The PI3K/AKT signalling pathway plays a crucial part in carcinogenesis, promoting cell survival and growth.1, 2 AKT is the central node of the PI3K/AKT pathway.3 Phosphatidylinositol (3,4,5)-triphosphate, a direct product of PI3K activity, promotes AKT trafficking to the cell membrane and association with other cell- signalling proteins.4 Full activation of AKT occurs via phosphorylation at two threonine and serine residues, leading to phosphorylation and regulation of numerous cellular proteins, including mTORC1 and S6 kinase.
The PI3K/AKT signalling pathway is often activated in breast cancer, and has attracted interest as a target in triple-negative breast cancer.5, 6 Large-scale comprehensive genomic analyses have characterised the heterogeneous nature of triple-negative breast cancer, including a subgroup with genetic activation of the PI3K/AKT pathway through activating mutations in PIK3CA or AKT1, and alterations in PTEN.7, 8, 9 Additionally, approximately half of triple-negative breast cancers have deficient expression of the tumour suppressor PTEN, which is associated with a higher degree of AKT pathway activation.2, 10
Research in context
Evidence before this study
We searched PubMed to identify publications published between Jan 1, 2001, and March 31, 2017, that included the search terms “AKT”, “PI3K”, and “triple-negative breast cancer”. We also searched PubMed for publications in the same period describing assessment of ipatasertib using the terms “ipatasertib” or “GDC-0068”. We did not use any language restrictions in our search. No previous randomised trials have investigated the targeting of AKT or PI3K specifically in triple-negative breast cancer. Analyses of single-arm studies in mesenchymal and metaplastic triple-negative breast cancer have suggested a more pronounced response to a combination of an mTOR inhibitor, bevacizumab, and pegylated liposomal doxorubicin in patients with PI3K/AKT/mTOR pathway aberrations. A phase 1 study showed potent inhibition of AKT signalling with ipatasertib, with notable activity in metastatic breast cancer showing PTEN loss or PIK3CA/AKT mutations.
Added value of this study
To our knowledge, these are the first prospective trial results supporting AKT targeting in triple-negative breast cancer. Prespecified analyses in the population of patients with PIK3CA/AKT1/PTEN-altered tumours suggest efficacy of ipatasertib in this population.
Implications of all of the available evidence
Our results support future investigation of ipatasertib plus paclitaxel in diseases with high prevalence of PI3K/AKT pathway activation, particularly in patients with PIK3CA/AKT1/PTEN-altered tumours.
Ipatasertib is a highly selective oral ATP-competitive small-molecule AKT inhibitor.11 In cell line and xenograft models, ipatasertib showed activity in a broad range of cancer types, including prostate, breast, ovarian, colorectal, and non-small-cell lung cancers.11 Sensitivity to ipatasertib tended to be associated with high phosphorylated AKT levels, PTEN protein loss or genetic mutations in PTEN, and PIK3CA mutations, whereas KRAS and BRAF mutations were typically associated with resistance to ipatasertib.11 As PI3K/AKT pathway activation is relevant for survival during periods of mitotic stress,12 the combination of ipatasertib and taxanes was explored. Preclinical studies showed synergy between ipatasertib and taxanes.13 Analysis of on-study tumour biopsy samples from a phase 1 clinical study showed robust AKT pathway inhibition by ipatasertib at clinically achievable doses.14
Based on these findings and its mechanism of action, ipatasertib is under clinical assessment in cancers with a high prevalence of PI3K/AKT pathway activation. A phase 1 study15 of single-agent ipatasertib in 52 pretreated patients with various tumour types, including breast cancer, showed an acceptable safety profile (characterised by gastrointestinal effects, asthenia or fatigue, and rash) and preliminary antitumour activity. Of note, many patients with disease stabilisation had PI3K/AKT pathway-activating alterations in their tumours. In breast cancer, the combination of ipatasertib (400 mg once daily, days 1–21) with paclitaxel 90 mg/m2 per week (days 1, 8, and 15), repeated every 28 days, was well tolerated and showed radiographic responses in the phase 1b PAM4983g study.13
We report results of a randomised phase 2 trial investigating the addition of ipatasertib to paclitaxel as first-line therapy for metastatic triple-negative breast cancer.