Elsevier

The Lancet Oncology

Volume 18, Issue 10, October 2017, Pages 1360-1372
The Lancet Oncology

Articles
Ipatasertib plus paclitaxel versus placebo plus paclitaxel as first-line therapy for metastatic triple-negative breast cancer (LOTUS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial

https://doi.org/10.1016/S1470-2045(17)30450-3Get rights and content

Summary

Background

The oral AKT inhibitor ipatasertib is being investigated in cancers with a high prevalence of PI3K/AKT pathway activation, including triple-negative breast cancer. The LOTUS trial investigated the addition of ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer.

Methods

In this randomised, placebo-controlled, double-blind, phase 2 trial, women aged 18 years or older with measurable, inoperable, locally advanced or metastatic triple-negative breast cancer previously untreated with systemic therapy were recruited from 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium. Enrolled patients were randomly assigned (1:1) to receive intravenous paclitaxel 80 mg/m2 (days 1, 8, 15) with either ipatasertib 400 mg or placebo once per day (days 1–21) every 28 days until disease progression or unacceptable toxicity. Randomisation was by stratified permuted blocks (block size of four) using an interactive web-response system with three stratification criteria: previous (neo)adjuvant therapy, chemotherapy-free interval, and tumour PTEN status. The co-primary endpoints were progression-free survival in the intention-to-treat population and progression-free survival in the PTEN-low (by immunohistochemistry) population. This ongoing trial is registered with ClinicalTrials.gov (NCT02162719).

Findings

Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were enrolled and randomly assigned to paclitaxel plus ipatasertib (n=62) or paclitaxel plus placebo (n=62). Median follow-up was 10·4 months (IQR 6·5–14·1) in the ipatasertib group and 10·2 months (6·0–13·6) in the placebo group. Median progression-free survival in the intention-to-treat population was 6·2 months (95% CI 3·8–9·0) with ipatasertib versus 4·9 months (3·6–5·4) with placebo (stratified hazard ratio [HR] 0·60, 95% CI 0·37–0·98; p=0·037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6·2 months (95% CI 3·6–9·1) with ipatasertib versus 3·7 months (1·9–7·3) with placebo (stratified HR 0·59, 95% CI 0·26–1·32, p=0·18). The most common grade 3 or worse adverse events were diarrhoea (14 [23%] of 61 ipatasertib-treated patients vs none of 62 placebo-treated patients), neutrophil count decreased (five [8%] vs four [6%]), and neutropenia (six [10%] vs one [2%]). No colitis, grade 4 diarrhoea, or treatment-related deaths were reported with ipatasertib. One treatment-related death occurred in the placebo group. Serious adverse events were reported in 17 (28%) of 61 patients in the ipatasertib group and nine (15%) of 62 patients in the placebo group.

Interpretation

Progression-free survival was longer in patients who received ipatasertib than in those who received placebo. To our knowledge, these are the first results supporting AKT-targeted therapy for triple-negative breast cancer. Ipatasertib warrants further investigation for the treatment of triple-negative breast cancer.

Funding

F Hoffmann-La Roche.

Introduction

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.

Section snippets

Study design and participants

LOTUS is a randomised, double-blind, placebo-controlled, phase 2 trial. Patients were enrolled at 44 hospitals in South Korea, the USA, France, Spain, Taiwan, Singapore, Italy, and Belgium (appendix pp 2–3).

Eligible patients were women aged 18 years or older, with Eastern Cooperative Oncology Group performance status 0 or 1, and locally advanced or metastatic triple-negative breast cancer (defined as <1% tumour cell expression of oestrogen and progesterone receptors and negative HER2 status

Results

Between Sept 2, 2014, and Feb 4, 2016, 166 patients were assessed for eligibility and 124 patients were randomly assigned to treatment with ipatasertib (62 patients) or placebo (62 patients; figure 1). One randomly assigned patient who received no study treatment was excluded from the safety analysis population. Baseline characteristics were generally balanced between treatment groups (table 1). Biomarker-assessable populations for both PTEN status and PIK3CA/AKT1/PTEN alterations showed

Discussion

Results of the randomised, double-blind, placebo-controlled, phase 2 LOTUS trial show that adding ipatasertib to paclitaxel as first-line therapy for triple-negative breast cancer increased progression-free survival compared with that for placebo plus paclitaxel. The increase in median progression-free survival was quite modest in the intention-to-treat population and PTEN-low subgroup but more pronounced in predefined analyses of the patient population with PIK3CA/AKT1/PTEN-altered tumours

References (30)

  • S Di Cosimo et al.

    Management of breast cancer with targeted agents: importance of heterogeneity

    Nat Rev Clin Oncol

    (2010)
  • Comprehensive molecular portraits of human breast tumours

    Nature

    (2012)
  • C Curtis et al.

    The genomic and transcriptomic architecture of 2000 breast tumours reveals novel subgroups

    Nature

    (2012)
  • B Pereira et al.

    The somatic mutation profiles of 2433 breast cancers refines their genomic and transcriptomic landscapes

    Nat Commun

    (2016)
  • SZ Millis et al.

    Predictive biomarker profiling of >6000 breast cancer patients shows heterogeneity in TNBC, with treatment implications

    Clin Breast Cancer

    (2015)
  • Cited by (0)

    *

    Contributed equally

    Listed in the appendix

    View full text