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

Abstract

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.

Figure 1. Trial profile

ECOG=Eastern Cooperative Oncology Group. LVEF=left ventricular ejection fraction. *The reasons for screen failure in 42 patients were: not meeting inclusion criteria (two signed informed consent, two ECOG performance status ≤1, one locally advanced or metastatic triple-negative breast cancer not amenable to curative resection, one measurable disease, and six adequate haematological and organ function), meeting exclusion criteria (one previous therapy for locally advanced or metastatic triple-negative breast cancer; two radiatiotherapy in previous 28 days; one major surgery, open biopsy, or significant traumatic injury in preceding 30 days; ten known brain or spinal cord metastasis; one New York Heart Association class II, III, or IV heart failure or LVEF <50%, or active ventricular arrhythmia requiring medication; one ongoing unstable angina or history of myocardial infarction in previous 6 months; one grade 3 uncontrolled or untreated hypercholesterolaemia or hypertriglyceridaemia; three congenital long QT syndrome or screening corrected QT interval ≥480 ms; three inability to comply with study and follow-up procedures; one other malignancy within 5 years; three potential contraindication); and 12 other reasons (more than one answer possible). ^†Five patients in the ipatasertib group and six in the placebo group received new anticancer therapy after discontinuing study therapy before disease progression. Further details of patients who discontinued without progression and received new anticancer therapy are provided in the appendix.

Figure 2. Biomarker prevalence

IHC=immunohistochemistry. FMI=Foundation Medicine Inc. NGS=next-generation sequencing. *Prevalence based on all available diagnostic data. Each vertical set of blocks represents an individual patient's tumour. Green blocks represent PTEN loss by IHC; pink blocks represent PTEN-altered by NGS; dark blue blocks represent PIK3CA/AKT1-mutant by NGS; grey blocks represent samples with no corresponding data available (assay failure or insufficient sample for testing). The bottom row shows whether samples are from primary (light blue) or metastatic (red) tumour sites.

Figure 3. Progression-free survival in the (A) intention-to-treat population, (B) PTEN-low subgroup, (C) PIK3CA/AKT1/ PTEN-altered subgroup

HR=hazard ratio.

Figure 4. Subgroup analysis of progression-free survival

Non-stratified analysis. DFI =disease free interval. lHC=immunohistochemistry. NA=not assessible. NGS=next-generation sequencing.