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dc.contributor.authorSmyth, LMen_US
dc.contributor.authorTamura, Ken_US
dc.contributor.authorOliveira, Men_US
dc.contributor.authorCiruelos, EMen_US
dc.contributor.authorMayer, IAen_US
dc.contributor.authorSablin, M-Pen_US
dc.contributor.authorBiganzoli, Len_US
dc.contributor.authorAmbrose, HJen_US
dc.contributor.authorAshton, Jen_US
dc.contributor.authorBarnicle, Aen_US
dc.contributor.authorCashell, DDen_US
dc.contributor.authorCorcoran, Cen_US
dc.contributor.authorde Bruin, ECen_US
dc.contributor.authorFoxley, Aen_US
dc.contributor.authorHauser, Jen_US
dc.contributor.authorLindemann, JPOen_US
dc.contributor.authorMaudsley, Ren_US
dc.contributor.authorMcEwen, Ren_US
dc.contributor.authorMoschetta, Men_US
dc.contributor.authorPass, Men_US
dc.contributor.authorRowlands, Ven_US
dc.contributor.authorSchiavon, Gen_US
dc.contributor.authorBanerji, Uen_US
dc.contributor.authorScaltriti, Men_US
dc.contributor.authorTaylor, BSen_US
dc.contributor.authorChandarlapaty, Sen_US
dc.contributor.authorBaselga, Jen_US
dc.contributor.authorHyman, DMen_US
dc.date.accessioned2020-06-22T09:47:12Z
dc.date.issued2020-04-20en_US
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2020en_US
dc.identifier.issn1078-0432en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/3758
dc.identifier.doi10.1158/1078-0432.ccr-19-3953en_US
dc.description.abstractPURPOSE:The activating mutation AKT1 E17K occurs in ~7% of ER+ metastatic breast cancer (MBC). We report, from a multipart, first-in-human, Phase I study (NCT01226316), tolerability and activity of capivasertib, an oral AKT inhibitor, as monotherapy or combined with fulvestrant in expansion cohorts of AKT1 E17K-mutant ER+ MBC patients. PATIENTS AND METHODS:Patients with an AKT1 E17K mutation, detected by local (NGS) or central (plasma-based BEAMing) testing, received capivasertib 480 mg bid, 4 days on, 3 days off, weekly or 400 mg bid combined with fulvestrant at the labeled dose. Study endpoints included safety, objective response rate (ORR; RECIST v1.1), progression-free survival (PFS) and clinical benefit rate at 24 weeks (CBR24). Biomarker analyses were conducted in the combination cohort. RESULTS:From October 2013 to August 2018, 63 heavily pretreated patients received capivasertib (20 monotherapy, 43 combination). ORR was 20% with monotherapy, and within the combination cohort was 36% in fulvestrant-pretreated and 20% in fulvestrant-naïve patients, although this latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), ddPCR (80%, 33/41) and NGS (76%, 31/41). A 50% decrease in AKT1 E17K at cycle 2 day 1 was associated with improved PFS. Combination therapy appeared more tolerable than monotherapy (most frequent grade ≥3 adverse events: rash [9% vs 20%], hyperglycemia [5% vs 30%], diarrhea [5% vs 10%]). CONCLUSIONS:Capivasertib demonstrated clinically meaningful activity in heavily pretreated AKT1 E17K-mutant ER+ MBC patients, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination.en_US
dc.formatPrint-Electronicen_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.titleCapivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination With Fulvestrant in Patients With AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2020-04-16en_US
rioxxterms.versionofrecord10.1158/1078-0432.ccr-19-3953en_US
rioxxterms.licenseref.startdate2020-04-20en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Researchen_US
pubs.notesNot knownen_US
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.publication-statusPublisheden_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
dc.contributor.icrauthorBanerji, Udaien_US


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