Final analysis of the LOTUS trial, after deaths in 70% of study population, shows numerically longer overall survival (OS) with ipatasertib plus paclitaxel versus placebo plus paclitaxel in patients with inoperable locally advanced/metastatic triple-negative breast cancer (TNBC). Median OS of more than 2 years represents a meaningful outcome in this setting. In all biomarker defined subgroups (PTEN normal or low, PIK3CA/AKT1/PTEN altered or non-altered), median OS favoured treatment with ipatasertib plus paclitaxel. However, the small sample size and heterogeneity of TNBC limit interpretation according to Prof. Rebecca Dent of the Division of Medical Oncology, National Cancer Centre Singapore, Singapore who presented the findings on behalf of study investigators during ESMO Breast Cancer Virtual Meeting 2020 (23-24 May).
Prof. Dent said that ipatasertib, an oral AKT inhibitor, is under evaluation in cancers with a high prevalence of PI3K/AKT pathway activation.
In LOTUS study (NCT02162719), addition of ipatasertib to first-line paclitaxel improved progression-free survival (PFS) in patients with metastatic TNBC. The PFS (study primary endpoint) results were reported by Kim et al. in the Lancet Oncology in 2017. The stratified PFS hazard ratio (HR) in the intent-to-treat (ITT) population was 0.60 (95% confidence interval [CI] 0.37-0.98; p = 0.037) with a median PFS of 6.2 vs 4.9 months with ipatasertib vs placebo and observed enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumours. The OS results were immature at the primary and updated analyses. At ESMO Breast Cancer Virtual Meeting 2020, the LOTUS investigators reported the final study results.
Eligible patients had measurable metastatic TNBC and were previously untreated with systemic therapy. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval and tumour PTEN status determined by immunohistochemistry. Patients were randomised 1:1 to paclitaxel plus either ipatasertib or placebo until disease progression or unacceptable toxicity.
The OS in ITT, PTEN-low and PIK3CA/AKT1/PTEN-altered populations was a prespecified secondary endpoint.
By the final data cut-off of 3 September 2019, all patients had discontinued treatment, predominantly because of disease progression. In the ITT population, median OS was 25.8 months in ipatasertib plus paclitaxel arm vs 16.9 months in placebo plus paclitaxel arm (HR 0.81; 95% CI 0.53-1.23).
Similarly, median OS favoured ipatasertib plus paclitaxel vs placebo plus paclitaxel in the PTEN-low (23.1 vs 15.8 months) and PIK3CA/AKT1/PTEN-altered (25.8 vs 22.1 months) subgroups.
Prof. Dent emphasised on OS difference in a group of patients younger than 50 years, in particular 35.2 months with ipatasertib plus paclitaxel vs 15.1 months with placebo plus paclitaxel (HR 0.41; CI 0.20-0.85).
There were few additional adverse events since previous reports and no new safety signals were observed.
The authors concluded that median OS exceeds 2 years with ipatasertib plus paclitaxel. Consistent with the previously observed PFS benefit, these findings support further evaluation of first-line ipatasertib plus paclitaxel for metastatic TNBC in the ongoing IPATunity130 (NCT03337724), double-blind, placebo-controlled, randomised phase III trial. IPATunity170 (NCT04177108) is evaluating first-line ipatasertib plus paclitaxel plus atezolizumab in locally advanced or metastatic TNBC.
Suzette Delaloge of the Gustave Roussy in Villejuif, France, who discussed the study findings, said that AKT inhibition in combination with paclitaxel deserves phase III development in advanced TNBC. Efficacy may not be limited to PIK3CA/AKT altered tumours. Advanced TNBC is heterogenous. Therefore, such trials would ideally involve extensive genomical definition of tumours. Adequate positioning of this approach in competition/complementation of other strategies remains to be defined. Translation to early phases is awaited.
The LOTUS study was funded by F. Hoffmann-La Roche Ltd.
Abstract 139O - Dent R, Oliveira M, Isakoff SJ, et al. Final results of the double-blind placebo (PBO)-controlled randomised phase II LOTUS trial of first-line ipatasertib (IPAT) + paclitaxel (PAC) for inoperable locally advanced/metastatic triple-negative breast cancer (mTNBC). ESMO Breast Cancer Virtual 2020 (23-24 May 2020).