Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer Journal Article
| Authors: | Smyth, L. M.; Batist, G.; Meric-Bernstam, F.; Kabos, P.; Spanggaard, I.; Lluch, A.; Jhaveri, K.; Varga, A.; Wong, A.; Schram, A. M.; Ambrose, H.; Carr, T. H.; de Bruin, E. C.; Salinas-Souza, C.; Foxley, A.; Hauser, J.; Lindemann, J. P. O.; Maudsley, R.; McEwen, R.; Moschetta, M.; Nikolaou, M.; Schiavon, G.; Razavi, P.; Banerji, U.; Baselga, J.; Hyman, D. M.; Chandarlapaty, S. |
| Article Title: | Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| 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. Comutations 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 ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 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. © 2021, The Author(s). |
| Journal Title: | npj Breast Cancer |
| Volume: | 7 |
| ISSN: | 2374-4677 |
| Publisher: | Nature Publishing Group |
| Date Published: | 2021-04-16 |
| Start Page: | 44 |
| Language: | English |
| DOI: | 10.1038/s41523-021-00251-7 |
| PROVIDER: | scopus |
| PUBMED: | 33863913 |
| PMCID: | PMC8052445 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 3 May 2021 -- Source: Scopus |
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