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. 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 ≥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.

Conflict of interest statement

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.

Figures

Fig. 1. PTEN mutations are associated with a poor prognosis in ER+ HER2– breast cancer.

a Early-stage ER+ HER2– breast cancers (METABRIC data). b Metastatic ER+ HER2– breast cancers (MSK-IMPACT data). Kaplan–Meier survival analysis for ER+ HER2– breast cancer patients by PTEN status in early-stage and metastatic BC: a overall survival of patients with ER+ HER2– primary breast tumors (n = 1398) by PTEN mutation status, using the same criteria employed in this study for enrollment; b overall survival from time of metastatic recurrence of patients with metastatic ER+ HER2– breast cancer (n = 949) by PTEN status. A patient with multiple metastatic samples sequenced by next-generation sequencing was considered PTEN altered if at least one sample harbored an eligible PTEN alteration. Overall survival for the METABRIC data utilized univariable or multivariable Cox proportional hazards models to examine the association between mutations and survival. Breast cancer-specific survival was used as the endpoint. Patients with deaths from other or unknown causes were censored at the date of death, and all other patients were censored at the date of last contact. Overall survival for the MSK-IMPACT data, as defined by time of metastatic recurrence until death or last follow-up, was analyzed utilizing the MSK cohort restricted to patients with metastatic ER+/HER2– disease (n = 949 patients). Univariate P values were calculated using the log-rank test. The models were further adjusted using left truncation methods for late entry when tumor sequencing to assess PTEN status was performed after metastatic recurrence. ER+ estrogen-receptor-positive, HER2– human epidermal growth factor receptor negative.

Fig. 2. Best RECIST response, PTEN, and broader mutation profiling in patients with PTEN-mutant ER+ MBC treated with capivasertib and fulvestrant.

AF allele fraction, ER+ estrogen-receptor-positive, FFPE formalin-fixed paraffin-embedded, IHC immunohistochemistry, MAF mutant allele fraction, MBC metastatic breast cancer, NGS next-generation sequencing, RECIST Response Evaluation Criteria in Solid Tumors.

Fig. 3. Study design of the PTEN-mutant breast cancer cohort.

Up to 24 patients in each cohort. Interim analyses were carried out after 12 patients were followed up for 24 weeks or withdrawn from the study. Subsequent patients were recruited only if sufficient antitumor activity (assessed by CBR24) was observed at the interim analyses. CBR24 clinical benefit rate at 24 weeks, ER+ estrogen-receptor-positive, ORR objective response rate, PFS progression-free survival.