1. Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer.
- Author
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Prasath V, Boutrid H, Wesolowski R, Abdel-Rasoul M, Timmers C, Lustberg M, Layman RM, Macrae E, Mrozek E, Shapiro C, Glover K, Vater M, Budd GT, Harris L, Isaacs C, Dees C, Perou CM, Johnson GL, Poklepovic A, Chen H, Villalona-Calero M, Carson W, Stover DG, and Ramaswamy B
- Subjects
- Humans, Female, Middle Aged, Aged, Adult, Proto-Oncogene Proteins c-akt metabolism, Neoplasm Metastasis, Treatment Outcome, Protein Kinase Inhibitors therapeutic use, Protein Kinase Inhibitors administration & dosage, Aged, 80 and over, Diamines, Pyrazoles, Pyridones therapeutic use, Pyridones administration & dosage, Pyrimidinones therapeutic use, Pyrimidinones administration & dosage, Triple Negative Breast Neoplasms drug therapy, Triple Negative Breast Neoplasms pathology, Triple Negative Breast Neoplasms mortality, Antineoplastic Combined Chemotherapy Protocols therapeutic use
- 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., Competing Interests: Declarations. Conflict of interest: Authors have no conflicts of interest related to the current analyses., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2025
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