Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.

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ICR Authors

Banerji, Udai

Authors

Smyth, LM
Batist, G
Meric-Bernstam, F
Kabos, P
Spanggaard, I
Lluch, A
Jhaveri, K
Varga, A
Wong, A
Schram, AM
Ambrose, H
Carr, TH
de Bruin, EC
Salinas-Souza, C
Foxley, A
Hauser, J
Lindemann, JPO
Maudsley, R
McEwen, R
Moschetta, M
Nikolaou, M
Schiavon, G
Razavi, P
Banerji, U
Baselga, J
Hyman, DM
Chandarlapaty, S

Document Type

Journal Article

Date

2021-04-16

Date Accepted

2021-03-24

Date Available

2021-05-14T08:17:05Z

Abstract

Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ā‰„3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both nā€‰=ā€‰2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.

Citation

NPJ breast cancer, 2021, 7 (1), pp. 44 - ?

DOI

10.1038/s41523-021-00251-7

URI

https://repository.icr.ac.uk/handle/internal/4553

Rights

https://creativecommons.org/licenses/by/4.0

Source Title

Publisher

NATURE PORTFOLIO

ISSN

2374-4677

eISSN

2374-4677

Collections

Clinical Studies

Research Team

Clinical Pharmacology ā€“ Adaptive Therapy
Clinical Pharmacology ā€“ Adaptive Therapy

Notes