2022
Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast CancerAlpelisib plus Olaparib for Triple-Negative Breast Cancer
Batalini F, Xiong N, Tayob N, Polak M, Eismann J, Cantley LC, Shapiro GI, Adalsteinsson V, Winer EP, Konstantinopoulos PA, D'Andrea A, Swisher EM, Matulonis UA, Wulf GM, Mayer EL. Phase 1b Clinical Trial with Alpelisib plus Olaparib for Patients with Advanced Triple-Negative Breast CancerAlpelisib plus Olaparib for Triple-Negative Breast Cancer. Clinical Cancer Research 2022, 28: 1493-1499. PMID: 35149538, PMCID: PMC9066379, DOI: 10.1158/1078-0432.ccr-21-3045.Peer-Reviewed Original ResearchConceptsTriple-negative breast cancerObjective response rateCirculating-free DNABreast cancerCommon treatment-related grade 3Treatment-related grade 3Longer progression-free survivalRecurrent triple-negative breast cancerHigh-grade serous ovarian cancerPARP inhibitionPhase 1b clinical trialPhase 2 dosePhase 1b trialSecondary end pointsProgression-free survivalRecurrent breast cancerGermline BRCA mutationsImportant prognostic informationSerous ovarian cancerBreast cancer cohortBRCA-mutant tumorsNon-BRCA carriersPI3K inhibitorsEligible patientsExpansion cohort
2019
A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB)
Mayer IA, Prat A, Egle D, Blau S, Fidalgo JAP, Gnant M, Fasching PA, Colleoni M, Wolff AC, Winer EP, Singer CF, Hurvitz S, Estévez LG, van Dam PA, Kümmel S, Mundhenke C, Holmes F, Babbar N, Charbonnier L, Diaz-Padilla I, Vogl FD, Sellami D, Arteaga CL. A Phase II Randomized Study of Neoadjuvant Letrozole Plus Alpelisib for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer (NEO-ORB). Clinical Cancer Research 2019, 25: 2975-2987. PMID: 30723140, PMCID: PMC6522303, DOI: 10.1158/1078-0432.ccr-18-3160.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAged, 80 and overAntineoplastic Combined Chemotherapy ProtocolsBiomarkers, TumorBreast NeoplasmsCell ProliferationClass I Phosphatidylinositol 3-KinasesFemaleHigh-Throughput Nucleotide SequencingHumansLetrozoleMiddle AgedMutationNeoadjuvant TherapyReceptor, ErbB-2Receptors, EstrogenReceptors, ProgesteroneSignal TransductionThiazolesTreatment OutcomeConceptsObjective response rateMetastatic breast cancerBreast cancerResponse rateLetrozole treatmentPathologic complete response ratePhase II Randomized StudyHuman epidermal growth factor receptor 2Epidermal growth factor receptor 2Human epidermal growth factor receptorComplete response rateHormone receptor positiveMaculo-papular rashProgression-free survivalGrowth factor receptor 2Early breast cancerPhase I studiesWild-type cohortsFactor receptor 2Epidermal growth factor receptorCombination of alpelisibGrowth factor receptorNeoadjuvant letrozoleNeoadjuvant settingPrimary endpointOlaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial
Konstantinopoulos PA, Barry WT, Birrer M, Westin SN, Cadoo KA, Shapiro GI, Mayer EL, O'Cearbhaill RE, Coleman RL, Kochupurakkal B, Whalen C, Curtis J, Farooq S, Luo W, Eismann J, Buss MK, Aghajanian C, Mills GB, Palakurthi S, Kirschmeier P, Liu J, Cantley LC, Kaufmann SH, Swisher EM, D'Andrea AD, Winer E, Wulf GM, Matulonis UA. Olaparib and α-specific PI3K inhibitor alpelisib for patients with epithelial ovarian cancer: a dose-escalation and dose-expansion phase 1b trial. The Lancet Oncology 2019, 20: 570-580. PMID: 30880072, PMCID: PMC7025391, DOI: 10.1016/s1470-2045(18)30905-7.Peer-Reviewed Original ResearchMeSH KeywordsAgedAntineoplastic Combined Chemotherapy ProtocolsCarcinoma, Ovarian EpithelialDose-Response Relationship, DrugDrug-Related Side Effects and Adverse ReactionsFemaleGenome, HumanHumansMaximum Tolerated DoseMiddle AgedMutationOvarian NeoplasmsPhosphoinositide-3 Kinase InhibitorsPhthalazinesPiperazinesPoly(ADP-ribose) Polymerase InhibitorsThiazolesTreatment OutcomeConceptsEpithelial ovarian cancerPhase 2 dosePI3K inhibitor alpelisibPrimary peritoneal cancerPhase 1b trialRecurrent breast cancerGermline BRCA mutationsOvarian cancerBreast cancerDose levelsPeritoneal cancerBRCA mutationsFallopian tubeCommon treatment-related grade 3High-grade serous histologyTreatment-related grade 3Breast Cancer Research FoundationDecreased neutrophil countDose-escalation cohortsDose-expansion cohortsTreatment-related deathsTriple negative histologyResponse Evaluation CriteriaSolid Tumors 1.1Key eligibility criteria
2017
A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer
Mayer IA, Abramson VG, Formisano L, Balko JM, Estrada MV, Sanders ME, Juric D, Solit D, Berger MF, Won HH, Li Y, Cantley LC, Winer E, Arteaga CL. A Phase Ib Study of Alpelisib (BYL719), a PI3Kα-Specific Inhibitor, with Letrozole in ER+/HER2− Metastatic Breast Cancer. Clinical Cancer Research 2017, 23: 26-34. PMID: 27126994, PMCID: PMC5085926, DOI: 10.1158/1078-0432.ccr-16-0134.Peer-Reviewed Original ResearchMeSH KeywordsAdultAgedAntineoplastic Combined Chemotherapy ProtocolsAromatase InhibitorsBiomarkers, TumorBreast NeoplasmsCell Line, TumorDNA Mutational AnalysisFemaleHumansIn Situ Hybridization, FluorescenceLetrozoleMaximum Tolerated DoseMiddle AgedMutationNeoplasm MetastasisNeoplasm StagingNitrilesPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsReceptor, ErbB-2Receptor, Fibroblast Growth Factor, Type 1Receptors, EstrogenThiazolesTreatment OutcomeTriazolesConceptsMaximum-tolerated doseBreast cancer cellsEndocrine therapyClinical benefitCommon drug-related adverse eventsDrug-related adverse eventsMutant breast cancer cellsBreast cancer refractoryPIK3CA mutation statusPIK3CA-mutated tumorsClinical benefit ratePhase Ib studyPI3K catalytic subunit p110αDose-limiting toxicityCancer cellsSelective oral inhibitorOverexpression of FGFR1Combination of letrozoleSynergistic antitumor activityCatalytic subunit p110αCancer refractoryFGFR1/2 amplificationMetastatic ERAdverse eventsObjective response
2015
PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers
Wang Q, Liu P, Spangle JM, Von T, Roberts TM, Lin NU, Krop IE, Winer EP, Zhao JJ. PI3K-p110α mediates resistance to HER2-targeted therapy in HER2+, PTEN-deficient breast cancers. Oncogene 2015, 35: 3607-3612. PMID: 26500061, PMCID: PMC4846581, DOI: 10.1038/onc.2015.406.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsBreast NeoplasmsCell Line, TumorCell SurvivalClass I Phosphatidylinositol 3-KinasesDrug Resistance, NeoplasmFemaleHumansLapatinibMammary Neoplasms, ExperimentalMice, KnockoutMolecular Targeted TherapyPhosphatidylinositol 3-KinasesPhosphoinositide-3 Kinase InhibitorsProtein Kinase InhibitorsProto-Oncogene Proteins c-aktPTEN PhosphohydrolaseQuinazolinesReceptor, ErbB-2Signal TransductionThiazolesTumor BurdenXenograft Model Antitumor AssaysConceptsBreast tumorsP110β inhibitorsHuman epidermal growth factor receptor 2 (HER2) amplificationP110α inhibitionPTEN lossInhibition of HER2Treatment of HER2Human cancersPI3K pathway activationPTEN-deficient breast cancersGenetic mouse modelsPI3K/Akt signalingPTEN-deficient tumorsPI3K/AktDual HER2Therapeutic regimenHER2 inhibitionPIK3CA mutationsTumor regressionBreast cancerMouse modelXenograft modelHER2Null tumorsHER2 activation
2003
Use of the Peroxisome Proliferator-Activated Receptor (PPAR) γ Ligand Troglitazone as Treatment for Refractory Breast Cancer: A Phase II Study
Burstein HJ, Demetri GD, Mueller E, Sarraf P, Spiegelman BM, Winer EP. Use of the Peroxisome Proliferator-Activated Receptor (PPAR) γ Ligand Troglitazone as Treatment for Refractory Breast Cancer: A Phase II Study. Breast Cancer Research And Treatment 2003, 79: 391-397. PMID: 12846423, DOI: 10.1023/a:1024038127156.Peer-Reviewed Original ResearchConceptsMetastatic breast cancerSerum tumor markersBreast cancerTumor markersTumor differentiationDisease progressionAdvanced breast cancer refractoryElevated serum tumor markersRefractory metastatic breast cancerPeroxisome proliferator-activated receptor γBreast cancer refractoryRefractory breast cancerPhase II studyPercentage of patientsProliferator-activated receptor γDifferent patient populationsCancer refractoryChemotherapy regimenII studyObjective responseSystemic therapyPO QDHormonal regimensHepatic toxicityPatient population