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

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\u201321) 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\ub74 months (IQR 6\ub75\u201314\ub71) in the ipatasertib group and 10\ub72 months (6\ub70\u201313\ub76) in the placebo group. Median progression-free survival in the intention-to-treat population was 6\ub72 months (95% CI 3\ub78\u20139\ub70) with ipatasertib versus 4\ub79 months (3\ub76\u20135\ub74) with placebo (stratified hazard ratio [HR] 0\ub760, 95% CI 0\ub737\u20130\ub798; p=0\ub7037) and in the 48 patients with PTEN-low tumours, median progression-free survival was 6\ub72 months (95% CI 3\ub76\u20139\ub71) with ipatasertib versus 3\ub77 months (1\ub79\u20137\ub73) with placebo (stratified HR 0\ub759, 95% CI 0\ub726\u20131\ub732, p=0\ub718). 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

Growing knowledge: an overview of Seed Plant diversity in Brazil

Abstract An updated inventory of Brazilian seed plants is presented and offers important insights into the country's biodiversity. This work started in 2010, with the publication of the Plants and Fungi Catalogue, and has been updated since by more than 430 specialists working online. Brazil is home to 32,086 native Angiosperms and 23 native Gymnosperms, showing an increase of 3% in its species richness in relation to 2010. The Amazon Rainforest is the richest Brazilian biome for Gymnosperms, while the Atlantic Rainforest is the richest one for Angiosperms. There was a considerable increment in the number of species and endemism rates for biomes, except for the Amazon that showed a decrease of 2.5% of recorded endemics. However, well over half of Brazillian seed plant species (57.4%) is endemic to this territory. The proportion of life-forms varies among different biomes: trees are more expressive in the Amazon and Atlantic Rainforest biomes while herbs predominate in the Pampa, and lianas are more expressive in the Amazon, Atlantic Rainforest, and Pantanal. This compilation serves not only to quantify Brazilian biodiversity, but also to highlight areas where there information is lacking and to provide a framework for the challenge faced in conserving Brazil's unique and diverse flora