Final analysis of the LOTUS trial has shown numerically longer overall survival with ipatasertib plus paclitaxel vs placebo plus paclitaxel in patients with inoperable locally advanced/metastatic triple-negative breast cancer. In all biomarker-defined subgroups (PTEN normal or low, PIK3CA/AKT1/PTEN altered or nonaltered), median overall survival favored treatment with ipatasertib plus paclitaxel. However, the small sample size and heterogeneity of triple-negative breast cancer limit interpretation, according to Rebecca A. Dent, MD, of the Division of Medical Oncology, National Cancer Centre Singapore, who presented the findings on behalf of study investigators during the ESMO Breast Cancer Virtual Meeting 2020 (Abstract 139O).

Rebecca A. Dent, MD

Dr. Dent explained that ipatasertib, an oral AKT inhibitor, is under evaluation in cancers with a high prevalence of PI3K/AKT pathway activation.

LOTUS Trial

In the LOTUS study, the addition of ipatasertib to first-line paclitaxel improved progression-free survival in patients with metastatic triple-negative breast cancer, as reported by Kim et al in The Lancet Oncology in 2017. The stratified progression-free survival hazard ratio (HR) in the intent-to-treat population was 0.60 (95% confidence interval [CI] = 0.37–0.98, P = .037), with a median progression-free survival of 6.2 vs 4.9 months with ipatasertib vs placebo and an observed enhanced effect in patients with PIK3CA/AKT1/PTEN-altered tumors.

The overall survival results were immature at the primary and updated analyses. At the ESMO Breast Cancer Virtual Meeting 2020, the LOTUS trial investigators reported the final study results.

Eligible patients had measurable metastatic triple-negative breast cancer and had not received prior systemic therapy. Patients were stratified by prior (neo)adjuvant therapy, chemotherapy-free interval, and tumor PTEN status as determined by immunohistochemistry.

Patients were randomly assigned 1:1 to receive paclitaxel plus either ipatasertib or placebo until disease progression or unacceptable toxicity. Overall survival in the intent-to-treat, PTEN-low, and PIK3CA/AKT1/PTEN-altered populations was a prespecified secondary endpoint.

Overall Survival Results

By final data cutoff in September 2019, all patients had discontinued treatment, predominantly because of disease progression. In the intent-to-treat population, median overall survival was 25.8 months in the ipatasertib-plus-paclitaxel arm vs 16.9 months in the placebo-plus-paclitaxel arm (HR = 0.81, 95% CI = 0.53–1.23). Similarly, median overall survival was longer for patients treated with 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.

Dr. Dent emphasized a difference in overall survival in a group of patients younger than age 50—in particular, 35.2 months with ipatasertib plus paclitaxel vs 15.1 months with placebo plus paclitaxel (HR = 0.41, 95% CI = 0.20–0.85).

There were few additional adverse events since previous reports. No new safety signals were observed.

The authors concluded that median overall survival exceeds 2 years with ipatasertib plus paclitaxel. Consistent with the previously observed progression-free survival benefit, these findings support further evaluation of first-line ipatasertib plus paclitaxel for metastatic triple-negative breast cancer in the ongoing IPATunity130 study, a double-blind, placebo-controlled, randomized phase III trial. IPATunity170 is evaluating first-line ipatasertib, paclitaxel, and atezolizumab in locally advanced or metastatic triple-negative breast cancer.

Disclosure: The LOTUS study was funded by F. Hoffmann-La Roche Ltd. For full disclosures of the study authors, visit cslide.ctimeetingtech.com.