TY - JOUR
T1 - Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer
AU - Smyth, Lillian M.
AU - Batist, Gerald
AU - Meric-Bernstam, Funda
AU - Kabos, Peter
AU - Spanggaard, Iben
AU - Lluch, Ana
AU - Jhaveri, Komal
AU - Varga, Andrea
AU - Wong, Andrea
AU - Schram, Alison M.
AU - Ambrose, Helen
AU - Carr, T. Hedley
AU - de Bruin, Elza C.
AU - Salinas-Souza, Carolina
AU - Foxley, Andrew
AU - Hauser, Joana
AU - Lindemann, Justin P.O.
AU - Maudsley, Rhiannon
AU - McEwen, Robert
AU - Moschetta, Michele
AU - Nikolaou, Myria
AU - Schiavon, Gaia
AU - Razavi, Pedram
AU - Banerji, Udai
AU - Baselga, José
AU - Hyman, David M.
AU - Chandarlapaty, Sarat
N1 - Funding Information:
L. M. S. has acted in a consultancy or advisory role for AstraZeneca, Loxo Oncology at Lilly, Novartis, Pfizer, and Roche Genentech and has received research funding from AstraZeneca, Puma Biotechnology, and Roche Genentech, travel or accommodation expenses from Pfizer, Puma Biotechnology, and Roche Genentech, honoraria from AstraZeneca, Pfizer, and Roche Genentech, employment from Loxo Oncology at Lilly, and stock and other ownership interests from Lilly. G. B. has acted in a consultancy or advisory role for Roche. F. M.-B. has received commercial research grants from Abbvie, Aileron, AstraZeneca, Bayer, Calithera, Curis, CytoMx, Daiichi Sankyo, eFFECTOR, GlaxoSmithKline, Guardant Health, Jounce, Millennium, Novartis, PUMA Biotechnology, Seattle Genetics, Takeda, and Zymeworks, grants and travel-related fees from Debiopharm Group, Genentech, Pfizer, and Taiho, has acted in a consultancy role for Aduro, Dialectica, Jackson Laboratory, Kolon Life Science, OrigiMed, Parexel International, Pieris, Samsung Bioepis, Sumitomo Dainippon, Xencor, and Zymeworks, and in an advisory role for Darwin Health, GRAIL, Inflection Biosciences, Mersana, Seattle Genetics, and Spectrum. P. K. has performed contracted research for AstraZeneca, Eli Lilly, Genentech, Pfizer, Radius Health, and Sanofi. I. S. has received research funding from PUMA Biotechnology and travel expenses from BMS, Novartis, and Pfizer. K. J. has reported consultant and advisory board activities for Novartis, Spectrum Pharmaceuticals, ADC Therapeutics, Pfizer, Bristol-Myers Squibb, Jounce Therapeutics, and Taiho Oncology and research funding from Novartis, Clovis Oncology, Genentech, AstraZeneca, ADC Therapeutics, Novita Pharmaceuticals, Debio Pharmaceuticals, and Pfizer. A. V. has received research grants from AstraZeneca, BMS, Boehringer Ingelheim, Janssen Cilag, Merck, Novartis, Pfizer, Roche, and Sanofi and non-financial support from AstraZeneca, Bayer, BMS, Boehringer Ingelheim, Johnson & Johnson, Lilly, Medimmune, Merck, NH TherAGuiX, Pfizer, and Roche. P. R. has performed consultation and attended advisory boards for Novartis and received institutional research funding from Grail, Inc and Illumina. U. B. has received research grants from AstraZeneca, Chugai, and Onyx Pharmaceuticals and consultancy fees from Astex and Novartis. D. M. H. reports stock ownership in Fount Therapeutics, has acted in a consultancy or advisory role for AstraZeneca, Bayer, Boehringer Ingelheim, Chugai Pharma, Eli Lilly, Genentech, and Pfizer, and has received research funding from AstraZeneca, Bayer, Loxo Oncology, and Puma Biotechnology and travel or accommodation expenses from Chugai Pharma and Genentech. S. C. has received a research grant from Daiichi Sankyo and consultancy fees from BMS, Context Therapeutics, Eli Lilly, Novartis, Revolution Medicines, and Sermonix Pharmaceutical. H. A., T. H. C., E. C. d. B., C. S.-S., A. F., J. H., J. P. O. L., R. Maudsley, R. McEwen, M. M., M. N., G. S., and J. B. are employees of AstraZeneca. A. L., A. W., and A. M. S. declare no conflict of interest.
Funding Information:
This work was supported by AstraZeneca. Capivasertib was discovered by AstraZeneca subsequent to a collaboration with Astex Therapeutics (and its collaboration with the Institute of Cancer Research and Cancer Research Technology Limited). U. B. acknowledges infrastructural funding from Cancer Research UK, Experimental Cancer Medicine Centre and Biomedical Research Centre grants, in addition to a National Institutes of Health Research Professorship award (RP-2016-07-028). All Memorial Sloan Kettering Cancer Center investigators wish to acknowledge the support of the NCI Cancer Center Support Grant (CCSG P30 CA08748). S. C. acknowledges support of the Breast Cancer Research Foundation. We thank the patients and their caregivers who participated in this study. Medical writing assistance was provided by Martin Goulding, DPhil, from Mudskipper Business Ltd, funded by AstraZeneca. Capivasertib (AZD5363) is an investigational medical product that is not currently approved.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/12
Y1 - 2021/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41523-021-00251-7
DO - 10.1038/s41523-021-00251-7
M3 - Article
C2 - 33863913
AN - SCOPUS:85104550884
SN - 2374-4677
VL - 7
JO - npj Breast Cancer
JF - npj Breast Cancer
IS - 1
M1 - 44
ER -