHost-dependent processesAdvanced disease