Dataset Information

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.

SUBMITTER: Smyth LM

PROVIDER: S-EPMC8052445 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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

Smyth Lillian M LM Batist Gerald G Meric-Bernstam Funda F Kabos Peter P Spanggaard Iben I Lluch Ana A Jhaveri Komal K Varga Andrea A Wong Andrea A Schram Alison M AM Ambrose Helen H Carr T Hedley TH de Bruin Elza C EC Salinas-Souza Carolina C Foxley Andrew A Hauser Joana J Lindemann Justin P O JPO Maudsley Rhiannon R McEwen Robert R Moschetta Michele M Nikolaou Myria M Schiavon Gaia G Razavi Pedram P Banerji Udai U Baselga José J Hyman David M DM Chandarlapaty Sarat S

NPJ breast cancer 20210416 1

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 ...[more]

PMID: 33863913

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Project description:BackgroundThe aromatase inhibitor anastrozole inhibits estrogen synthesis. Fulvestrant binds and accelerates degradation of estrogen receptors. We hypothesized that these two agents in combination might be more effective than anastrozole alone in patients with hormone-receptor (HR)-positive metastatic breast cancer.MethodsPostmenopausal women with previously untreated metastatic disease were randomly assigned, in a 1:1 ratio, to receive either 1 mg of anastrozole orally every day (group 1), with crossover to fulvestrant alone strongly encouraged if the disease progressed, or anastrozole and fulvestrant in combination (group 2). Patients were stratified according to prior or no prior receipt of adjuvant tamoxifen therapy. Fulvestrant was administered intramuscularly at a dose of 500 mg on day 1 and 250 mg on days 14 and 28 and monthly thereafter. The primary end point was progression-free survival, with overall survival designated as a prespecified secondary outcome.ResultsThe median progression-free survival was 13.5 months in group 1 and 15.0 months in group 2 (hazard ratio for progression or death with combination therapy, 0.80; 95% confidence interval [CI], 0.68 to 0.94; P=0.007 by the log-rank test). The combination therapy was generally more effective than anastrozole alone in all subgroups, with no significant interactions. Overall survival was also longer with combination therapy (median, 41.3 months in group 1 and 47.7 months in group 2; hazard ratio for death, 0.81; 95% CI, 0.65 to 1.00; P=0.05 by the log-rank test), despite the fact that 41% of the patients in group 1 crossed over to fulvestrant after progression. Three deaths that were possibly associated with treatment occurred in group 2. The rates of grade 3 to 5 toxic effects did not differ significantly between the two groups.ConclusionsThe combination of anastrozole and fulvestrant was superior to anastrozole alone or sequential anastrozole and fulvestrant for the treatment of HR-positive metastatic breast cancer, despite the use of a dose of fulvestrant that was below the current standard. (Funded by the National Cancer Institute and AstraZeneca; SWOG ClinicalTrials.gov number, NCT00075764.).

Project description:BackgroundCapivasertib (AZD5363) is a potent selective oral inhibitor of all three isoforms of the serine/threonine kinase AKT. The FAKTION trial investigated whether the addition of capivasertib to fulvestrant improved progression-free survival in patients with aromatase inhibitor-resistant advanced breast cancer.MethodsIn this randomised, double-blind, placebo-controlled, phase 2 trial, postmenopausal women aged at least 18 years with an Eastern Cooperative Oncology Group performance status of 0-2 and oestrogen receptor-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer who had relapsed or progressed on an aromatase inhibitor were recruited from 19 hospitals in the UK. Enrolled participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off (starting on cycle 1 day 15) until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment allocation was done using an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival with a one-sided alpha of 0·20. Analyses were done by intention to treat. Recruitment is complete, and the trial is in follow-up. This trial is registered with ClinicalTrials.gov, number NCT01992952.FindingsBetween March 16, 2015, and March 6, 2018, 183 patients were screened for eligibility, of whom 140 (76%) were eligible and were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up for progression-free survival was 4·9 months (IQR 1·6-11·6). At the time of primary analysis for progression-free survival (Jan 30, 2019), 112 progression-free survival events had occurred, 49 (71%) in 69 patients in the capivasertib group compared with 63 (89%) of 71 in the placebo group. Median progression-free survival was 10·3 months (95% CI 5·0-13·2) in the capivasertib group versus 4·8 months (3·1-7·7) in the placebo group, giving an unadjusted hazard ratio (HR) of 0·58 (95% CI 0·39-0·84) in favour of the capivasertib group (two-sided p=0·0044; one-sided log rank test p=0·0018). The most common grade 3-4 adverse events were hypertension (22 [32%] of 69 patients in the capivasertib group vs 17 [24%] of 71 in the placebo group), diarrhoea (ten [14%] vs three [4%]), rash (14 [20%] vs 0), infection (four [6%] vs two [3%]), and fatigue (one [1%] vs three [4%]). Serious adverse reactions occurred only in the capivasertib group, and were acute kidney injury (two), diarrhoea (three), rash (two), hyperglycaemia (one), loss of consciousness (one), sepsis (one), and vomiting (one). One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. One further death in the capivasertib group had an unknown cause; all remaining deaths in both groups (19 in the capivasertib group and 31 in the placebo group) were disease related.InterpretationProgression-free survival was significantly longer in participants who received capivasertib than in those who received placebo. The combination of capivasertib and fulvestrant warrants further investigation in phase 3 trials.FundingAstraZeneca and Cancer Research UK.

Project description:BackgroundActivation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss.Patients and methodsmCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated.ResultsSixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples.ConclusionsThe combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway.Clinical trial numberNCT02525068.

Project description:BackgroundHER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T.Patients and methodsPatients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing.ResultsORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response.ConclusionsThe benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.

Dataset Information

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

Publications

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

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