2024
Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2– and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study
Bardia A, Krop I, Kogawa T, Juric D, Tolcher A, Hamilton E, Mukohara T, Lisberg A, Shimizu T, Spira A, Tsurutani J, Damodaran S, Papadopoulos K, Greenberg J, Kobayashi F, Zebger-Gong H, Wong R, Kawasaki Y, Nakamura T, Meric-Bernstam F. Datopotamab Deruxtecan in Advanced or Metastatic HR+/HER2– and Triple-Negative Breast Cancer: Results From the Phase I TROPION-PanTumor01 Study. Journal Of Clinical Oncology 2024, 42: 2281-2294. PMID: 38652877, PMCID: PMC11210948, DOI: 10.1200/jco.23.01909.Peer-Reviewed Original ResearchTriple-negative BCHR+/HER2- BCBreast cancerHormone receptor-positive/human epidermal growth factor receptor 2-negativeAll-causality treatment-emergent adverse eventsMedian duration of responseTopoisomerase I inhibitor payloadTreatment-emergent adverse eventsBlinded independent central reviewTriple-negative breast cancerDose-expansion studyProgression-free survivalDuration of responsePhase III studyIndependent central reviewTreating solid tumorsPrimary study objectiveAntibody-drug conjugatesDose escalationData cutoffTriple-negativeBC cohortEvaluation of antitumor activityIII studiesMedian durationThe HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results
Lewis G, Li G, Guo J, Yu S, Fields C, Lee G, Zhang D, Dragovich P, Pillow T, Wei B, Sadowsky J, Leipold D, Wilson T, Kamath A, Mamounas M, Lee M, Saad O, Choeurng V, Ungewickell A, Monemi S, Crocker L, Kalinsky K, Modi S, Jung K, Hamilton E, LoRusso P, Krop I, Schutten M, Commerford R, Sliwkowski M, Cho E. The HER2-directed antibody-drug conjugate DHES0815A in advanced and/or metastatic breast cancer: preclinical characterization and phase 1 trial results. Nature Communications 2024, 15: 466. PMID: 38212321, PMCID: PMC10784567, DOI: 10.1038/s41467-023-44533-z.Peer-Reviewed Original ResearchConceptsHER2 antibody-drug conjugatesAntibody-drug conjugatesMetastatic breast cancerPhase 1 trialBreast cancerHER2-positive metastatic breast cancerHER2-positive breast cancerObjective response rateDose-escalation studyDuration of responseModel of HER2Anti-tumor activityMechanism of actionTrastuzumab deruxtecanPulmonary toxicityTrastuzumab emtansinePreclinical characterizationResponse rateHigh dosesVivo efficacySecondary objectiveEarly signsPotent cytotoxic agentCytotoxic agentsCancer
2023
Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial
Krop I, Masuda N, Mukohara T, Takahashi S, Nakayama T, Inoue K, Iwata H, Yamamoto Y, Alvarez R, Toyama T, Takahashi M, Osaki A, Saji S, Sagara Y, O'Shaughnessy J, Ohwada S, Koyama K, Inoue T, Li L, Patel P, Mostillo J, Tanaka Y, Sternberg D, Sellami D, Yonemori K. Patritumab Deruxtecan (HER3-DXd), a Human Epidermal Growth Factor Receptor 3–Directed Antibody-Drug Conjugate, in Patients With Previously Treated Human Epidermal Growth Factor Receptor 3–Expressing Metastatic Breast Cancer: A Multicenter, Phase I/II Trial. Journal Of Clinical Oncology 2023, 41: 5550-5560. PMID: 37801674, PMCID: PMC10730028, DOI: 10.1200/jco.23.00882.Peer-Reviewed Original ResearchConceptsTreatment-emergent adverse eventsHuman epidermal growth factor receptor 3Epidermal growth factor receptor 3Metastatic breast cancerGrowth factor receptor 3Breast cancerReceptor 3Dose expansionPrevious therapyClinical subtypesCommon treatment-emergent adverse eventsPhase I/II trialHER2-positive breast cancerTriple-negative breast cancerDose-escalation partDose-expansion partManageable safety profileAdvanced breast cancerEpidermal growth factor receptorAntibody-drug conjugatesGrowth factor receptorAdvanced diseaseHematologic toxicityII trialObjective responseTrastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial
André F, Hee Park Y, Kim S, Takano T, Im S, Borges G, Lima J, Aksoy S, Gavila Gregori J, De Laurentiis M, Bianchini G, Roylance R, Miyoshi Y, Armstrong A, Sinha R, Ruiz Borrego M, Lim E, Ettl J, Yerushalmi R, Zagouri F, Duhoux F, Fehm T, Gambhire D, Cathcart J, Wu C, Chu C, Egorov A, Krop I. Trastuzumab deruxtecan versus treatment of physician's choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. The Lancet 2023, 401: 1773-1785. PMID: 37086745, DOI: 10.1016/s0140-6736(23)00725-0.Peer-Reviewed Original ResearchConceptsHER2-positive metastatic breast cancerMetastatic breast cancerPhysician's choice groupTreatment-emergent adverse eventsBlinded independent central reviewPhase 3 trialProgression-free survivalTrastuzumab deruxtecanIndependent central reviewBreast cancerPhysician's choiceAdverse eventsCentral reviewTrastuzumab emtansineEastern Cooperative Oncology Group performance statusCommon treatment-emergent adverse eventsHigher treatment-emergent adverse eventsMedian progression-free survivalPositive metastatic breast cancerFavorable benefit-risk profilePalmar-plantar erythrodysaesthesiaInterstitial lung diseaseBenefit-risk profileAntibody-drug conjugatesChoice group
2022
Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC).
Krop I, Masuda N, Mukohara T, Takahashi S, Nakayama T, Inoue K, Iwata H, Toyama T, Yamamoto Y, Hansra D, Takahashi M, Osaki A, Koyama K, Inoue T, Yonekura T, Mostillo J, Ohwada S, Tanaka Y, Sternberg D, Yonemori K. Results from the phase 1/2 study of patritumab deruxtecan, a HER3-directed antibody-drug conjugate (ADC), in patients with HER3-expressing metastatic breast cancer (MBC). Journal Of Clinical Oncology 2022, 40: 1002-1002. DOI: 10.1200/jco.2022.40.16_suppl.1002.Peer-Reviewed Original ResearchMetastatic breast cancerAntibody-drug conjugatesAnti-HER3 monoclonal antibodyInvestigational antibody-drug conjugateTopoisomerase I inhibitor payloadWhite blood cell countDose-finding portionGrade 5 eventsMedian treatment durationPhase 1/2 studyInterstitial lung diseaseBlood cell countMedian study durationECOG PSData cutoffDose expansionCentral adjudicationMetastatic diseaseNeutrophil countPrior linesMedian agePhase 1/2Platelet countSafety profileLung diseasePhase 2 trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (HER2CLIMB-04, trial in progress).
Krop I, Carey L, Ramos J, Chen Y, Hamilton E. Phase 2 trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ locally advanced or metastatic breast cancer with and without brain metastases (HER2CLIMB-04, trial in progress). Journal Of Clinical Oncology 2022, 40: tps1111-tps1111. DOI: 10.1200/jco.2022.40.16_suppl.tps1111.Peer-Reviewed Original ResearchHuman epidermal growth factor receptor 2Metastatic breast cancerDisease control rateProgression-free survivalDuration of responseBrain metastasesAntibody-drug conjugatesRECIST 1.1Trastuzumab deruxtecanInvestigator assessmentBreast cancerSmall molecule tyrosine kinase inhibitorsTopoisomerase I inhibitor payloadEpidermal growth factor receptor 2Monoclonal antibodiesBreast cancer xenograft modelActive brain metastasesResponse-evaluable patientsManageable safety profileObjective response ratePhase 2 studyPhase 2 trialGrowth factor receptor 2Limited treatment optionsPatient-reported outcomes
2021
LBA4 Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC), for triple-negative breast cancer (TNBC): Preliminary results from an ongoing phase I trial
Bardia A, Juric D, Shimizu T, Tolcher A, Karim R, Spira A, Mukohara T, Lisberg A, Kogawa T, Krop I, Papadopoulos K, Hamilton E, Damodaran S, Greenberg J, Gu W, Kobayashi F, Guevara F, Jikoh T, Kawasaki Y, Meric-Bernstam F. LBA4 Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate (ADC), for triple-negative breast cancer (TNBC): Preliminary results from an ongoing phase I trial. Annals Of Oncology 2021, 32: s60. DOI: 10.1016/j.annonc.2021.03.213.Peer-Reviewed Original ResearchTriple-negative breast cancerAntibody-drug conjugatesOngoing phase I trialPhase I trialI trialBreast cancerCancerTrials
2020
SGNLVA-001: A phase I open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer.
Beckwith H, Medgyesy D, Abraham J, Nanda R, Tkaczuk K, Krop I, Pusztai L, Modi S, Mita M, Specht J, Hurvitz S, Han H, Kalinsky K, Wilks S, O'Shaughnessy J, Hart L, Rugo H, Mitri Z, Garfin P, Burris III H. SGNLVA-001: A phase I open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer. Journal Of Clinical Oncology 2020, 38: tps1104-tps1104. DOI: 10.1200/jco.2020.38.15_suppl.tps1104.Peer-Reviewed Original ResearchMetastatic breast cancerMonomethyl auristatin EDose-expansion cohortsAntibody-drug conjugatesDose escalationBreast cancerRECIST v1.1Expansion cohortPrior linesCytotoxic chemotherapyMetastatic triple-negative breast cancerGrade 2 peripheral neuropathyInvestigational antibody-drug conjugateNegative metastatic breast cancerLIV-1Triple-negative breast cancerAdequate organ functionHumanized IgG1 monoclonal antibodyKey efficacy endpointsPrimary safety endpointProgression-free survivalDose-limiting toxicityDuration of responseOverall response rateMonths of completion
2014
Trastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer
Krop I, Winer EP. Trastuzumab Emtansine: A Novel Antibody–Drug Conjugate for HER2-Positive Breast Cancer. Clinical Cancer Research 2014, 20: 15-20. PMID: 24135146, DOI: 10.1158/1078-0432.ccr-13-0541.Peer-Reviewed Original ResearchConceptsMetastatic breast cancerT-DM1Breast cancerAntibody-drug conjugatesAntibody-dependent cell-mediated cytotoxicityRecent phase III trialsHER2-positive breast cancerNovel antibody-drug conjugateCapecitabine/lapatinibFirst-line settingHepatic transaminase elevationsCombination of trastuzumabPhase II studyProgression-free survivalPhase III trialsInhibition of HER2Cell-mediated cytotoxicityFavorable toxicity profileHER2-positive tumor cellsMonoclonal antibody trastuzumabTransaminase elevationII studyIII trialsOverall survivalAdverse events
2013
Beyond Trastuzumab and Lapatinib: New Options for HER2-Positive Breast Cancer
Zardavas D, Cameron D, Krop I, Piccart M. Beyond Trastuzumab and Lapatinib: New Options for HER2-Positive Breast Cancer. American Society Of Clinical Oncology Educational Book 2013, e2-e11. DOI: 10.14694/edbook_am.2013.33.e2.Peer-Reviewed Original ResearchHER2-positive breast cancerDual HER2 blockadeAntibody-drug conjugatesHER2 blockadeMetastatic settingBreast cancerAdjuvant settingTrastuzumab-DM1Clinical trialsSmall molecule inhibitorsClinical practiceMonoclonal antibodiesAnti-HER2 resistanceAnti-HER2 agentsLarge randomized trialsEfficacy of trastuzumabSubset of patientsAdvanced clinical testingHER2-targeted agentsNew treatment optionsAggressive biologic behaviorDrug conjugatesMajor clinical issueImproved treatment outcomesMolecule inhibitorsBeyond trastuzumab and lapatinib: new options for HER2-positive breast cancer .
Zardavas D, Cameron D, Krop I, Piccart M. Beyond trastuzumab and lapatinib: new options for HER2-positive breast cancer . American Society Of Clinical Oncology Educational Book 2013, 33: e2-e11. PMID: 23714441, DOI: 10.1200/edbook_am.2013.33.e2.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntibodies, Monoclonal, HumanizedAntineoplastic AgentsBreast NeoplasmsChemotherapy, AdjuvantDrug Resistance, NeoplasmFemaleHumansLapatinibMolecular Targeted TherapyNeoadjuvant TherapyProtein Kinase InhibitorsQuinazolinesReceptor, ErbB-2Signal TransductionTrastuzumabTreatment OutcomeConceptsHER2-positive breast cancerDual HER2 blockadeAntibody-drug conjugatesHER2 blockadeBreast cancerMetastatic settingClinical trialsAnti-HER2 resistanceAnti-HER2 agentsLarge randomized trialsHER2-targeted agentsNew treatment optionsAggressive biologic behaviorMajor clinical issueImproved treatment outcomesNew therapeutic avenuesDevelopment of agentsAdjuvant settingNeoadjuvant settingAdvanced diseaseTrastuzumab-DM1Randomized trialsTreatment optionsBiologic rationaleHER2 inhibition
2012
A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer
Bender BC, Schaedeli-Stark F, Koch R, Joshi A, Chu YW, Rugo H, Krop IE, Girish S, Friberg LE, Gupta M. A population pharmacokinetic/pharmacodynamic model of thrombocytopenia characterizing the effect of trastuzumab emtansine (T-DM1) on platelet counts in patients with HER2-positive metastatic breast cancer. Cancer Chemotherapy And Pharmacology 2012, 70: 591-601. PMID: 22886072, DOI: 10.1007/s00280-012-1934-7.Peer-Reviewed Original ResearchConceptsT-DM1 3.6Incidence of gradePK/PD modelBaseline characteristicsPlatelet countT-DM1Semimechanistic PK/PD modelHER2-positive metastatic breast cancerPharmacodynamic modelPD modelHuman epidermal growth factor receptorGrade 3 thrombocytopeniaPatient baseline characteristicsPhase II studyDose-limiting toxicityMetastatic breast cancerPatient's platelet countSingle-agent studiesPD parametersEpidermal growth factor receptorAntibody-drug conjugatesGrowth factor receptorDose delaysFirst doseII studyClinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer
Girish S, Gupta M, Wang B, Lu D, Krop IE, Vogel CL, Burris III HA, LoRusso PM, Yi JH, Saad O, Tong B, Chu YW, Holden S, Joshi A. Clinical pharmacology of trastuzumab emtansine (T-DM1): an antibody–drug conjugate in development for the treatment of HER2-positive cancer. Cancer Chemotherapy And Pharmacology 2012, 69: 1229-1240. PMID: 22271209, PMCID: PMC3337408, DOI: 10.1007/s00280-011-1817-3.Peer-Reviewed Original ResearchConceptsSingle-agent T-DM1Anti-therapeutic antibodiesT-DM1 exposureTotal trastuzumabT-DM1Positive metastatic breast cancerHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Standard noncompartmental approachT-DM1 pharmacokineticsGrowth factor receptor 2Key adverse eventsMetastatic breast cancerHER2-positive cancersStable thioether linkerConcentrations of transaminasesFactor receptor 2Enzyme-linked immunosorbent assayEnzyme-linked immunosorbentHER2 extracellular domainAntibody-drug conjugatesEvaluable patientsPrior therapyClinical responseAdverse events
2010
Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer
Krop IE, Beeram M, Modi S, Jones SF, Holden SN, Yu W, Girish S, Tibbitts J, Yi JH, Sliwkowski MX, Jacobson F, Lutzker SG, Burris HA. Phase I Study of Trastuzumab-DM1, an HER2 Antibody-Drug Conjugate, Given Every 3 Weeks to Patients With HER2-Positive Metastatic Breast Cancer. Journal Of Clinical Oncology 2010, 28: 2698-2704. PMID: 20421541, DOI: 10.1200/jco.2009.26.2071.Peer-Reviewed Original ResearchMeSH KeywordsAdo-Trastuzumab EmtansineAdultAgedAntibodies, MonoclonalAntibodies, Monoclonal, HumanizedBiopsy, NeedleBone NeoplasmsBreast NeoplasmsDose-Response Relationship, DrugDrug Administration ScheduleFemaleFollow-Up StudiesHalf-LifeHumansImmunoconjugatesImmunohistochemistryLiver NeoplasmsLung NeoplasmsMaximum Tolerated DoseMaytansineMiddle AgedNeoplasm StagingPatient SelectionReceptor, ErbB-2Risk AssessmentSurvival AnalysisThrombocytopeniaTrastuzumabTreatment OutcomeConceptsMaximum-tolerated doseAdvanced HER2-positive breast cancerHER2-positive breast cancerTrastuzumab-DM1Breast cancerAdverse eventsCommon drug-related adverse eventsHER2-positive metastatic breast cancerDrug-related adverse eventsHER2 antibody-drug conjugatesClinical benefit rateConfirmed response rateSubstantial clinical activityTrastuzumab-based therapyMetastatic breast cancerHER2-positive cellsAntibody-drug conjugatesMeasurable diseaseNeuropathy eventsElevated transaminasesCardiac effectsDose modificationMetastatic diseaseObjective responseReversible toxicity
2009
5020 Pharmacokinetics (PK), safety, and efficacy of trastuzumab (T)-DM1, a HER2 antibody-drug conjugate (ADC), in patients with HER2+ metastatic breast cancer (MBC): phase I and phase II trial results
Burris H, Vukelja S, Krop I, Modi S, Klencke B, Girish S, Sliwkowski M, Dresser M, Phillips G, Rugo H. 5020 Pharmacokinetics (PK), safety, and efficacy of trastuzumab (T)-DM1, a HER2 antibody-drug conjugate (ADC), in patients with HER2+ metastatic breast cancer (MBC): phase I and phase II trial results. European Journal Of Cancer Supplements 2009, 7: 266-267. DOI: 10.1016/s1359-6349(09)70912-7.Peer-Reviewed Original ResearchA phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast cancer.
Krop I, Mita M, Burris H, Birkner M, Girish S, Tibbitts J, Holden S, Lutzker S, Modi S. A phase I study of weekly dosing of trastuzumab-DM1 (T-DM1) in patients with advanced HER2+ breast cancer. Cancer Research 2009, 69: 3136. DOI: 10.1158/0008-5472.sabcs-3136.Peer-Reviewed Original ResearchTrastuzumab-DM1Advanced HER2Antibody-drug conjugatesBreast cancerChemotherapy regimenCycle 1 day 1HER2 antibody-drug conjugatesFirst antibody-drug conjugatePhase IActivity of trastuzumabGrade 4 thrombocytopeniaReversible transaminase elevationT-DM1 exposureDose-escalation studyPhase II trialMeasurable diseaseQ3W dosingTransaminase elevationEscalation studyII trialPartial responseWeekly dosingCardiac toxicityTumor responseClinical trials
2008
A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC)
Beeram M, Burris H, Modi S, Birkner M, Girish S, Tibbitts J, Holden S, Lutzker S, Krop I. A phase I study of trastuzumab-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with advanced HER2+ breast cancer (BC). Journal Of Clinical Oncology 2008, 26: 1028-1028. DOI: 10.1200/jco.2008.26.15_suppl.1028.Peer-Reviewed Original ResearchAntibody-drug conjugatesTrastuzumab-DM1Breast cancerHER2 antibody-drug conjugatesAdvanced HER2Phase IPatientsHER2Cancer
2007
A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC)
Beeram M, Krop I, Modi S, Tolcher A, Rabbee N, Girish S, Tibbitts J, Holden S, Lutzker S, Burris H. A phase I study of trastuzumab-MCC-DM1 (T-DM1), a first-in-class HER2 antibody-drug conjugate (ADC), in patients (pts) with HER2+ metastatic breast cancer (BC). Journal Of Clinical Oncology 2007, 25: 1042-1042. DOI: 10.1200/jco.2007.25.18_suppl.1042.Peer-Reviewed Original ResearchAntibody-drug conjugatesMetastatic breast cancerAdverse eventsT-DM1Breast cancerDose levelsHER2 antibody-drug conjugatesFirst antibody-drug conjugatePhase IOngoing partial responsePrincipal adverse eventsReversible transaminase elevationT-DM1 pharmacokineticsObjective tumor responseHuman phase IDose-dependent decreasePotent anti-tumor agentAntigen-specific monoclonal antibodiesAnti-tumor agentsCancer ptsQ3 weeksResistant HER2Transaminase elevationHepatic transaminasesPartial response