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

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.

Survival Outcomes by TP53 Mutation Status in Metastatic Breast Cancer

“…In most breast cancer series this is the most frequently altered potentially actionable pathway, thus these alterations are actively being pursued in trials with PI3K/AKT/ mTOR inhibitors. 2,23,24 CDH1 mutations, as expected, were almost exclusively found in invasive lobular carcinoma. CDH1 loss is pathognomonic for lobular carcinomas; the fact that we found CDH1 mutations in only 56% of patients suggests that CDH1 loss may also be mediated through non-genomic mechanisms.…”

A Bayesian network meta‐analysis of the efficacy of targeted therapies and chemotherapy for treatment of triple‐negative breast cancer

“…The treatment arms of the screened 28 studies were recorded, yet Dieras’ study, which compared the efficacy between onartuzumab + bevacizumab + CT, bevacizumab + CT + placebo, and onartuzumab + CT + placebo for TNBC patients, was excluded because the treatments did not share common nodes with the others . Finally, 27 RCTs involving 6924 TNBC patients were included and the characteristics of the included trials are displayed in Table …”

ESR1 mutations in breast cancer

“…A single-arm, phase 2 neoadjuvant clinical trial was conducted using the AKT inhibitor MK-2206 in combination with anastrozole in advanced breast cancer patients with a PIK3CA mutation. The LOTUS phase 2 clinical trial found that patients with TNBC treated with ipatasertib and paclitaxel had improved PFS compared with paclitaxel alone (6.2 vs 4.9 months), 63 providing the rationale for IPATunity130. 62 Furthermore, a patient in this study acquired an ESR1 mutation detected at the time of surgery.…”