2024
Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer
Hartwich T, Mansolf M, Demirkiran C, Greenman M, Bellone S, McNamara B, Nandi S, Alexandrov L, Yang‐Hartwich Y, Coma S, Pachter J, Santin A. Preclinical evaluation of avutometinib and defactinib in high‐grade endometrioid endometrial cancer. Cancer Medicine 2024, 13: e70210. PMID: 39240189, PMCID: PMC11378359, DOI: 10.1002/cam4.70210.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsAntineoplastic Combined Chemotherapy ProtocolsBenzamidesCarcinoma, EndometrioidCell Line, TumorCell ProliferationEndometrial NeoplasmsExome SequencingFemaleFocal Adhesion Kinase 1HumansImidazolesMiceNeoplasm GradingOxazepinesProtein Kinase InhibitorsPyrazinesSulfonamidesXenograft Model Antitumor AssaysConceptsFocal adhesion kinaseWhole-exome sequencingEndometrial cancer cell linesVS-4718Cell linesRas/MAPK pathwayPhosphorylated focal adhesion kinaseWestern blot assayWhole-exome sequencing resultsRAF/MEK inhibitionEAC cell linesBlot assayP-FAKGenetic landscapeCell cycleEndometrial cancerGenetic derangementsDefactinibP-MEKGrowth inhibitionRAF/MEKRas/MAPKCell viabilityP-ERKHigh-grade endometrial cancerEfficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer
Santin A, Corr B, Spira A, Willmott L, Butrynski J, Tse K, Patel J, Mekan S, Wu T, Lin K, Kuo P, Dumbrava E. Efficacy and Safety of Sacituzumab Govitecan in Patients With Advanced Solid Tumors (TROPiCS-03): Analysis in Patients With Advanced Endometrial Cancer. Journal Of Clinical Oncology 2024, 42: 3421-3429. PMID: 39083724, PMCID: PMC11458108, DOI: 10.1200/jco.23.02767.Peer-Reviewed Original ResearchProgression-free survivalDuration of responseTreatment-related adverse eventsAdvanced endometrial cancerEndometrial cancerSacituzumab govitecanTrop-2Investigator assessmentSolid tumorsTrophoblast cell surface antigen 2Median duration of responsePhase II basket studyMedian progression-free survivalEnd pointsBaseline tumor specimensClinical benefit ratePlatinum-based therapyStudy drug discontinuationAdvanced solid tumorsMedian follow-upMetastatic solid tumorsTrop-2 expressionSecondary end pointsPrimary end pointEfficacy of SG
2023
TROPiCS-03: A phase 2 basket study of sacituzumab govitecan (SG) in patients (pts) with metastatic solid tumors—Early analysis in pts with advanced/metastatic endometrial cancer (EC).
Santin A, Corr B, Spira A, Willmott L, Butrynski J, Tse K, Patel J, Mekan S, Wu T, Dumbrava E. TROPiCS-03: A phase 2 basket study of sacituzumab govitecan (SG) in patients (pts) with metastatic solid tumors—Early analysis in pts with advanced/metastatic endometrial cancer (EC). Journal Of Clinical Oncology 2023, 41: 5610-5610. DOI: 10.1200/jco.2023.41.16_suppl.5610.Peer-Reviewed Original ResearchTreatment-related adverse eventsClinical benefit rateProgression-free survivalDuration of responseWeeks of follow-upPt-based chemotherapyStable diseasePartial responseOpen-labelEndometrial cancerSafety profileFollow-upECOG PS 0-1Median duration of responseMedian progression-free survivalMedian study follow-upEC cohortAnti-PD-(L)1Metastatic solid tumorsStandard therapeutic regimensLimited treatment optionsStudy follow-upEfficacy of SGAntibody-drug conjugatesECOG PSMonitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers
Bellone S, McNamara B, Mutlu L, Demirkiran C, Hartwich T, Harold J, Yang-Hartwich Y, Siegel E, Santin A. Monitoring Treatment Response, Early Recurrence, and Survival in Uterine Serous Carcinoma and Carcinosarcoma Patients Using Personalized Circulating Tumor DNA Biomarkers. International Journal Of Molecular Sciences 2023, 24: 8873. PMID: 37240216, PMCID: PMC10219151, DOI: 10.3390/ijms24108873.Peer-Reviewed Original ResearchConceptsUterine serous carcinomaCS patientsEarly recurrenceDroplet digital polymerase chain reactionCA 125Serous carcinomaCtDNA testingTime of surgeryTime of recurrenceReliable tumor biomarkersTumour DNA biomarkersCarcinosarcoma patientsUSC patientsRecurrent diseaseOccult diseaseOverall survivalEndometrial cancerAggressive variantInitial treatmentRecurrent tumorsResidual tumorClinical findingsTreatment courseTreatment trialsPIK3CA mutationsLenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775
Makker V, Colombo N, Herráez A, Monk B, Mackay H, Santin A, Miller D, Moore R, Baron-Hay S, Ray-Coquard I, Ushijima K, Yonemori K, Kim Y, Alia E, Sanli U, Bird S, Orlowski R, McKenzie J, Okpara C, Barresi G, Lorusso D. Lenvatinib Plus Pembrolizumab in Previously Treated Advanced Endometrial Cancer: Updated Efficacy and Safety From the Randomized Phase III Study 309/KEYNOTE-775. Journal Of Clinical Oncology 2023, 41: 2904-2910. PMID: 37058687, PMCID: PMC10414727, DOI: 10.1200/jco.22.02152.Peer-Reviewed Original ResearchConceptsObjective response rateProgression-free survivalPrimary end pointAdvanced endometrial cancerOverall survivalEndometrial cancerEnd pointMismatch repair-proficient tumorsClinical trial updateMetastatic endometrial cancerNew safety signalsSubgroups of interestManageable safetyPrespecified analysisTrial updateProficient tumorsClinical trialsSafety signalsPembrolizumabLenvatinibPhysician's choiceMultiple end pointsResponse rateSecondary analysisChemotherapyHealth-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician’s Choice
Lorusso D, Colombo N, Herraez A, Santin A, Colomba E, Miller D, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Kim Y, McCormack M, Massaad R, Nguyen A, Zhao Q, McKenzie J, Prabhu V, Makker V. Health-Related Quality of Life in Patients With Advanced Endometrial Cancer Treated With Lenvatinib Plus Pembrolizumab or Treatment of Physician’s Choice. European Journal Of Cancer 2023, 186: 172-184. PMID: 37086595, PMCID: PMC11003310, DOI: 10.1016/j.ejca.2023.03.015.Peer-Reviewed Original ResearchConceptsAdvanced endometrial cancerEndometrial cancerWeek 12Life QuestionnaireDefinitive deteriorationFunctional scalesPhysician's choiceGlobal health status/qualityFavorable benefit/risk profileHealth status/qualityBenefit/risk profileEuroQol-5 DimensionsHealth-related qualityTreatment of patientsTingling/numbnessImpact of treatmentQuality of lifeRate of completionHRQOL endpointsAppetite lossPoor body imageCancer QualityLife scoresMuscular painSafety resultsMismatch repair deficiency, next-generation sequencing-based microsatellite instability, and tumor mutational burden as predictive biomarkers for immune checkpoint inhibitor effectiveness in frontline treatment of advanced stage endometrial cancer
Hill B, Graf R, Shah K, Danziger N, Lin D, Quintanilha J, Li G, Haberberger J, Ross J, Santin A, Slomovitz B, Elvin J, Eskander R. Mismatch repair deficiency, next-generation sequencing-based microsatellite instability, and tumor mutational burden as predictive biomarkers for immune checkpoint inhibitor effectiveness in frontline treatment of advanced stage endometrial cancer. International Journal Of Gynecological Cancer 2023, 33: 504-513. PMID: 36750267, PMCID: PMC10086481, DOI: 10.1136/ijgc-2022-004026.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsAdvanced endometrial cancerTumor mutational burdenAdjusted hazard ratioEndometrial cancerCheckpoint inhibitorsOverall survivalMismatch repair deficiencyFrontline treatmentMicrosatellite instabilityMutational burdenNext treatmentTreatment discontinuationSingle-agent immune checkpoint inhibitorsAdvanced stage endometrial cancerImmune checkpoint inhibitor effectivenessImmune checkpoint inhibitor monotherapyImmune checkpoint inhibitor treatmentCox proportional hazards modelCheckpoint inhibitor monotherapyStage endometrial cancerPhase III trialsRepair deficiencyCheckpoint inhibitor treatmentLog-rank test
2022
O018/#482 Updated safety of lenvatinib + pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/keynote-775
Makker V, Colombo N, Herráez A, Monk B, Mackay H, Santin A, Miller D, Moore R, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Yonemori K, Kim Y, Alia E, Sanli U, Xie R, Zale M, Mckenzie J, Barresi G, Lorusso D. O018/#482 Updated safety of lenvatinib + pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/keynote-775. 2022, a11-a11. DOI: 10.1136/ijgc-2022-igcs.20.Peer-Reviewed Original ResearchDistinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma.
Chow RD, Michaels T, Bellone S, Hartwich T, Bonazzoli E, Iwasaki A, Song E, Santin AD. Distinct Mechanisms of Mismatch-Repair Deficiency Delineate Two Modes of Response to Anti-PD-1 Immunotherapy in Endometrial Carcinoma. Cancer Discovery 2022, 13: 312-331. PMID: 36301137, PMCID: PMC9905265, DOI: 10.1158/2159-8290.cd-22-0686.Peer-Reviewed Original ResearchConceptsAnti-PD-1 immunotherapyImmune checkpoint blockadeMMRd tumorsNK cellsEndometrial carcinomaICB responseMutation burdenT-cell-driven immunityPhase II clinical trialMMRd endometrial cancersPD-1 inhibitorsMismatch repair-deficient cancersTumor-extrinsic factorsHigh response rateEffector CD8Antitumor immunityEndometrial cancerCancer immunotherapyImmune cellsLonger survivalClinical trialsPrimary resistanceT cellsResponse rateMMRdEndometrial Cancer in Reproductive Age: Fertility-Sparing Approach and Reproductive Outcomes
Mutlu L, Manavella D, Gullo G, McNamara B, Santin A, Patrizio P. Endometrial Cancer in Reproductive Age: Fertility-Sparing Approach and Reproductive Outcomes. Cancers 2022, 14: 5187. PMID: 36358604, PMCID: PMC9656291, DOI: 10.3390/cancers14215187.Peer-Reviewed Original ResearchFertility-preserving approachEndometrial cancerLow-grade endometrial cancerFertility sparing approachStandard surgical treatmentCommon gynecologic malignancyGynecologic malignanciesOncologic outcomesSurgical treatmentPatient goalsReproductive ageReproductive outcomesClose monitoringCancerYoung womenConservative approachFertility goalsReproductive technologiesPatientsWomenAgeOutcomesEarly stagesHysterectomyMalignancy2022-RA-653-ESGO The impact of histology, prior therapy, and dMMR status on lenvatinib + pembrolizumab outcomes in patients with advanced endometrial cancer: A subgroup analysis of Study 309/KEYNOTE-775
Lorusso D, Makker V, Herraez A, Monk B, Mackay H, Santin A, Miller D, Moore R, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Yonemori K, Kim Y, Guerra Alia E, Sanli U, Huang J, McKenzie J, Barresi G, Colombo N. 2022-RA-653-ESGO The impact of histology, prior therapy, and dMMR status on lenvatinib + pembrolizumab outcomes in patients with advanced endometrial cancer: A subgroup analysis of Study 309/KEYNOTE-775. 2022, a102.1-a102. DOI: 10.1136/ijgc-2022-esgo.223.Peer-Reviewed Original Research525MO Updated efficacy and safety of lenvatinib (LEN) + pembrolizumab (pembro) vs treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): Study 309/KEYNOTE-775
Makker V, Colombo N, Herraez A, Monk B, Mackay H, Santin A, Miller D, Moore R, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Yonemori K, Kim Y, Alia E, Sanli U, Huang J, McKenzie J, Barresi G, Lorusso D. 525MO Updated efficacy and safety of lenvatinib (LEN) + pembrolizumab (pembro) vs treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): Study 309/KEYNOTE-775. Annals Of Oncology 2022, 33: s785-s786. DOI: 10.1016/j.annonc.2022.07.653.Peer-Reviewed Original ResearchEfficacy of next line of therapy after treatment with lenvatinib (LEN) in combination with pembrolizumab (pembro) versus treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): Exploratory analysis of Study 309/KEYNOTE-775.
Makker V, Colombo N, Santin A, Miller D, Fujiwara K, Pignata S, Ray-Coquard I, Kim Y, Guerra E, Huang J, Barresi G, McKenzie J, Lorusso D. Efficacy of next line of therapy after treatment with lenvatinib (LEN) in combination with pembrolizumab (pembro) versus treatment of physician’s choice (TPC) in patients (pts) with advanced endometrial cancer (aEC): Exploratory analysis of Study 309/KEYNOTE-775. Journal Of Clinical Oncology 2022, 40: 5587-5587. DOI: 10.1200/jco.2022.40.16_suppl.5587.Peer-Reviewed Original ResearchAdvanced endometrial cancerComers populationTPC armEastern Cooperative Oncology Group performance statusPrior platinum-based chemotherapy regimenPlatinum-based chemotherapy regimenObjective response rateOverall survival benefitPrespecified exploratory analysisSystemic anticancer therapyPlatinum-based treatmentMedian PFS2PMMR tumorsChemotherapy regimenPelvic radiationData cutoffPerformance statusEndometrial cancerInvestigator assessmentSurvival benefitStudy treatmentMMR statusLenvatinibPembroPhysician's choice20MO Time to deterioration in quality of life in patients (pts) with advanced endometrial cancer (aEC) treated with lenvatinib plus pembrolizumab (L+P) or treatment of physician’s choice (TPC)
Lorusso D, Colombo N, Herraez A, Santin A, Colomba E, Miller D, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Kim Y, McCormack M, Massaad R, Nguyen A, Zhao Q, McKenzie J, Prabhu V, Makker V. 20MO Time to deterioration in quality of life in patients (pts) with advanced endometrial cancer (aEC) treated with lenvatinib plus pembrolizumab (L+P) or treatment of physician’s choice (TPC). Annals Of Oncology 2022, 33: s391-s392. DOI: 10.1016/j.annonc.2022.04.038.Peer-Reviewed Original ResearchSynergistic activity of neratinib in combination with olaparib in uterine serous carcinoma overexpressing HER2/neu
Yadav G, Roque DM, Bellone S, Manavella DD, Hartwich TMP, Zipponi M, Harold J, Tymon-Rosario J, Mutlu L, Altwerger G, Menderes G, Ratner E, Buza N, Hui P, Huang GS, Andikyan V, Clark M, Azodi M, Schwartz PE, Alexandrov LB, Santin AD. Synergistic activity of neratinib in combination with olaparib in uterine serous carcinoma overexpressing HER2/neu. Gynecologic Oncology 2022, 166: 351-357. PMID: 35641325, DOI: 10.1016/j.ygyno.2022.05.021.Peer-Reviewed Original ResearchConceptsUterine serous carcinomaHER2/neu expressionHER2/neuCombination of olaparibUSC xenograftsUSC cell linesNeu expressionSerous carcinomaLow HER2/neu expressionHER2/neu 3Cell linesHER2/neu gene amplificationNovel therapeutic optionsPolymerase inhibitor olaparibNeu gene amplificationDurable growth inhibitionNeratinib treatmentUSC cellsUSC patientsEndometrial cancerAggressive variantTherapeutic optionsPoor prognosisHER2/Single agentLenvatinib Plus Pembrolizumab for Advanced Endometrial Cancer
Makker V, Colombo N, Herráez A, Santin A, Colomba E, Miller D, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim Y, Guerra E, Sanli U, McCormack M, Smith A, Keefe S, Bird S, Dutta L, Orlowski R, Lorusso D. Lenvatinib Plus Pembrolizumab for Advanced Endometrial Cancer. Obstetrical & Gynecological Survey 2022, 77: 275-276. DOI: 10.1097/ogx.0000000000001032.Peer-Reviewed Original ResearchEndometrial cancerRecurrent endometrial cancerSecond-line treatmentAdvanced endometrial cancerPlatinum-based chemotherapyRecurrent endometrial carcinomaTyrosine kinase inhibitorsEndometrial carcinomaOptimal treatmentDisease progressionLimited efficacySingle agentKinase inhibitorsLenvatinibCancerTreatmentPembrolizumabLittle consensusChemotherapyCarcinomaProgressionImmune checkpoint inhibitors for recurrent endometrial cancer
Mutlu L, Harold J, Tymon-Rosario J, Santin AD. Immune checkpoint inhibitors for recurrent endometrial cancer. Expert Review Of Anticancer Therapy 2022, 22: 249-258. PMID: 35176955, DOI: 10.1080/14737140.2022.2044311.Peer-Reviewed Original ResearchConceptsImmune checkpoint inhibitorsRecurrent endometrial cancerCheckpoint inhibitorsEndometrial cancerEC patientsAdvanced/recurrent endometrial cancerPD-1/PD-L1 inhibitorsRecurrent EC patientsUse of chemotherapyCommon gynecologic malignancyMajor clinical trialsPD-L1 inhibitorsBiomarkers of responseViable treatment optionHuman cancer treatmentTumor microenvironment immunosuppressionRecurrent diseaseGynecologic malignanciesPD-1Clinical efficacyPatient populationTreatment optionsTumor immunogenicityRecent trialsClinical trialsLenvatinib plus Pembrolizumab for Advanced Endometrial Cancer
Makker V, Colombo N, Casado Herráez A, Santin AD, Colomba E, Miller DS, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira-Frommer R, Ushijima K, Sakata J, Yonemori K, Kim YM, Guerra EM, Sanli UA, McCormack MM, Smith AD, Keefe S, Bird S, Dutta L, Orlowski RJ, Lorusso D. Lenvatinib plus Pembrolizumab for Advanced Endometrial Cancer. New England Journal Of Medicine 2022, 386: 437-448. PMID: 35045221, DOI: 10.1056/nejmoa2108330.Peer-Reviewed Original ResearchConceptsAdvanced endometrial cancerProgression-free survivalEndometrial cancerOverall survivalMedian progression-free survivalPlatinum-based chemotherapy regimenLonger progression-free survivalEnd pointBlinded independent central reviewMedian overall survivalPrimary end pointPhase 3 trialResponse Evaluation CriteriaPlatinum-based chemotherapyIndependent central reviewChemotherapy regimenAdverse eventsStandard therapyCentral reviewPembrolizumabGrade 3LenvatinibChemotherapyPhysician's choicePatients
2021
A phase 2 evaluation of pembrolizumab for recurrent Lynch‐like versus sporadic endometrial cancers with microsatellite instability
Bellone S, Roque DM, Siegel ER, Buza N, Hui P, Bonazzoli E, Guglielmi A, Zammataro L, Nagarkatti N, Zaidi S, Lee J, Silasi D, Huang GS, Andikyan V, Damast S, Clark M, Azodi M, Schwartz PE, Tymon‐Rosario J, Harold JA, Mauricio D, Zeybek B, Menderes G, Altwerger G, Ratner E, Alexandrov LB, Iwasaki A, Kong Y, Song E, Dong W, Elvin JA, Choi J, Santin AD. A phase 2 evaluation of pembrolizumab for recurrent Lynch‐like versus sporadic endometrial cancers with microsatellite instability. Cancer 2021, 128: 1206-1218. PMID: 34875107, PMCID: PMC9465822, DOI: 10.1002/cncr.34025.Peer-Reviewed Original ResearchConceptsObjective response rateImmune checkpoint inhibitorsProgression-free survivalEndometrial cancerWhole-exome sequencingSporadic endometrial cancerOverall survivalEnd pointPhase 2 pilot studyPrimary end pointSecondary end pointsTumor mutation burdenPhase 2 evaluationLarger confirmatory studiesAntigen processing/presentationProcessing/presentationCheckpoint inhibitorsSurgical resectionICI resistanceDMMR patientsPrognostic significanceDMMR tumorsMechanisms of resistanceLocal treatmentSporadic MSIO008/#785 A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/keynote-775
Makker V, Colombo N, Herráez A, Santin A, Colomba E, Miller D, Fujiwara K, Pignata S, Baron-Hay S, Ray-Coquard I, Shapira R, Ushijima K, Sakata J, Yonemori K, Kim Y, Guerra E, Sanli U, Mccormack M, Huang J, Smith A. O008/#785 A multicenter, open-label, randomized, phase 3 study to compare the efficacy and safety of lenvatinib in combination with pembrolizumab vs treatment of physician’s choice in patients with advanced endometrial cancer: study 309/keynote-775. International Journal Of Gynecological Cancer 2021, 31: a4-a5. DOI: 10.1136/ijgc-2021-igcs.8.Peer-Reviewed Original ResearchTreatment-emergent adverse eventsAdvanced endometrial cancerObjective response rateEndometrial cancerPhysician's choiceCommon treatment-emergent adverse eventsPrior platinum-based chemotherapy regimenPhase 3 study resultsPlatinum-based chemotherapy regimenPrior platinum-based chemotherapyDNA mismatch repair (MMR) statusBlinded independent central reviewPhase 1b/2 studySafety of lenvatinibKey secondary endpointMedian treatment durationAdvanced endometrial carcinomaPhase 3 studyPlatinum-based chemotherapyIndependent central reviewPlatinum-based therapyMismatch repair statusEligible ptsRECIST v1.1Adjuvant setting