2024
The 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
Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial
Desai J, Alonso G, Kim S, Cervantes A, Karasic T, Medina L, Shacham-Shmueli E, Cosman R, Falcon A, Gort E, Guren T, Massarelli E, Miller W, Paz-Ares L, Prenen H, Amatu A, Cremolini C, Kim T, Moreno V, Ou S, Passardi A, Sacher A, Santoro A, Stec R, Ulahannan S, Arbour K, Lorusso P, Luo J, Patel M, Choi Y, Shi Z, Mandlekar S, Lin M, Royer-Joo S, Chang J, Jun T, Dharia N, Schutzman J, Han S. Divarasib plus cetuximab in KRAS G12C-positive colorectal cancer: a phase 1b trial. Nature Medicine 2023, 30: 271-278. PMID: 38052910, PMCID: PMC10803265, DOI: 10.1038/s41591-023-02696-8.Peer-Reviewed Original ResearchPhase 1b trialColorectal cancerSafety profileMedian progression-free survivalTreatment-related adverse eventsInhibitor-naive patientsKRAS G12C inhibitionAntitumor activityManageable safety profileObjective response rateProgression-free survivalPreliminary antitumor activityKRAS G12C mutationKRAS G12C inhibitorsEpidermal growth factor receptorVariant allele frequencyGrowth factor receptorAdverse eventsMedian durationTreatment withdrawalPoor prognosisDisease progressionArm CDose reductionG12C inhibitorsAnti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors
Kim T, Bedard P, LoRusso P, Gordon M, Bendell J, Oh D, Ahn M, Garralda E, D’Angelo S, Desai J, Hodi F, Wainberg Z, Delord J, Cassier P, Cervantes A, Gil-Martin M, Wu B, Patil N, Jin Y, Hoang T, Mendus D, Wen X, Meng R, Cho B. Anti-TIGIT Antibody Tiragolumab Alone or With Atezolizumab in Patients With Advanced Solid Tumors. JAMA Oncology 2023, 9: 1574-1582. PMID: 37768658, PMCID: PMC10540058, DOI: 10.1001/jamaoncol.2023.3867.Peer-Reviewed Original ResearchConceptsObjective response rateAdvanced solid tumorsAdverse eventsPhase 1bAntitumor activityCancer cohortNon-small cell lung cancer (NSCLC) cohortFrequent treatment-related adverse eventsInvestigator-assessed objective response rateSolid tumorsCell lung cancer cohortTreatment-related adverse eventsMajority of AEsEnd pointClinical cutoff dateDose-escalation cohortsDose-expansion cohortsEsophageal cancer cohortPhase 2 dosePrior cancer therapyPrimary end pointSecondary end pointsHalf of patientsNew safety signalsAntitumor immune responsePlatinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All “BRCAness” Is Created Equal
Doroshow D, Wei W, Mehrotra M, Sia D, Eder J, Bindra R, Houldsworth J, LoRusso P, Walther Z. Platinum Sensitivity in IDH1/2 Mutated Intrahepatic Cholangiocarcinoma: Not All “BRCAness” Is Created Equal. Cancer Investigation 2023, 41: 646-655. PMID: 37505929, DOI: 10.1080/07357907.2023.2242957.Peer-Reviewed Original ResearchConceptsClinical benefit rateIntrahepatic cholangiocarcinomaPlatinum sensitivityUnresectable intrahepatic cholangiocarcinomaObjective response rateMulticenter retrospective studyHomologous recombination repairDefective homologous recombination (HR) repairPrimary endpointPlatinum chemotherapyRetrospective studyPreclinical dataBenefit rateWildtype tumorsResponse rateMT tumorsWT diseasePatientsGene defectsCholangiocarcinomaTumorsA phase 2 study of the WEE1 inhibitor AZD1775 in SETD2-deficient advanced solid tumor malignancies.
Maldonado E, Rathmell W, Shapiro G, Rodon Ahnert J, Mahalingam D, Trikalinos N, Rezazadeh A, Adorno Febles V, Parikh M, Boerner S, Krings G, Takebe N, LoRusso P, Aggarwal R. A phase 2 study of the WEE1 inhibitor AZD1775 in SETD2-deficient advanced solid tumor malignancies. Journal Of Clinical Oncology 2023, 41: 3104-3104. DOI: 10.1200/jco.2023.41.16_suppl.3104.Peer-Reviewed Original ResearchClear cell renal cell carcinomaSolid tumor malignanciesClinical benefit rateObjective response rateDuration of responseTumor malignancyEvaluable ptsStable diseaseObjective responseAdverse eventsTumor regressionMetastatic clear cell renal cell carcinomaAdvanced solid tumor malignanciesMetastatic solid tumor malignanciesCommon adverse eventsDurable stable diseaseECOG PS 0RECIST 1.1 criteriaSubset of ptsPhase 2 studyCohort of patientsCell renal cell carcinomaNext-generation sequencing panelBest overall responseRenal cell carcinomaFirst-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors
Bendell J, LoRusso P, Overman M, Noonan A, Kim D, Strickler J, Kim S, Clarke S, George T, Grimison P, Barve M, Amin M, Desai J, Wise-Draper T, Eck S, Jiang Y, Khan A, Wu Y, Martin P, Cooper Z, Elgeioushi N, Mueller N, Kumar R, Patel S. First-in-human study of oleclumab, a potent, selective anti-CD73 monoclonal antibody, alone or in combination with durvalumab in patients with advanced solid tumors. Cancer Immunology, Immunotherapy 2023, 72: 2443-2458. PMID: 37016126, PMCID: PMC10264501, DOI: 10.1007/s00262-023-03430-6.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsPancreatic ductal adenocarcinomaColorectal cancerExpansion cohortHuman studiesResponse rateAnti-CD73 monoclonal antibodyProgression-free survival ratesTumor cellsMonoclonal antibodiesCommon being fatigueManageable safety profileObjective response rateAdvanced colorectal cancerAdvanced solid tumorsCell lung cancerPeripheral T cellsDate of registrationCD73 enzymatic activityAdverse eventsEscalation cohortsLocal immunosuppressionCD73 expressionSafety profileLung cancerTrial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations.
Tolcher A, Park W, Wang J, Spira A, Janne P, Lee H, Gill S, LoRusso P, Herzberg B, Goldman J, Morgensztern D, Berlin J, Kasi A, Fujii H, Pelster M. Trial in progress: A phase 1, first-in-human, open-label, multicenter, dose-escalation and dose-expansion study of ASP3082 in patients with previously treated advanced solid tumors and KRAS G12D mutations. Journal Of Clinical Oncology 2023, 41: tps764-tps764. DOI: 10.1200/jco.2023.41.4_suppl.tps764.Peer-Reviewed Original ResearchKRAS G12DAdverse eventsLung cancerKRAS G12D mutationCancer cellsEastern Cooperative Oncology Group performance statusSolid tumorsNon-small cell lung cancerMetastatic solid tumor malignanciesSolid Tumors version 1.1Dose-escalation cohortsDose-expansion studyPhase 2 doseDisease control rateObjective response rateSerious adverse eventsAdvanced solid tumorsResponse Evaluation CriteriaDose-limiting toxicityPancreatic ductal cancerPhase 1 studyCell lung cancerDuration of responseSolid tumor malignanciesG12D mutation
2022
Phase 1 study of SGN-ALPV, a novel, investigational vedotin antibody–drug conjugate directed to ALPP/ALPPL2 in advanced solid tumors (SGNALPV-001, trial in progress).
Lakhani N, Friedman C, Perez C, Wehr A, McGoldrick S, LoRusso P. Phase 1 study of SGN-ALPV, a novel, investigational vedotin antibody–drug conjugate directed to ALPP/ALPPL2 in advanced solid tumors (SGNALPV-001, trial in progress). Journal Of Clinical Oncology 2022, 40: tps3159-tps3159. DOI: 10.1200/jco.2022.40.16_suppl.tps3159.Peer-Reviewed Original ResearchMonomethyl auristatin EAdvanced solid tumorsSolid tumorsNon-small cell lungTesticular germ cell tumorsECOG PS 0Objective response rateProgression-free survivalDose-limiting toxicityPhase 1 studyDuration of responseGerm cell tumorsDisease-specific cohortsPromising preclinical dataImmunogenic cell deathClinical trial informationNormal tissue expressionAntibody-drug conjugatesMechanism of actionProtease-cleavable linkerAdult ptsCumulative safetyRECIST v1.1Exploratory endpointsMeasurable diseasePhase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies and dose escalation update.
Muller C, Chaney M, Cohen J, Garyantes T, Lin J, LoRusso P, Mita A, Mita M, Natale C, Orloff M, Papadopoulos K, Patel S, Ahnert J. Phase 1b study of the novel first-in-class G protein-coupled estrogen receptor (GPER) agonist, LNS8801, in combination with pembrolizumab in patients with immune checkpoint inhibitor (ICI)-relapsed and refractory solid malignancies and dose escalation update. Journal Of Clinical Oncology 2022, 40: 2574-2574. DOI: 10.1200/jco.2022.40.16_suppl.2574.Peer-Reviewed Original ResearchG protein-coupled estrogen receptorFavorable safety profileStable diseaseLong-term benefitsHuman dose-escalation studyProtein-coupled estrogen receptorMetastatic uveal melanoma patientsEncouraging anti-tumor activityClinical benefit rateDose-escalation portionPhase 1b studyRefractory solid malignanciesImmune checkpoint inhibitorsObjective response rateDose-escalation studyMetastatic solid tumorsUveal melanoma patientsDuration of treatmentAnti-tumor activityEstrogen receptor agonistsSmall molecule agonistsCTCAE v5.0Evaluable patientsMeasurable diseaseRECIST v1.1A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS).
Gounder M, Yamamoto N, Patel M, Bauer T, Schöffski P, Grempler R, Durland-Busbice S, Geng J, Maerten A, LoRusso P. A phase Ia/Ib, dose-escalation/expansion study of the MDM2–p53 antagonist BI 907828 in patients with solid tumors, including advanced/metastatic liposarcoma (LPS). Journal Of Clinical Oncology 2022, 40: 3004-3004. DOI: 10.1200/jco.2022.40.16_suppl.3004.Peer-Reviewed Original ResearchAdvanced liposarcomaDay 1Solid tumorsECOG PS 0/1Manageable safety profileObjective response rateOverall safety dataPrior systemic therapyTreatment-related AEsGDF-15 levelsAdvanced solid tumorsSubgroup of patientsNumber of patientsPatient-derived xenograftsHigher plasma exposureTarget engagement markerPart AEvaluable patientsIA/IBPS 0/1Dose expansionPrimary endpointMetastatic liposarcomaOverall survivalArm BFirst in Human Phase 1/2 ICONIC Trial of the ICOS agonist vopratelimab alone and with nivolumab: ICOS high CD4 T cell populations and predictors of response
Yap TA, Gainor JF, Callahan MK, Falchook GS, Pachynski RK, LoRusso P, Kummar S, Gibney GT, Burris HA, Tykodi SS, Rahma OE, Seiwert TY, Papadopoulos KP, Murphy M, Park H, Hanson A, Hashambhoy-Ramsay Y, McGrath L, Hooper E, Xiao X, Cohen H, Fan M, Felitsky D, Hart C, McComb R, Brown K, Sepahi A, Jimenez J, Zhang W, Baeck J, Laken H, Murray R, Trehu E, Harvey CJ. First in Human Phase 1/2 ICONIC Trial of the ICOS agonist vopratelimab alone and with nivolumab: ICOS high CD4 T cell populations and predictors of response. Clinical Cancer Research 2022, 28: 3695-3708. PMID: 35511938, PMCID: PMC9433959, DOI: 10.1158/1078-0432.ccr-21-4256.Peer-Reviewed Original ResearchConceptsSubset of patientsPredictive biomarkersPharmacodynamic biomarkersModest objective response rateNon-small cell lung cancer trialsCD4 T cell populationCell lung cancer trialsPhase IObjective response ratePhase II doseAdvanced solid tumorsCD4 T cellsFavorable safety profilePotential predictive biomarkersLung cancer trialsPredictors of responseT cell populationsGreater clinical benefitClinical outcomesClinical benefitSafety profileCancer trialsNivolumabT cellsPatients
2021
Phase 1 Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844)
Roussos Torres ET, Rafie C, Wang C, Lim D, Brufsky A, LoRusso P, Eder JP, Chung V, Downs M, Geare M, Piekarz R, Streicher H, Anforth L, Rudek MA, Zhu Q, Besharati S, Cimino-Mathews A, Anders RA, Stearns V, Jaffee EM, Connolly RM. Phase 1 Study of Entinostat and Nivolumab with or without Ipilimumab in Advanced Solid Tumors (ETCTN-9844). Clinical Cancer Research 2021, 27: clincanres.5017.2021. PMID: 34135021, PMCID: PMC8563383, DOI: 10.1158/1078-0432.ccr-20-5017.Peer-Reviewed Original ResearchConceptsCD8/FOXP3 ratioAdvanced solid tumorsAdverse eventsAddition of ICIFOXP3 ratioSolid tumorsGrade 3/4 adverse eventsRegulatory T cell ratioTreatment-related adverse eventsImmune checkpoint inhibitor efficacyTriple-negative breast cancerMulticenter phase I clinical trialPhase I clinical trialObjective response ratePhase II doseT cell ratioCheckpoint inhibitor efficacyPhase 1 studyCombination of entinostatHistone deacetylase inhibitor entinostatRECIST 1.1Primary endpointSecondary endpointsComplete responseDose escalationClinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation
Kim J, Cardin DB, Vaishampayan UN, Kato S, Grossman SR, Glazer P, Shyr Y, Ivy SP, LoRusso P. Clinical Activity and Safety of Cediranib and Olaparib Combination in Patients with Metastatic Pancreatic Ductal Adenocarcinoma without BRCA Mutation. The Oncologist 2021, 26: e1104-e1109. PMID: 33742489, PMCID: PMC8265343, DOI: 10.1002/onco.13758.Peer-Reviewed Original ResearchConceptsMetastatic pancreatic adenocarcinomaHomologous recombination DNA repair deficiencyMetastatic pancreatic ductal adenocarcinomaPancreatic ductal adenocarcinomaOlaparib combinationStable diseaseBRCA mutationsAdverse eventsDuctal adenocarcinomaCommon treatment-related adverse eventsVascular endothelial growth factor receptor inhibitorEndothelial growth factor receptor inhibitorTreatment-related adverse eventsGrowth factor receptor inhibitorsPrior systemic chemotherapyMedian overall survivalObjective response rateGermline BRCA mutationsBest overall responseExpression of BRCA1/2Restaging scanCancer cell linesPrimary endpointStudy drugSystemic chemotherapy
2019
Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors
Hong DS, LoRusso P, Hamid O, Janku F, Kittaneh M, Catenacci DVT, Chan E, Bekaii-Saab T, Gadgeel S, Loberg RD, Amore BM, Hwang YC, Tang R, Ngarmchamnanrith G, Kwak EL. Phase I Study of AMG 337, a Highly Selective Small-molecule MET Inhibitor, in Patients with Advanced Solid Tumors. Clinical Cancer Research 2019, 25: 2403-2413. PMID: 30425090, PMCID: PMC6892342, DOI: 10.1158/1078-0432.ccr-18-1341.Peer-Reviewed Original ResearchConceptsTreatment-related adverse eventsAdvanced solid tumorsAMG 337Adverse eventsFrequent treatment-related adverse eventsResponse rateSolid tumorsOpen-label phase ISmall-molecule MET inhibitorDose-escalation cohortsObjective response ratePhase II dosePromising response ratesDose-limiting toxicityMaximum plasma concentrationTumors warrants further investigationWarrants further investigationManageable toxicityDose expansionPrimary endpointSecondary endpointsDaily dosingMedian durationClinical responseMET inhibitors
2017
A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors
Kristeleit R, Shapiro GI, Burris HA, Oza AM, LoRusso P, Patel MR, Domchek SM, Balmaña J, Drew Y, Chen LM, Safra T, Montes A, Giordano H, Maloney L, Goble S, Isaacson J, Xiao J, Borrow J, Rolfe L, Shapira-Frommer R. A Phase I–II Study of the Oral PARP Inhibitor Rucaparib in Patients with Germline BRCA1/2-Mutated Ovarian Carcinoma or Other Solid Tumors. Clinical Cancer Research 2017, 23: 4095-4106. PMID: 28264872, DOI: 10.1158/1078-0432.ccr-16-2796.Peer-Reviewed Original ResearchConceptsHigh-grade ovarian carcinomaObjective response rateInvestigator-assessed objective response rateOral rucaparibAdverse eventsCommon treatment-emergent adverse eventsTreatment-emergent adverse eventsAspartate transaminase elevationsAsthenia/fatigueProtocol-defined criteriaRECIST version 1.1Phase II doseAdvanced solid tumorsProgression-free intervalSmall molecule PARP inhibitorsClin Cancer ResManageable toxicityPrior regimensPrimary endpointTransaminase elevationPlatinum therapyMultiple dosesOvarian carcinomaAlanine transaminaseClinical activity
2013
Trastuzumab emtansine (T-DM1) in previously treated HER2-positive metastatic breast cancer (MBC): Results from an expanded access study.
Yardley D, Krop I, LoRusso P, Robert N, Mayer M, Abidoye O, Lai C, Yoo B, Perez E. Trastuzumab emtansine (T-DM1) in previously treated HER2-positive metastatic breast cancer (MBC): Results from an expanded access study. Journal Of Clinical Oncology 2013, 31: 166-166. DOI: 10.1200/jco.2013.31.26_suppl.166.Peer-Reviewed Original ResearchMetastatic breast cancerObjective response rateHER2-positive metastatic breast cancerT-DM1Investigator-assessed objective response rateMedian cumulative anthracycline doseAccess StudyCumulative anthracycline doseCytotoxic agent DM1HER2-directed agentsMost common gradeUS multicenter studyNew safety signalsRate of gradeConventional clinical trialsAnthracycline doseGrade AEsMBC therapyMeasurable diseaseMedian LVEFPrior anthracyclineSecondary endpointsMUGA scanCardiac dysfunctionMulticenter study