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.

Clinical Development of AKT Inhibitors and Associated Predictive Biomarkers to Guide Patient Treatment in Cancer Medicine

“…median PFS was 5.5 months, with a median duration of response of 4.4 months among responders; one patient achieved complete response (CR). 61 Of those patients with confirmed PR, 7 had HR-positive/ERBB2-negative breast cancer, 1 had uterine leiomyosarcoma, and 1 had oncocytic parotid gland carcinoma. 61 The majority of patients treated had either breast cancer (51%) or gynecologic cancers (31%), and while responses were seen across different subgroups, it may be difficult to extrapolate these findings to non-breast and non-gynecology cancers due to the small numbers treated.…”

“…60 Recently, capivasertib (AZD5363) a selective ATP-competitive pan-AKT kinase inhibitor has shown clinically meaningful activity in patients with various tumor histologies who have AKT1 E17K mutations or PTEN mutations. 61,62 The AKT1 E17K mutation plays a crucial role in cancer development and is mutually exclusive to PIK3CA mutations and PTEN loss, 30,63,64 suggesting that the mutational activation of the phosphatidylinositol 3-kinase pathway by any one of these means may be biologically equivalent. Significant antitumor responses were initially reported using capivasertib in patients with heavily pretreated AKT1 E17K mutant solid tumors in a basket trial (including 20 patients with ER-positive (ER+) metastatic breast cancer, where the objective response rate (ORR) was 20% and median progression-free survival (PFS) was 5.5 months.…”

“…65 Recently, the results of a subprotocol of the National Cancer Institute Molecular Analysis for Therapy Choice (NCI-Match) trial reported promising ORR with capivasertib in AKT1 E17K-mutated tumors. 61 For personal use only.…”

“…In addition, the documented adverse event profile in this study was higher than that reported in similar studies of capivasertib, as there were 26% of patients with grade 3 or higher hyperglycemia, and 11% with grade 3 rash. 61 Capivasertib plus fulvestrant has also shown antitumor activity in heavily pretreated patients with PTEN-mutated ER+ metastatic breast cancer, particularly in patients with prior progression on fulvestrant. 61 Five to ten percent of ER+ metastatic breast cancer tumors harbor somatic PTEN mutations and loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease.…”

Targeting Akt in cancer for precision therapy

“…The phase I clinical trials demonstrate that the pan-Akt inhibitors are generally tolerable in cancer patients either as a monotherapy or in combination with chemotherapy, while these drugs have some side effects including diarrhea, hypertension, rash, hyperglycemia and fatigue [ 210 , 211 ]. Combination of MK-2206 with the aromatase inhibitor anasterozole appears to be unable to enhance the efficacy of anasterozole in patients with PIK3CA -mutant ER + /Her2 − breast cancer [ 212 ].…”