dc.contributor.author | Smyth, LM | |
dc.contributor.author | Tamura, K | |
dc.contributor.author | Oliveira, M | |
dc.contributor.author | Ciruelos, EM | |
dc.contributor.author | Mayer, IA | |
dc.contributor.author | Sablin, M-P | |
dc.contributor.author | Biganzoli, L | |
dc.contributor.author | Ambrose, HJ | |
dc.contributor.author | Ashton, J | |
dc.contributor.author | Barnicle, A | |
dc.contributor.author | Cashell, DD | |
dc.contributor.author | Corcoran, C | |
dc.contributor.author | de Bruin, EC | |
dc.contributor.author | Foxley, A | |
dc.contributor.author | Hauser, J | |
dc.contributor.author | Lindemann, JPO | |
dc.contributor.author | Maudsley, R | |
dc.contributor.author | McEwen, R | |
dc.contributor.author | Moschetta, M | |
dc.contributor.author | Pass, M | |
dc.contributor.author | Rowlands, V | |
dc.contributor.author | Schiavon, G | |
dc.contributor.author | Banerji, U | |
dc.contributor.author | Scaltriti, M | |
dc.contributor.author | Taylor, BS | |
dc.contributor.author | Chandarlapaty, S | |
dc.contributor.author | Baselga, J | |
dc.contributor.author | Hyman, DM | |
dc.date.accessioned | 2020-06-22T09:47:12Z | |
dc.date.issued | 2020-08-01 | |
dc.identifier.citation | Clinical cancer research : an official journal of the American Association for Cancer Research, 2020 | |
dc.identifier.issn | 1078-0432 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/3758 | |
dc.identifier.doi | 10.1158/1078-0432.ccr-19-3953 | |
dc.description.abstract | PURPOSE: The activating mutation AKT1 E17K occurs in approximately 7% of estrogen receptor-positive (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 patients with AKT1 E17K-mutant ER+ MBC. PATIENTS AND METHODS: Patients with an AKT1 E17K mutation, detected by local (next-generation sequencing) or central (plasma-based BEAMing) testing, received capivasertib 480 mg twice daily, 4 days on, 3 days off, weekly or 400 mg twice daily 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 the latter group may have had more aggressive disease at baseline. AKT1 E17K mutations were detectable in plasma by BEAMing (95%, 41/43), droplet digital PCR (80%, 33/41), and next-generation sequencing (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 patients with AKT1 E17K-mutant ER+ MBC, including those with prior disease progression on fulvestrant. Tolerability and activity appeared improved by the combination. | |
dc.format | Print-Electronic | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | AMER ASSOC CANCER RESEARCH | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2020-04-16 | |
rioxxterms.versionofrecord | 10.1158/1078-0432.ccr-19-3953 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.licenseref.startdate | 2020-04-20 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Clinical cancer research : an official journal of the American Association for Cancer Research | |
pubs.notes | Not known | |
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.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-status | Published | |
pubs.embargo.terms | Not known | |
icr.researchteam | Clinical Pharmacology – Adaptive Therapy | |
dc.contributor.icrauthor | Banerji, Udai | |