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 assess...
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Nature Portfolio
2021
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oai:doaj.org-article:97cb292e26054c75a968bad21fc37c9b2021-12-02T14:27:10ZSelective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer10.1038/s41523-021-00251-72374-4677https://doaj.org/article/97cb292e26054c75a968bad21fc37c9b2021-04-01T00:00:00Zhttps://doi.org/10.1038/s41523-021-00251-7https://doaj.org/toc/2374-4677Abstract 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.Lillian M. SmythGerald BatistFunda Meric-BernstamPeter KabosIben SpanggaardAna LluchKomal JhaveriAndrea VargaAndrea WongAlison M. SchramHelen AmbroseT. Hedley CarrElza C. de BruinCarolina Salinas-SouzaAndrew FoxleyJoana HauserJustin P. O. LindemannRhiannon MaudsleyRobert McEwenMichele MoschettaMyria NikolaouGaia SchiavonPedram RazaviUdai BanerjiJosé BaselgaDavid M. HymanSarat ChandarlapatyNature PortfolioarticleNeoplasms. Tumors. Oncology. Including cancer and carcinogensRC254-282ENnpj Breast Cancer, Vol 7, Iss 1, Pp 1-7 (2021) |
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Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 |
| spellingShingle |
Neoplasms. Tumors. Oncology. Including cancer and carcinogens RC254-282 Lillian M. Smyth Gerald Batist Funda Meric-Bernstam Peter Kabos Iben Spanggaard Ana Lluch Komal Jhaveri Andrea Varga Andrea Wong Alison M. Schram Helen Ambrose T. Hedley Carr Elza C. de Bruin Carolina Salinas-Souza Andrew Foxley Joana Hauser Justin P. O. Lindemann Rhiannon Maudsley Robert McEwen Michele Moschetta Myria Nikolaou Gaia Schiavon Pedram Razavi Udai Banerji José Baselga David M. Hyman Sarat Chandarlapaty Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| description |
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. |
| format |
article |
| author |
Lillian M. Smyth Gerald Batist Funda Meric-Bernstam Peter Kabos Iben Spanggaard Ana Lluch Komal Jhaveri Andrea Varga Andrea Wong Alison M. Schram Helen Ambrose T. Hedley Carr Elza C. de Bruin Carolina Salinas-Souza Andrew Foxley Joana Hauser Justin P. O. Lindemann Rhiannon Maudsley Robert McEwen Michele Moschetta Myria Nikolaou Gaia Schiavon Pedram Razavi Udai Banerji José Baselga David M. Hyman Sarat Chandarlapaty |
| author_facet |
Lillian M. Smyth Gerald Batist Funda Meric-Bernstam Peter Kabos Iben Spanggaard Ana Lluch Komal Jhaveri Andrea Varga Andrea Wong Alison M. Schram Helen Ambrose T. Hedley Carr Elza C. de Bruin Carolina Salinas-Souza Andrew Foxley Joana Hauser Justin P. O. Lindemann Rhiannon Maudsley Robert McEwen Michele Moschetta Myria Nikolaou Gaia Schiavon Pedram Razavi Udai Banerji José Baselga David M. Hyman Sarat Chandarlapaty |
| author_sort |
Lillian M. Smyth |
| title |
Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| title_short |
Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| title_full |
Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| title_fullStr |
Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| title_full_unstemmed |
Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer |
| title_sort |
selective akt kinase inhibitor capivasertib in combination with fulvestrant in pten-mutant er-positive metastatic breast cancer |
| publisher |
Nature Portfolio |
| publishDate |
2021 |
| url |
https://doaj.org/article/97cb292e26054c75a968bad21fc37c9b |
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