Abstract 6427: 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
Authors: Prasath Vishnu , Boutrid Hinda , Mrozek Ewa , Lustberg Maryam , Weslowski Robert , Layman Rachel , Abdel-Rasoul Mahmoud , Timmers Cynthia , MacRae Erin , Budd G. Thomas , Harris Lyndsay , Isaacs Claudine , Ismail-Khan Roohi , Dees Elizabeth Claire , Poklepovic Andrew S. , Chen Helen X. , Villalona-Calero Miguel , Carson William , Johnson Gary L. , Stover Daniel G. , Ramaswamy Bhuvaneswari 
Published: March 2024

Abstract
Introduction: Triple negative breast cancers (TNBCs) are a poor prognosis subset of breast cancer and preclinical data implicate activation of the RAS/MEK/ERK pathway in TNBC chemotherapy resistance. Preclinical data demonstrate that blockade of both RAS/MEK/ERK and PI3K/AKT pathways synergizes to overcome resistance to single agent MEK inhibitors. The purpose of this study was to determine the response rate for the selective allosteric MEK1/MEK2 inhibitor trametinib alone and in combination with AKT inhibitor uprosertib in patients with metastatic TNBC previously treated with chemotherapy.
Patients and Methods: This was an open-label, two-part, phase II, single-arm, multicenter study through the ETCTN. Eligibility criteria included patients with metastatic TNBC with measurable disease who had received between 1-3 prior chemotherapy regimens. All patients underwent a mandatory pretreament biopsy and received trametinib alone (2mg) as Part I of the study. At progression, patients underwent a second biopsy and moved to Part II with trametinib (1.5mg) and uprosertib (50mg). Available biopsies were profiled quantitative targeted absolute proteomics (QTAP) for kinome assay and whole transcriptome profiling via microarray. Blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and at progression for circulating tumor DNA (ctDNA) analysis via ultra-low pass whole genome sequencing.
Results: Between October 2013 and January 2017, 37 patients were enrolled at 8 centers and, subsequently, 19 of these patients entered Part II. Adverse event data has been previously presented. On trametinib alone (Part I), 2 patients had a partial response (PR) and 6 patients had stable disease (SD) as best response. Of the 19 evaluable patients on trametinib + uprosertib (Part II), 3 patients had a PR and 3 patients had SD. Integrated analysis of matched samples with QTAP kinome and transcriptome data QTAP kinome assay in demonstrated MEK1/2 inhibition at progression on trametinib alone in 4/4 patients with evaluable tissue confirming target engagement and one patient with biopsy after trametinib+uprosertib demonstrated AKT1 inhibition. ctDNA was evaluable in 34 patients at C1D1 with tumor fraction (TFx) range 0-75.9%. 6/23 patients had ctDNA ‘clearance’ (tumor fraction of 0%) at C2D1. Of these 6, 3 (50%) had PR as best response, compared with only PR in only 1/17 patients without ctDNA clearance at C2D1.
Conclusions: Trametinib alone and in combination with uprosertib demonstrates anti-tumor activity in a subset of TNBC patients with kinome evidence of target engagment. ctDNA clearance at C2D1 may be useful as an early biomarker to identify patients most likely to respond. Understanding biomarkers of response and resistance may guide future opportunities for MEK/AKT inhibition in TNBC.
Citation Format: Vishnu Prasath, Hinda Boutrid, Ewa Mrozek, Maryam Lustberg, Robert Weslowski, Rachel Layman, Mahmoud Abdel-Rasoul, Cynthia Timmers, Erin MacRae, G. Thomas Budd, Lyndsay Harris, Claudine Isaacs, Roohi Ismail-Khan, Elizabeth Claire Dees, Andrew S. Poklepovic, Helen X. Chen, Miguel Villalona-Calero, William Carson, Gary L. Johnson, Daniel G. Stover, Bhuvaneswari Ramaswamy. 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 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6427.