2024
A Pooled Analysis of Trastuzumab Deruxtecan in Patients With HER2-Positive Metastatic Breast Cancer With Brain Metastases
André F, Cortés J, Curigliano G, Modi S, Li W, Park Y, Chung W, Kim S, Yamashita T, Pedrini J, Im S, Tseng L, Harbeck N, Krop I, Nakatani S, Tecson K, Ashfaque S, Egorov A, Hurvitz S. A Pooled Analysis of Trastuzumab Deruxtecan in Patients With HER2-Positive Metastatic Breast Cancer With Brain Metastases. Annals Of Oncology 2024 PMID: 39241960, DOI: 10.1016/j.annonc.2024.08.2347.Peer-Reviewed Original ResearchHER2-positive metastatic breast cancerBlinded independent central reviewMetastatic breast cancerBrain metastasesT-DXdOverall survivalCNS-PFSTrastuzumab deruxtecanBreast cancerCentral nervous system progression-free survivalIntracranial responsePooled analysisIntracranial objective response rateSafety of trastuzumab deruxtecanSystemic progression-free survivalObjective response rateORR of patientsProgression-free survivalDuration of responseFood and Drug Administration criteriaIndependent central reviewUS Food and Drug Administration criteriaCompare treatmentsExploratory pooled analysisBM statusTBCRC 048 (olaparib expanded) expansion cohorts: Phase 2 study of olaparib monotherapy in patients (pts) with metastatic breast cancer (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2.
Tung N, Robson M, Nanda R, Li T, Vinayak S, Shah P, Khoury K, Kimmick G, Santa-Maria C, Brufsky A, DeMeo M, Vieira J, Carey L, Wulf G, Domchek S, Krop I, Wolff A, Winer E, Garber J. TBCRC 048 (olaparib expanded) expansion cohorts: Phase 2 study of olaparib monotherapy in patients (pts) with metastatic breast cancer (MBC) with germline (g) mutations in PALB2 or somatic (s) mutations in BRCA1 or BRCA2. Journal Of Clinical Oncology 2024, 42: 1021-1021. DOI: 10.1200/jco.2024.42.16_suppl.1021.Peer-Reviewed Original ResearchProgression-free survivalDuration of responseMetastatic breast cancerClinical benefit rateTriple-negative breast cancerMedian duration of responseMedian progression-free survivalMutant allele frequencyExpansion cohortHER2-negativeHER2-positiveCohort 2aNon-respondersBreast cancerEarly due to slow enrollmentMetastatic chemotherapy regimensResponse to olaparibPhase 2 studyPhase II trialKaplan-Meier methodPredictors of responseCohort of womenWilcoxon rank sum testRank sum testBRCA1mPooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03.
Saura C, Cortés J, Modi S, Kim S, Hamilton E, Hurvitz S, Krop I, Curigliano G, Iwata H, Im S, Herbolsheimer P, Karnoub M, Gambhire D, Egorov A, Andre F. Pooled analysis by best confirmed response to trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2+ metastatic breast cancer (mBC) from DESTINY-Breast-01, -02, and -03. Journal Of Clinical Oncology 2024, 42: 1023-1023. DOI: 10.1200/jco.2024.42.16_suppl.1023.Peer-Reviewed Original ResearchTreatment-emergent adverse eventsHER2+ metastatic breast cancerProgression-free survivalMetastatic breast cancerComplete responsePartial responseT-DXdOverall survivalPooled analysisInterstitial lung disease (ILD)/pneumonitisStable disease (SD)/progressive diseaseProlonged progression-free survivalDuration of responseIndependent central reviewNumerically lower ratesLonger treatment durationMetastatic settingRECIST v1.1Trastuzumab deruxtecanOS outcomesCentral reviewAdverse eventsBreast cancerTreatment durationDrug-relatedDatopotamab 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
Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01) ☆
Saura C, Modi S, Krop I, Park Y, Kim S, Tamura K, Iwata H, Tsurutani J, Sohn J, Mathias E, Liu Y, Cathcart J, Singh J, Yamashita T. Trastuzumab deruxtecan in previously treated patients with HER2-positive metastatic breast cancer: updated survival results from a phase II trial (DESTINY-Breast01) ☆. Annals Of Oncology 2023, 35: 302-307. PMID: 38092229, PMCID: PMC11322859, DOI: 10.1016/j.annonc.2023.12.001.Peer-Reviewed Original ResearchHER2-positive metastatic breast cancerTreatment-emergent adverse eventsMetastatic breast cancerObjective response rateProgression-free survivalDuration of responseIndependent central reviewT-DXdAdverse eventsOverall survivalTrastuzumab deruxtecanCentral reviewBreast cancerDrug-related treatment-emergent adverse eventsInterstitial lung disease/pneumonitisResponse rateMedian progression-free survivalPositive metastatic breast cancerHuman epidermal growth factor receptor 2End pointEpidermal growth factor receptor 2Sustained antitumor activityAntitumor activityMedian overall survivalPrimary end point
2022
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).
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
HER2CLIMB-04: Phase 2 open label trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ unresectable locally advanced or metastatic breast cancer with and without brain metastases (trial in progress).
Krop I, Ramos J, Zhang C, Hamilton E. HER2CLIMB-04: Phase 2 open label trial of tucatinib plus trastuzumab deruxtecan in patients with HER2+ unresectable locally advanced or metastatic breast cancer with and without brain metastases (trial in progress). Journal Of Clinical Oncology 2021, 39: tps1097-tps1097. DOI: 10.1200/jco.2021.39.15_suppl.tps1097.Peer-Reviewed Original ResearchHuman epidermal growth factor receptor 2Metastatic breast cancerProgression-free survivalDisease control rateDuration of responseBrain metastasesOverall survivalT-DXdEpidermal growth factor receptorRECIST v1.1Metastatic settingTrastuzumab deruxtecanBreast cancerOpen-label phase 2 trialPhase 2 open-label trialSmall molecule tyrosine kinase inhibitorsTopoisomerase I inhibitor payloadTreatment of HER2Epidermal growth factor receptor 2Molecule tyrosine kinase inhibitorsHuman epidermal growth factor receptorActive brain metastasesCombination of tucatinibSolid Tumors v1.1Objective response rate
2020
TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded).
Tung N, Robson M, Ventz S, Santa-Maria C, Marcom P, Nanda R, Shah P, Ballinger T, Yang E, Melisko M, Brufsky A, Vinayak S, Demeo M, Jenkins C, Domchek S, Wulf G, Krop I, Wolff A, Winer E, Garber J. TBCRC 048: A phase II study of olaparib monotherapy in metastatic breast cancer patients with germline or somatic mutations in DNA damage response (DDR) pathway genes (Olaparib Expanded). Journal Of Clinical Oncology 2020, 38: 1002-1002. DOI: 10.1200/jco.2020.38.15_suppl.1002.Peer-Reviewed Original ResearchSGNLVA-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
2017
A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (mBC) (HER2CLIMB).
Anders C, Murthy R, Hamilton E, Borges V, Cameron D, Carey L, Müller V, Curigliano G, Gelmon K, Hortobagyi G, Krop I, Loibl S, Pivot X, Pegram M, Slamon D, Hurvitz S, Tsai M, Winer E. A randomized, double-blinded, controlled study of tucatinib (ONT-380) vs. placebo in combination with capecitabine (C) and trastuzumab (Tz) in patients with pretreated HER2+ unresectable locally advanced or metastatic breast carcinoma (mBC) (HER2CLIMB). Journal Of Clinical Oncology 2017, 35: tps1107-tps1107. DOI: 10.1200/jco.2017.35.15_suppl.tps1107.Peer-Reviewed Original ResearchProgression-free survivalMetastatic breast carcinomaBrain metsIndependent data monitoring committeeClinical benefit ratePhase 1b studyDuration of responseIndependent central reviewPrimary study objectiveData monitoring committeeCNS progressionEGFR agentsPo bidBrain metastasesAdult patientsObjective responseOverall survivalCentral reviewStudy treatmentT-DM1CNS therapyTrastuzumab emtansineBenefit rateSelective small molecule inhibitorsBreast carcinoma
2012
LBA12 Results from Emilia, A Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine (X) and Lapatinib (L) in Her2-Positive Locally Advanced or Metastatic Breast Cancer (MBC)
Verma S, Miles D, Gianni L, Krop I, Welslau M, Baselga J, Pegram M, Oh D, Diéras V, Guardino E, Fang L, Lu M, Olsen S, Blackwell K. LBA12 Results from Emilia, A Phase 3 Study of Trastuzumab Emtansine (T-DM1) vs Capecitabine (X) and Lapatinib (L) in Her2-Positive Locally Advanced or Metastatic Breast Cancer (MBC). Annals Of Oncology 2012, 23: ixe5-ixe6. DOI: 10.1016/s0923-7534(20)34362-3.Peer-Reviewed Original ResearchProgression-free survivalGenentech/RocheMetastatic breast cancerClinical benefit rateSecondary end pointsT-DM1Overall survivalEnd pointObjective responseTreatment failureBenefit ratePrior treatmentKey secondary end pointInterim overall survivalObjective response ratePrimary end pointSubgroups of ptsHormone receptor statusStudy end pointPhase 3 studyDuration of responsePotential new therapiesFinal PFS analysisCardiac AEsMBC therapyResults from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab.
Modi S, Elias A, LoRusso P, Samant M, Guardino E, Althaus B, Krop I. Results from a phase Ib study of trastuzumab emtansine (T-DM1), paclitaxel (T), and pertuzumab (P) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. Journal Of Clinical Oncology 2012, 30: 528-528. DOI: 10.1200/jco.2012.30.15_suppl.528.Peer-Reviewed Original ResearchHER2-positive metastatic breast cancerMetastatic breast cancerT-DM1Prior systemic therapyPhase Ib studyPhase II studyDose-escalation studySingle-agent activityDuration of responseDose escalation schemeFuture clinical trialsDLT criteriaII studyMedian ageSystemic therapyExtension trialPreclinical dataTrastuzumab emtansineClinical trialsMedian numberToxicity CriteriaBreast cancerIb studyPhase IbQ3w