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07-12-2024 | Breast Cancer | Research

Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer

Authors: Vishnu Prasath, Hinda Boutrid, Robert Wesolowski, Mahmoud Abdel-Rasoul, Cynthia Timmers, Maryam Lustberg, Rachel M. Layman, Erin Macrae, Ewa Mrozek, Charles Shapiro, Kristyn Glover, Mark Vater, G. Thomas Budd, Lyndsay Harris, Claudine Isaacs, Claire Dees, Charles M. Perou, Gary L. Johnson, Andrew Poklepovic, Helen Chen, Miguel Villalona-Calero, William Carson, Daniel G. Stover, Bhuvaneswari Ramaswamy

Published in: Breast Cancer Research and Treatment | Issue 1/2025

Abstract

Purpose

While MEK inhibitors demonstrated activity in metastatic triple negative breast cancer (mTNBC) preclinical studies, preclinical, and clinical studies implicate rapid development of resistance limiting clinical benefit. The purpose of this study was to determine response rate for Trametinib alone and in combination with Uprosertib in patients with mTNBC previously treated with chemotherapy.

Methods

This was an open-label, two-part, phase II, single-arm, multicenter study. Patients first received Trametinib monotherapy (2 mg daily; Part I) then at progression transitioned to Trametinib (1.5 mg) plus Uprosertib (50 mg; Part II).

Results

Between October 2013 and January 2017, 37 patients were enrolled to Part I. Subsequently, 19 patients entered Part II. Of the 37 patients receiving Trametinib monotherapy, 2 patients achieved partial response (PR) for an ORR of 5.4% (2/37) and an additional 6/37 (16.2%) achieved stable disease (SD). The clinical benefit rate (PR+SD) for patients receiving monotherapy was 21.6% (8/37). Of the 19 patients in Part II, 3 patients achieved PR for an ORR to Part II of 15.8% (3/19) and an additional 3 achieved SD. Median progression-free survival (PFS) was 7.7 weeks for Part I and 7.8 weeks for Part II. Circulating tumor DNA (ctDNA) clearance at C2D1 of Trametinib monotherapy was associated with improved PFS and overall survival.

Conclusion

In patients with mTNBC, Trametinib monotherapy demonstrated limited efficacy and addition of Uprosertib was associated with numerically greater objective responses but no difference in PFS. Translational analyses suggest ctDNA clearance as a potential early biomarker of response.

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Title: Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer
Authors: Vishnu Prasath
Hinda Boutrid
Robert Wesolowski
Mahmoud Abdel-Rasoul
Cynthia Timmers
Maryam Lustberg
Rachel M. Layman
Erin Macrae
Ewa Mrozek
Charles Shapiro
Kristyn Glover
Mark Vater
G. Thomas Budd
Lyndsay Harris
Claudine Isaacs
Claire Dees
Charles M. Perou
Gary L. Johnson
Andrew Poklepovic
Helen Chen
Miguel Villalona-Calero
William Carson
Daniel G. Stover
Bhuvaneswari Ramaswamy
Publication date: 07-12-2024
Publisher: Springer US
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research and Treatment / Issue 1/2025
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-024-07551-z

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Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer

Abstract

Purpose

Methods

Results

Conclusion

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