2024
Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer
Greenman M, Bellone S, Demirkiran C, Hartwich T, Santin A. Sacituzumab govitecan in heavily pretreated, platinum-resistant high grade serous ovarian cancer. Gynecologic Oncology Reports 2024, 54: 101459. PMID: 39108617, PMCID: PMC11300917, DOI: 10.1016/j.gore.2024.101459.Peer-Reviewed Original ResearchHigh grade serous ovarian cancerAntibody-drug conjugatesSerous ovarian cancerSacituzumab govitecanOvarian cancerTreatment optionsPlatinum-resistant ovarian cancer patientsDose-limiting toxicityOvarian cancer patientsNovel treatment optionsPartial responseRecurrent diseaseDose reductionCancer patientsClinical trialsBackground treatmentTargeted treatmentChemotherapyTreatmentCancerDoseDiseaseOptionsTrop2PatientsPreclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma
McNamara B, Greenman M, Bellone S, Santin L, Demirkiran C, Mutlu L, Hartwich T, Yang-Hartwich Y, Ratner E, Schwartz P, Santin A. Preclinical activity of datopotamab deruxtecan, a novel TROP2 directed antibody-drug conjugate targeting trophoblast cell-surface antigen 2 (TROP2) in ovarian carcinoma. Gynecologic Oncology 2024, 189: 16-23. PMID: 38981151, DOI: 10.1016/j.ygyno.2024.07.002.Peer-Reviewed Original ResearchTargets trophoblast cell-surface antigen-2Epithelial ovarian cancerAntibody-dependent cellular cytotoxicityPreclinical activityAntibody drug conjugatesOvarian cancerCell linesTumor cellsTrophoblast cell surface antigen 2Cell line-derived xenograft modelFlow cytometryCompared to tumor cellsEpithelial ovarian cancer cell linesOvarian cancer cell linesTumor cells in vitroOvarian cancer patientsPeripheral-blood lymphocytesEOC cell linesTumor growth suppressionAnnexin V-positiveGynecologic cancer mortalityIn vivo antitumor activityCells in vitroPrimary cell linesUnmet medical needTrastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2
Mutlu L, McNamara B, Bellone S, Manavella D, Demirkiran C, Greenman M, Verzosa M, Buza N, Hui P, Hartwich T, Harold J, Yang-Hartwich Y, Zipponi M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Schwartz P, Santin A. Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody–drug conjugate, demonstrates in vitro and in vivo antitumor activity against primary and metastatic ovarian tumors overexpressing HER2. Clinical & Experimental Metastasis 2024, 1-11. PMID: 38909139, DOI: 10.1007/s10585-024-10297-z.Peer-Reviewed Original ResearchHigh-grade serous ovarian cancerClear cell carcinomaHER2-targeting antibody-drug conjugateAntibody-drug conjugatesT-DXdReceptor over-expressionTrastuzumab deruxtecanXenograft modelCell linesOvarian clear cell carcinomaOvarian cancer cell linesTumors overexpressing HER2Biologically aggressive tumorsFluorescence in situ hybridization assaySerous ovarian cancerEffective antibody-drug conjugatesIn vivo antitumor activityMouse xenograft modelMetastatic cell linesDS-8201aCancer cell linesAggressive tumorsHER2 expressionCell carcinomaOvarian cancerRandomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer (NCT03093155): Updated survival and subgroup analyses
Roque D, Siegel E, Buza N, Bellone S, Huang G, Altwerger G, Andikyan V, Clark M, Azodi M, Schwartz P, Rao G, Ratner E, Santin A. Randomized phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer (NCT03093155): Updated survival and subgroup analyses. BJC Reports 2024, 2: 43. DOI: 10.1038/s44276-024-00067-5.Peer-Reviewed Original ResearchPre-treated ovarian cancerOverall survivalBev armsDose reductionOvarian cancerTaxane responseRandomized phase 2 trialRandomized phase II trialPaclitaxel-resistant diseaseResultsThirty-seven patientsTreated with paclitaxelPhase 2 trialBiweekly bevacizumabDays 1,8,15Taxane-sensitiveUpdate survivalProgression-freePeritoneal cancerDose modificationTaxane sensitivityPlatinum resistanceSubset analysisSubgroup analysisResponse ratePatientsPreclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition in low grade serous ovarian cancer
McNamara B, Demirkiran C, Hartwich T, Bellone S, Manavella D, Mutlu L, Greenman M, Zipponi M, Yang-Hartwich Y, Yang K, Ratner E, Schwartz P, Coma S, Pachter J, Santin A. Preclinical efficacy of RAF/MEK clamp avutometinib in combination with FAK inhibition in low grade serous ovarian cancer. Gynecologic Oncology 2024, 183: 133-140. PMID: 38493021, DOI: 10.1016/j.ygyno.2024.01.028.Peer-Reviewed Original ResearchLow grade serous ovarian carcinomaWhole-exome-sequencingGain-of-function mutationsVS-4718Preclinical efficacyLow grade serous ovarian cancerSerous ovarian cancerControl-treated miceTumor growth inhibitionWild-type KRASLoss of heterozygosityDecreased p-ERKRAF/MEK inhibitionMedian survivalOvarian cancerRecurrence rateTherapeutic optionsOral gavageTumor growthTumor samplesIn vivo activityMAPK pathway genesRAF/MEK inhibitorsP-ERKEx vivo
2023
#523 Initial efficacy and safety results from ENGOT-Ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC)
Banerjee S, Ring K, Niewenhuysen E, Fabbro M, Aghajanian C, Oaknin A, Colombo N, Santin A, Clamp A, Moore K, Rose P, David M O, Chon H, Salinas E, Prendergast E, Lustgarten S, Rodrigues M, Gennigens C, Monk B, Grisham R. #523 Initial efficacy and safety results from ENGOT-Ov60/GOG-3052/RAMP 201: a phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). 2023, a20-a21. DOI: 10.1136/ijgc-2023-esgo.29.Peer-Reviewed Original ResearchHyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer
Gelissen J, Adjei N, McNamara B, Mutlu L, Harold J, Clark M, Altwerger G, Dottino P, Huang G, Santin A, Azodi M, Ratner E, Schwartz P, Andikyan V. Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. Annals Of Surgical Oncology 2023, 30: 5597-5609. PMID: 37358686, DOI: 10.1245/s10434-023-13757-0.Peer-Reviewed Original ResearchConceptsHyperthermic intraperitoneal chemotherapyIntraperitoneal chemotherapyOvarian cancerStage III epithelial ovarian cancerUse of HIPECEpithelial ovarian cancerHigh-quality evidenceOvarian cancer treatmentHIPEC useInterval cytoreductionCytoreductive surgeryNeoadjuvant chemotherapyPerioperative careHIPEC protocolsHIPEC techniqueTreatment modalitiesPatient outcomesSingle administrationTumor disseminationChemotherapyCancerCancer treatmentOptimal candidatesMain siteLife dataInitial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC).
Banerjee S, Ring K, Van Nieuwenhuysen E, Fabbro M, Aghajanian C, Oaknin A, Colombo N, Santin A, Clamp A, Moore K, Rose P, O'Malley D, Chon H, Salinas E, Prendergast E, Lustgarten S, Rodrigues M, Gennigens C, Monk B, Grisham R. Initial efficacy and safety results from ENGOT-ov60/GOG-3052/RAMP 201: A phase 2 study of avutometinib (VS-6766) ± defactinib in recurrent low-grade serous ovarian cancer (LGSOC). Journal Of Clinical Oncology 2023, 41: 5515-5515. DOI: 10.1200/jco.2023.41.16_suppl.5515.Peer-Reviewed Original ResearchRecurrent low-grade serous ovarian cancerLow-grade serous ovarian cancerOptimal regimenPartial responseKRAS statusOvarian cancerHigher disease control rateMost AEsMEK inhibitorsBlinded independent central reviewRAF/MEK inhibitionDisease control ratePrior systemic regimensSimilar AE profilesNew safety signalsPhase 2 studyIndependent central reviewKey inclusion criteriaSerous ovarian cancerSynergistic antitumor activityMajority of treatmentsDermatitis acneiformEvaluable patientsCombination armSystemic regimensThe Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo
Han C, McNamara B, Bellone S, Harold J, Manara P, Hartwich T, Mutlu L, Yang-Hartwich Y, Zipponi M, Demirkiran C, Verzosa M, Altwerger G, Ratner E, Huang G, Clark M, Andikyan V, Azodi M, Dottino P, Schwartz P, Santin A. The Poly (ADP-ribose) polymerase inhibitor olaparib and pan-ErbB inhibitor neratinib are highly synergistic in HER2 overexpressing epithelial ovarian carcinoma in vitro and in vivo. Gynecologic Oncology 2023, 170: 172-178. PMID: 36706643, PMCID: PMC10023457, DOI: 10.1016/j.ygyno.2023.01.015.Peer-Reviewed Original ResearchConceptsCombination of olaparibOvarian cancerHER2 expressionSingle agentCell linesGynecologic cancer mortalityHER2-negative tumorsOvarian cancer cell linesOvarian cancer patientsEpithelial ovarian carcinomaNovel therapeutic optionsOC cell linesUnmet medical needPoly (ADP-ribose) polymerase (PARP) inhibitorsPan-ErbB inhibitorSingle-agent olaparibPolymerase inhibitor olaparibPoly (ADP-ribose) polymerase (PARP) inhibitor olaparibPrimary HER2Cancer cell linesNegative tumorsTherapeutic optionsCancer mortalityCancer patientsNeu expressionChapter 3 Ovarian carcinosarcoma
Tymon-Rosario J, Chui M, Santin A. Chapter 3 Ovarian carcinosarcoma. 2023, 41-54. DOI: 10.1016/b978-0-323-82938-0.00003-3.Peer-Reviewed Original ResearchHigh-grade serous ovarian carcinomaSurvival of womenEpithelial ovarian cancerSerous ovarian carcinomaEpithelial-mesenchymal transitionCarcinosarcoma patientsGynecologic tractHistologic subtypeOvarian carcinosarcomaAggressive diseaseAggressive malignancyCarcinoma componentOvarian tumorsClinical managementOvarian carcinomaClinical trialsOvarian cancerSarcomatous elementsAggressive natureCarcinosarcomaTumorsDiseaseSurvivalMolecular studiesPatients
2022
Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study
Santin A, Vergote I, González-Martín A, Moore K, Oaknin A, Romero I, Diab S, Copeland L, Monk B, Coleman R, Herzog T, Siegel J, Kasten L, Schlicker A, Schulz A, Köchert K, Walter A, Childs B, Elbi C, Bulat I. Safety and activity of anti-mesothelin antibody–drug conjugate anetumab ravtansine in combination with pegylated-liposomal doxorubicin in platinum-resistant ovarian cancer: multicenter, phase Ib dose escalation and expansion study. International Journal Of Gynecological Cancer 2022, 33: ijgc-2022-003927. PMID: 36564099, PMCID: PMC10086500, DOI: 10.1136/ijgc-2022-003927.Peer-Reviewed Original ResearchConceptsPlatinum-resistant ovarian cancerProgression-free survivalMedian progression-free survivalAnetumab ravtansineObjective response rateOvarian cancerLiposomal doxorubicinMedian durationAdverse eventsDose escalationMesothelin expressionCommon treatment-emergent adverse eventsPlatinum-resistant epithelial ovarian cancerResponse rateAnti-mesothelin monoclonal antibodyTreatment-emergent adverse eventsHigh mesothelin expressionPegylated-liposomal doxorubicinPhase Ib studyPhase III studyDose-limiting toxicityPromising clinical activityEpithelial ovarian cancerAnti-tumor activityCentral immunohistochemistryEP015/#546 In vitro and in vivo efficacy of trastuzumab deruxtecan (T-DXd) in epithelial ovarian cancer with HER2/NEU overexpression
Mutlu L, Manavella D, Bellone S, Santin A. EP015/#546 In vitro and in vivo efficacy of trastuzumab deruxtecan (T-DXd) in epithelial ovarian cancer with HER2/NEU overexpression. 2022, a54.2-a54. DOI: 10.1136/ijgc-2022-igcs.106.Peer-Reviewed Original Research2022-LBA-325-ESGO Patients with newly diagnosed ovarian cancer treated with maintenance rucaparib: exploratory biomarker analysis from the phase 3 ATHENA-MONO study (GOG-3020/ENGOT-ov45; NCT03522246)
Oaknin A, Kristeleit R, Mahdi H, Lim M, de Vivo R, Salinas E, Wilson M, Liontos M, Santin A, Provencher D, Demirkiran F, Willmott L, Chudecka-Głaz A, Herzog T, Beiner M, Copeland L, McNeish I, Lin K, Monk B. 2022-LBA-325-ESGO Patients with newly diagnosed ovarian cancer treated with maintenance rucaparib: exploratory biomarker analysis from the phase 3 ATHENA-MONO study (GOG-3020/ENGOT-ov45; NCT03522246). 2022, a472.1-a472. DOI: 10.1136/ijgc-2022-esgo.1018.Peer-Reviewed Original ResearchRandomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer
Roque DM, Siegel ER, Buza N, Bellone S, Silasi DA, Huang GS, Andikyan V, Clark M, Azodi M, Schwartz PE, Rao GG, Reader JC, Hui P, Tymon-Rosario JR, Harold J, Mauricio D, Zeybek B, Menderes G, Altwerger G, Ratner E, Santin AD. Randomised phase II trial of weekly ixabepilone ± biweekly bevacizumab for platinum-resistant or refractory ovarian/fallopian tube/primary peritoneal cancer. British Journal Of Cancer 2022, 126: 1695-1703. PMID: 35149854, PMCID: PMC8853032, DOI: 10.1038/s41416-022-01717-6.Peer-Reviewed Original ResearchConceptsPrimary peritoneal cancerPeritoneal cancerPredictive biomarkersDay 1Taxane-resistant ovarian cancerPhase II trialM2 days 1Bevacizumab 10Evaluable patientsPrior bevacizumabWeekly ixabepiloneII trialPrimary endpointSecondary endpointsRefractory statusTUBB3 expressionPrior receiptSubgroup analysisClinical trialsOvarian cancerIxabepilonePFSCancerBevacizumabPatientsMicrotentacle Formation in Ovarian Carcinoma
Reader JC, Fan C, Ory EC, Ju J, Lee R, Vitolo MI, Smith P, Wu S, Ching MMN, Asiedu EB, Jewell CM, Rao GG, Fulton A, Webb TJ, Yang P, Santin AD, Huang HC, Martin SS, Roque DM. Microtentacle Formation in Ovarian Carcinoma. Cancers 2022, 14: 800. PMID: 35159067, PMCID: PMC8834106, DOI: 10.3390/cancers14030800.Peer-Reviewed Original ResearchHuman ovarian surface epitheliumOvarian cancerCell linesCancer cellsMajor therapeutic challengeIntraperitoneal drug deliveryOvarian surface epitheliumOvarian cancer metastasisNew therapeutic targetsDevelopment of chemoresistanceEffect of treatmentBreast cancer cellsOSC cell linesExtrapelvic metastasesMalignant ascitesTherapeutic challengeOvarian carcinomaSurface epitheliumTherapeutic targetMetastatic potentialAscitesCancer metastasisΒ-tubulin isotypesIndividual cancer cellsMetastasis
2021
Microtubule-Interfering Drugs: Current and Future Roles in Epithelial Ovarian Cancer Treatment
Tymon-Rosario J, Adjei NN, Roque DM, Santin AD. Microtubule-Interfering Drugs: Current and Future Roles in Epithelial Ovarian Cancer Treatment. Cancers 2021, 13: 6239. PMID: 34944858, PMCID: PMC8699494, DOI: 10.3390/cancers13246239.Peer-Reviewed Original ResearchEpithelial ovarian cancerOvarian cancerClinical dataEpithelial ovarian cancer treatmentTaxane-treated patientsUse of ixabepiloneRefractory ovarian cancerOngoing clinical trialsStandard of careOvarian cancer treatmentClinical trialsRecurrent treatmentTaxane resistanceCurrent standard practiceChemotherapeutic agentsTherapeutic agentsCancerCancer treatmentPutative mechanismsMicrotubular functionTreatmentDrugs partTaxanesCell deathCurrent useNovel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer
Mauricio D, Harold J, Tymon-Rosario JR, Zeybek B, Santin AD. Novel mesothelin antibody-drug conjugates: current evidence and future role in the treatment of ovarian cancer. Expert Opinion On Biological Therapy 2021, 21: 1087-1096. PMID: 33356644, DOI: 10.1080/14712598.2021.1869210.Peer-Reviewed Original ResearchConceptsAntibody-drug conjugatesOvarian cancerProgressive diseaseFavorable adverse effect profilePromising novel therapeutic agentAdverse effect profilePhase II trialDeadliest gynecologic malignancyPhase III dataNovel therapeutic agentsII trialGynecologic malignanciesEffect profileClinical resultsEffective therapyAvailable agentsCurrent evidenceNovel treatmentsChemotherapeutic agentsCancerTherapeutic agentsAdverse effectsMesothelinVivo dataDisease
2020
Association of gene expression signatures and TMB with response to pembrolizumab (pembro) in patients (pts) with recurrent ovarian cancer (ROC) enrolled in KEYNOTE-100
Ledermann J, Shapira-Frommer R, Santin A, Lisyanskaya A, Pignata S, Vergote I, Raspagliesi F, Sonke G, Birrer M, Provencher D, Sehouli J, Colombo N, Martín A, Oaknin A, Saadatpour A, Kobie J, Jelinic P, Stein K, Matulonis U. Association of gene expression signatures and TMB with response to pembrolizumab (pembro) in patients (pts) with recurrent ovarian cancer (ROC) enrolled in KEYNOTE-100. Annals Of Oncology 2020, 31: s631-s632. DOI: 10.1016/j.annonc.2020.08.982.Peer-Reviewed Original ResearchFinal results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer.
Matulonis U, Shapira R, Santin A, Lisyanskaya A, Pignata S, Vergote I, Raspagliesi F, Sonke G, Birrer M, Sehouli J, Colombo N, González-Martín A, Oaknin A, Ottevanger P, Rudaitis V, Wu H, Keefe S, Stein K, Ledermann J. Final results from the KEYNOTE-100 trial of pembrolizumab in patients with advanced recurrent ovarian cancer. Journal Of Clinical Oncology 2020, 38: 6005-6005. DOI: 10.1200/jco.2020.38.15_suppl.6005.Peer-Reviewed Original ResearchRecurrent advanced ovarian cancerAdvanced ovarian cancerPD-L1 expressionECOG PS 0Prior chemotherapy linesCohort AChemotherapy linesMedian OSPS 0Ovarian cancerFront-line platinum-based therapyAdvanced recurrent ovarian cancerHigh PD-L1 expressionHigh-grade serous diseaseProtocol-specified final analysisTumor PD-L1 expressionTreatment-related AEsPrimary peritoneal cancerRecurrent ovarian cancerTreatment-free intervalTreatment-related deathsModest antitumor activityModest clinical activityNew safety signalsPrimary study endpointPreclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer
Perrone E, Lopez S, Zeybek B, Bellone S, Bonazzoli E, Pelligra S, Zammataro L, Manzano A, Manara P, Bianchi A, Buza N, Tymon-Rosario J, Altwerger G, Han C, Menderes G, Ratner E, Silasi DA, Azodi M, Hui P, Schwartz PE, Scambia G, Santin AD. Preclinical Activity of Sacituzumab Govitecan, an Antibody-Drug Conjugate Targeting Trophoblast Cell-Surface Antigen 2 (Trop-2) Linked to the Active Metabolite of Irinotecan (SN-38), in Ovarian Cancer. Frontiers In Oncology 2020, 10: 118. PMID: 32117765, PMCID: PMC7028697, DOI: 10.3389/fonc.2020.00118.Peer-Reviewed Original ResearchTrop-2 expressionEOC cell linesSacituzumab govitecanEpithelial ovarian cancerPrimary tumor cell linesPreclinical activityTrop-2EOC xenograftsOvarian cancerTrophoblast cell surface antigen 2Cell linesActive metaboliteTumor cell linesImpressive anti-tumor activityCell surface antigen 2Lethal gynecologic malignancyHigh ADCC activityAnti-tumor activityParaffin-embedded tumorsSignificant bystander killingGynecologic malignanciesADCC activityEOC tissuesOvarian tumorsClinical trials