2024
Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022 ☆
Freedman R, Heiling H, Li T, Trapani D, Tayob N, Smith K, Davis R, Pereslete A, DeMeo M, Cotter C, Chen W, Parsons H, Santa-Maria C, Van Poznak C, Moy B, Brufsky A, Melisko M, O’Sullivan C, Ashai N, Rauf Y, Nangia J, Burns R, Savoie J, Wolff A, Winer E, Rimawi M, Krop I, Lin N. Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022 ☆. Annals Of Oncology 2024, 35: 993-1002. PMID: 38977064, DOI: 10.1016/j.annonc.2024.07.245.Peer-Reviewed Original ResearchHER2-positive breast cancer brain metastasesBreast cancer brain metastasesT-DM1Ado-trastuzumab emtansineCentral nervous systemOverall survivalCNS objective response rateEfficacy of neratinibT-DM1 exposureObjective response rateCancer brain metastasesPhase II studyMedian OSRANO-BMBrain MetastasesSlow accrualIntracranial activityII studyPrimary endpointPreclinical dataCohort 4Response assessmentTreatment optionsNeratinibPatients
2020
Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases
Leone JP, Emblem KE, Weitz M, Gelman RS, Schneider BP, Freedman RA, Younger J, Pinho MC, Sorensen AG, Gerstner ER, Harris G, Krop IE, Morganstern D, Sohl J, Hu J, Kasparian E, Winer EP, Lin NU. Phase II trial of carboplatin and bevacizumab in patients with breast cancer brain metastases. Breast Cancer Research 2020, 22: 131. PMID: 33256829, PMCID: PMC7706261, DOI: 10.1186/s13058-020-01372-w.Peer-Reviewed Original ResearchMeSH KeywordsAdultAntineoplastic Combined Chemotherapy ProtocolsBevacizumabBrainBrain NeoplasmsBreastBreast NeoplasmsCarboplatinFemaleGenotyping TechniquesHumansKaplan-Meier EstimateMagnetic Resonance ImagingMiddle AgedPolymorphism, Single NucleotideProgression-Free SurvivalTrastuzumabVascular Endothelial Growth Factor AConceptsProgression-free survivalBreast cancer brain metastasesEarly MRI changesCancer brain metastasesBrain metastasesOverall survivalMRI changesBreast cancerEastern Cooperative Oncology Group performance statusDay 1Cycle 1 day 1Cycle 1 day 8Median progression-free survivalWorse progression-free survivalRegimen warrants further investigationDurable objective responsesECOG PS 1Efficacy of bevacizumabHER2-positive diseaseProgressive brain metastasesResultsThirty-eight patientsMedian overall survivalObjective response ratePhase II trialContrast-enhanced brain MRIPhase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases
Filho O, Leone JP, Li T, Tan-Wasielewski Z, Trippa L, Barry WT, Younger J, Lawler E, Walker L, Freedman RA, Tolaney SM, Krop I, Winer EP, Lin NU. Phase I dose-escalation trial of tucatinib in combination with trastuzumab in patients with HER2-positive breast cancer brain metastases. Annals Of Oncology 2020, 31: 1231-1239. PMID: 32461105, DOI: 10.1016/j.annonc.2020.05.014.Peer-Reviewed Original ResearchConceptsClinical benefit rateHER2-positive brain metastasesAlanine aminotransferase elevationCohort ABrain metastasesCohort BAminotransferase elevationBreast cancerHER2-positive breast cancer brain metastasesPhase I dose-escalation trialMedian progression-free survivalBreast cancer brain metastasesCommon dose-limiting toxicityI dose-escalation trialHER2-positive breast cancerCombination of tucatinibSecondary end pointsCancer brain metastasesDose-escalation trialProgression-free survivalDose-limiting toxicityMetastatic breast cancerBrain radiationObjective responseIntracranial activity
2019
Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022
Freedman RA, Gelman RS, Agar NYR, Santagata S, Randall EC, Lopez B, Connolly RM, Dunn IF, Van Poznak CH, Anders CK, Melisko ME, Silvestri K, Cotter CM, Componeschi KP, Marte JM, Moy B, Blackwell KL, Puhalla SL, Ibrahim N, Moynihan TJ, Nangia J, Tung N, Burns R, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU, Consortium T. Pre- and Postoperative Neratinib for HER2-Positive Breast Cancer Brain Metastases: Translational Breast Cancer Research Consortium 022. Clinical Breast Cancer 2019, 20: 145-151.e2. PMID: 31558424, PMCID: PMC7035200, DOI: 10.1016/j.clbc.2019.07.011.Peer-Reviewed Original ResearchMeSH KeywordsAdministration, OralAdultAntineoplastic Combined Chemotherapy ProtocolsBrainBrain NeoplasmsBreastBreast NeoplasmsChemotherapy, AdjuvantCraniotomyDrug Administration ScheduleFemaleHumansMiddle AgedNeoadjuvant TherapyPilot ProjectsQuinolinesReceptor, ErbB-2Tissue DistributionTreatment OutcomeConceptsCentral nervous system penetrationCerebrospinal fluidBrain metastasesStudy treatmentDisease progressionHER2-positive breast cancer brain metastasesHER2-positive metastatic breast cancerHER2-positive brain metastasesBreast cancer brain metastasesGrade 3 diarrheaCancer brain metastasesMetastatic breast cancerCentral nervous systemResected tumor tissueBlood-based analysesNeratinib monotherapyPostoperative cyclesParenchymal tumorsStudy protocolBreast cancerTumor histopathologyPatientsNervous systemSmall cohortSurgical tissuesTBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases
Freedman RA, Gelman RS, Anders CK, Melisko ME, Parsons HA, Cropp AM, Silvestri K, Cotter CM, Componeschi KP, Marte JM, Connolly RM, Moy B, Van Poznak CH, Blackwell KL, Puhalla SL, Jankowitz RC, Smith KL, Ibrahim N, Moynihan TJ, O’Sullivan C, Nangia J, Niravath P, Tung N, Pohlmann PR, Burns R, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU, . TBCRC 022: A Phase II Trial of Neratinib and Capecitabine for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases. Journal Of Clinical Oncology 2019, 37: jco.18.01511. PMID: 30860945, PMCID: PMC6494354, DOI: 10.1200/jco.18.01511.Peer-Reviewed Original ResearchConceptsCNS objective response rateObjective response rateHER2-positive breast cancer brain metastasesBreast cancer brain metastasesCancer brain metastasesBrain metastasesBreast cancerCommon grade 3 toxicitiesHER2-positive brain metastasesMedian progression-free survivalHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Human epidermal growth factor receptorEfficacy of HER2Non-CNS progressionGrade 3 toxicityPrimary end pointPhase II trialProgression-free survivalGrowth factor receptor 2Positive breast cancerProgressive neurologic signsEvidence-based treatmentsFactor receptor 2Epidermal growth factor receptor
2017
TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM).
Freedman R, Gelman R, Melisko M, Anders C, Moy B, Blackwell K, Connolly R, Niravath P, Van Poznak C, Puhalla S, Farooq S, Cropp A, Cotter C, Liu M, Krop I, Nangia J, Tung N, Wolff A, Winer E, Lin N. TBCRC 022: Phase II trial of neratinib + capecitabine for patients (Pts) with human epidermal growth factor receptor 2 (HER2+) breast cancer brain metastases (BCBM). Journal Of Clinical Oncology 2017, 35: 1005-1005. DOI: 10.1200/jco.2017.35.15_suppl.1005.Peer-Reviewed Original ResearchBreast cancer brain metastasesObjective response rateCombination of neratinibCentral nervous system (CNS) objective response rateCNS objective response rateNeurologic signs/symptomsGrade 3 toxicityGrade 4 toxicityMedian age 51Cancer brain metastasesPhase II trialSigns/symptomsEvidence-based treatmentsNon-CNS lesionsCNS progressionPrior lapatinibPrior WBRTPrimary endpointProtocol therapyBrain metastasesII trialCNS lesionsNew lesionsMedian numberBrain MRI
2016
Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases
Ni J, Ramkissoon SH, Xie S, Goel S, Stover DG, Guo H, Luu V, Marco E, Ramkissoon LA, Kang YJ, Hayashi M, Nguyen QD, Ligon AH, Du R, Claus EB, Alexander BM, Yuan GC, Wang ZC, Iglehart JD, Krop IE, Roberts TM, Winer EP, Lin NU, Ligon KL, Zhao JJ. Combination inhibition of PI3K and mTORC1 yields durable remissions in mice bearing orthotopic patient-derived xenografts of HER2-positive breast cancer brain metastases. Nature Medicine 2016, 22: 723-726. PMID: 27270588, PMCID: PMC4938731, DOI: 10.1038/nm.4120.Peer-Reviewed Original ResearchMeSH KeywordsAdaptor Proteins, Signal TransducingAminopyridinesAnimalsAntineoplastic AgentsApoptosisBrain NeoplasmsBreast NeoplasmsCarrier ProteinsCaspase 3Cell Cycle ProteinsDNA RepairDrug Resistance, NeoplasmDrug Therapy, CombinationEukaryotic Initiation FactorsEverolimusFemaleGene Expression ProfilingGenomic InstabilityHumansImmunohistochemistryKi-67 AntigenMagnetic Resonance ImagingMechanistic Target of Rapamycin Complex 1MiceMice, SCIDMolecular Targeted TherapyMorpholinesMultiprotein ComplexesNeoplasm TransplantationPhosphoinositide-3 Kinase InhibitorsPhosphoproteinsPhosphorylationReceptor, ErbB-2Remission InductionTOR Serine-Threonine KinasesXenograft Model Antitumor AssaysConceptsBreast cancer brain metastasesCancer brain metastasesBrain metastasesHER2-positive breast cancer brain metastasesOrthotopic patient-derived xenograftsPI3KPatient-derived xenograftsDurable remissionsTherapeutic responseMouse modelCombined inhibitionCombination inhibitionMetastasisInhibitionRemissionXenograftsMiceTranslational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases
Freedman RA, Gelman RS, Wefel JS, Melisko ME, Hess KR, Connolly RM, Van Poznak CH, Niravath PA, Puhalla SL, Ibrahim N, Blackwell KL, Moy B, Herold C, Liu MC, Lowe A, Agar NY, Ryabin N, Farooq S, Lawler E, Rimawi MF, Krop IE, Wolff AC, Winer EP, Lin NU. Translational Breast Cancer Research Consortium (TBCRC) 022: A Phase II Trial of Neratinib for Patients With Human Epidermal Growth Factor Receptor 2–Positive Breast Cancer and Brain Metastases. Journal Of Clinical Oncology 2016, 34: 945-952. PMID: 26834058, PMCID: PMC5070554, DOI: 10.1200/jco.2015.63.0343.Peer-Reviewed Original ResearchConceptsObjective response rateWhole brain radiotherapyBrain metastasesBreast cancerHER2-positive breast cancer brain metastasesCNS objective response rateHER2-positive brain metastasesMedian progression-free survivalNeurologic signs/symptomsPrevious whole-brain radiotherapyBreast cancer brain metastasesHuman epidermal growth factor receptor 2HER2-positive breast cancerEpidermal growth factor receptor 2Human epidermal growth factor receptorCNS-directed therapyNon-CNS progressionNon-target lesionsOpen-label trialCancer brain metastasesPhase II trialProgression-free survivalGrowth factor receptor 2Positive breast cancerSigns/symptoms
2013
Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM).
Lin N, Gelman R, Younger W, Sohl J, Freedman R, Sorensen A, Bullitt E, Harris G, Morganstern D, Schneider B, Krop I, Winer E. Phase II trial of carboplatin (C) and bevacizumab (BEV) in patients (pts) with breast cancer brain metastases (BCBM). Journal Of Clinical Oncology 2013, 31: 513-513. DOI: 10.1200/jco.2013.31.15_suppl.513.Peer-Reviewed Original ResearchBreast cancer brain metastasesCNS responseDay 1CNS objective response rateNon-target lesionsObjective response rateAnti-edema effectCancer brain metastasesPhase II trialProgressive neurologic signsStandard brain MRINon-CNS diseasesMultiple tumor typesPrior lapatinibPrior trastuzumabRECIST 1.0Steroid dosePrimary endpointProtocol therapyBrain metastasesFirst doseII trialCNS lesionsOverall survivalPartial response
2011
A Phase II Study of Sagopilone (ZK 219477; ZK-EPO) in Patients With Breast Cancer and Brain Metastases
Freedman RA, Bullitt E, Sun L, Gelman R, Harris G, Ligibel JA, Krop IE, Partridge AH, Eisenberg E, Winer EP, Lin NU. A Phase II Study of Sagopilone (ZK 219477; ZK-EPO) in Patients With Breast Cancer and Brain Metastases. Clinical Breast Cancer 2011, 11: 376-383. PMID: 21697017, PMCID: PMC3773692, DOI: 10.1016/j.clbc.2011.03.024.Peer-Reviewed Original ResearchConceptsMedian progression-free survivalProgression-free survivalObjective response ratePhase II studyBrain metastasesChallenging clinical problemBreast cancerCentral nervous systemII studyOverall survivalMagnetic resonance angiographyClinical problemCentral nervous system (CNS) objective response rateResponse rateCNS objective response rateCommon grade 3 toxicitiesProgressive metastatic breast cancerBreast cancer brain metastasesProgressive CNS diseaseGrade 3 toxicityRecurrent brain metastasesWhole brain radiotherapyCancer brain metastasesMetastatic breast cancerHigh-resolution magnetic resonance angiography