KEY TAKEAWAYS
- The phase 2 trial aimed to investigate the efficacy of trametinib and prosertib in patients with metastatic TNBC previously treated with chemotherapy.
- Researchers noticed promising efficacy with trametinib and uprosertib in metastatic TNBC patients resistant to prior chemotherapy.
Triple-negative breast cancers (TNBCs) are a poor prognosis subset of BC, often associated with chemotherapy resistance linked to RAS/MEK/ERK pathway activation. Preclinical evidence underscores the potential synergy between RAS/MEK/ERK and PI3K/AKT pathway inhibition to overcome resistance to MEK inhibitors.
V. Prasath and the team aimed to assess the response rate of the selective allosteric MEK1/MEK2 inhibitor trametinib alone and combined with the AKT inhibitor uprosertib in patients with metastatic TNBC previously treated with chemotherapy.
Researchers performed an inclusive analysis of an open-label, two-part, phase II, single-arm, multicenter study conducted through the ETCTN. Eligible patients with metastatic TNBC and measurable disease, having received 1-3 prior chemotherapy regimens, underwent mandatory pretreatment biopsy. Trametinib alone (2mg) was administered in Part I, followed by a second biopsy at progression and progression to Part II with trametinib (1.5mg) and uprosertib (50mg).
Biopsies were profiled using quantitative targeted absolute proteomics (QTAP) for kinome assay and whole transcriptome profiling via microarray. Blood samples were collected at baseline, cycle 2 day 1 (C2D1), and progression for circulating tumor DNA (ctDNA) analysis via ultra-low pass whole genome sequencing.
About 37 patients were enrolled at 8 centers between October 2013 and January 2017, with 19 proceeding to Part II. On trametinib alone (Part I), 2 patients achieved partial response (PR) and 6 had stable disease (SD). In Part II (trametinib + uprosertib), 3 patients had PR, and 3 had SD.
Analysis of matched samples with QTAP kinome and transcriptome data QTAP kinome assay demonstrated MEK1/2 inhibition in 4/4 patients at progression on trametinib alone and AKT1 inhibition in 1 patient after trametinib + uprosertib. ctDNA evaluation at C1D1 showed tumor fraction (TFx) ranging from 0-75.9% in 34 patients, with 6/23 showing ctDNA ‘clearance’ (TFx of 0%) at C2D1. Of these 6, 3 (50%) achieved PR, compared to 1/17 patients without ctDNA clearance.
The study concluded that trametinib alone and with uprosertib exhibits anti-tumor activity in a subset of TNBC patients, supported by kinome evidence of target engagement. Additionally, ctDNA clearance at C2D1 emerges as a potential early biomarker for identifying patients most likely to respond. This understanding of response and resistance biomarkers may inform future MEK/AKT inhibition opportunities in TNBC.
The trial was sponsored by the National Cancer Institute (NCI)
Source: https://www.abstractsonline.com/pp8/#!/20272/presentation/2154
Clinical Trial: https://clinicaltrials.gov/study/NCT01964924
Prasath V, Boutrid H, Mrozek E, et al. (2024). “Phase II study of trametinib alone and in combination with uprosertib in patients with metastatic triple negative breast cancer previously treated with chemotherapy: OSU 13317.” Presented at AACR 2024 (Abstract 6427 / 6).
