Capivasertib, an AKT Kinase Inhibitor, as Monotherapy or in Combination with Fulvestrant in Patients with AKT1 E17K-Mutant, ER-Positive Metastatic Breast Cancer.
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Date
2020-08-01ICR Author
Author
Smyth, LM
Tamura, K
Oliveira, M
Ciruelos, EM
Mayer, IA
Sablin, M-P
Biganzoli, L
Ambrose, HJ
Ashton, J
Barnicle, A
Cashell, DD
Corcoran, C
de Bruin, EC
Foxley, A
Hauser, J
Lindemann, JPO
Maudsley, R
McEwen, R
Moschetta, M
Pass, M
Rowlands, V
Schiavon, G
Banerji, U
Scaltriti, M
Taylor, BS
Chandarlapaty, S
Baselga, J
Hyman, DM
Type
Journal Article
Metadata
Show full item recordAbstract
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.
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Research team
Clinical Pharmacology – Adaptive Therapy
Language
eng
Date accepted
2020-04-16
License start date
2020-04-20
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2020
Publisher
AMER ASSOC CANCER RESEARCH