Adding ipatasertib to first-line paclitaxel “modestly” improved progression-free survival (PFS) in women with triple-negative breast cancer (TNBC), according to authors of the double-blind, placebo-controlled, randomized phase II LOTUS trial (NCT02162719) presented (abstract 1009) at the 2017 American Society of Clinical Oncology (ASCO) Annual Meeting, held June 2–6 in Chicago. Improved PFS was seen in both the entire intention-to-treat (ITT) population and a predefined biomarker-selected subgroup of patients.
“The effect was more pronounced in the prespecified subgroup with PIK3CA/AKT1/PTEN gene alterations,” reported lead study author Rebecca Alexandra Dent, MD, of the National Cancer Centre in Singapore.
Ipatasertib is an investigational oral AKT inhibitor. The research team enrolled patients with unresectable locally-advanced or metastatic, systemic treatment-naïve TNBC. Patients were stratified by neoadjuvant treatment, chemotherapy-free interval duration, and tumor PTEN status, before they were randomly assigned 1:1 to receive paclitaxel (80 mg/m2 on days 1, 8, and 15) with placebo or ipatasertib (400 mg) every 28 days until tumor progression or the development of unacceptable toxicity.
PIK3CA/AKT1/PTEN mutation status was determined using next-generation sequencing (NGS).
Objective response rate (ORR) was 40% vs 32% for the ITT population’s ipatasertib and placebo groups, respectively, and 9% vs 4.9% for the treatment and placebo group patients with PIK3CA/AKT1/PTEN gene mutation-harboring disease.
Median PFS time in ITT, a co-primary study endpoint, was 6.2 months for the ipatasertib group vs 4.9 months for patients in the placebo group (n = 124; hazard ratio [HR], 0.60; 95% CI: 0.40–0.91). However, PFS benefits for PTEN-low patients (n = 48), the other study co-primary endpoint, failed to achieve statistical significance.
Median PFS among patients with PIK3CA/AKT1/PTEN mutation-harboring disease, a secondary study endpoint, was 9 vs 4.9 months (n = 42; HR, 0.44; 95% CI: 0.22–0.87).
Median duration of response was 7.9 vs 7.4 months in the ITT population ipatasertib and placebo groups, respectively, and 9 and 4.9 months for patients with PIK3CA/AKT1/PTEN mutation-harboring disease.
Adverse events were manageable, Dent reported. The most frequent high-grade (3+) adverse events in the ipatasertib group were diarrhea (affecting 23% of patients in the treatment group vs 0% in the placebo group), neutropenia (18% vs 8%), and pneumonia (5% vs 0%). Neuropathy (5% vs 5%) and physical weakness (asthenia; 5% vs 6%) occurred at similar rates between the placebo and treatment groups.
Diarrhea was reversible and caused discontinuation for only 3% of patients receiving ipatasertib, but affected > 90% of patients taking ipatasertib, raising potential concerns about combinatorial treatment strategies with other agents that cause diarrhea or gastrointestinal toxicity.
Patient-reported health-related quality of life was stable throughout treatment.