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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

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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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Data availability

Bhuvaneswari Ramaswamy and Daniel G. Stover had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

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Acknowledgements

This study is in memorial of senior author, Dr. Bhuvaneswari Ramaswamy, who envisioned, designed, and oversaw the conduct of this study reflecting her unwavering passion and dedication to difficult to treat types of breast cancer. The authors would like to acknowledge Catherine Carson, Celia Garr, Katherine Weber, and Danielle Nickell for clinical support making this research possible.

Funding

N01 Grant NIH Contract No. HHSN261201100070C (BR), NCI UH3CA239105 (DGS) and Pelotonia Grant. NCI was involved in the design and conduct of the study and in review of the manuscript. Funders were not involved in collection, management, analysis, and interpretation of the data; preparation or approval of the manuscript; and decision to submit the manuscript for publication.

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Authors and Affiliations

  1. Division of Medical Oncology, Ohio State University College of Medicine, Columbus, OH, USA

    Vishnu Prasath, Hinda Boutrid, Robert Wesolowski, Cynthia Timmers, Kristyn Glover, Mark Vater, Daniel G. Stover & Bhuvaneswari Ramaswamy

  2. The Ohio State University Comprehensive Cancer Center, Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, Columbus, OH, USA

    Robert Wesolowski, Kristyn Glover, Mark Vater, Daniel G. Stover & Bhuvaneswari Ramaswamy

  3. Stefanie Spielman Comprehensive Breast Center, 1145 Olentangy River Rd, Columbus, OH, USA

    Robert Wesolowski

  4. Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH, USA

    Mahmoud Abdel-Rasoul

  5. Yale Cancer Center, New Haven, CT, USA

    Maryam Lustberg

  6. The University of Texas MD Anderson Cancer Center, Houston, TX, USA

    Rachel M. Layman

  7. Columbus Oncology, Columbus, OH, USA

    Erin Macrae

  8. OhioHealth Marion Cancer Center, Columbus, OH, USA

    Ewa Mrozek

  9. Mount Sinai, New York, NY, USA

    Charles Shapiro

  10. Cleveland Clinic Cancer Center, Cleveland, OH, USA

    G. Thomas Budd

  11. Division of Cancer Treatment and Diagnosis, National Cancer Institute, Bethesda, MD, USA

    Lyndsay Harris

  12. Division of Medical Oncology, Georgetown University, Washington, DC, USA

    Claudine Isaacs

  13. University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC, USA

    Claire Dees, Charles M. Perou & Gary L. Johnson

  14. Division of Medical Oncology, Virginia Commonwealth University, Richmond, VA, USA

    Andrew Poklepovic

  15. Cancer Therapy Evolution Program, National Cancer Institute, Bethesda, MD, USA

    Helen Chen

  16. Department of Medical Oncology & Therapeutics Research, City of Hope, Duarte, CA, USA

    Miguel Villalona-Calero

  17. Department of Surgery, Ohio State University College of Medicine, Columbus, OH, USA

    William Carson

  18. The Ohio State University Comprehensive Cancer Center, 2049 Pelotonia Research Center, 2255 Kenny Road, Columbus, OH, 43210, USA

    Daniel G. Stover

Authors
  1. Vishnu Prasath
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  2. Hinda Boutrid
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Contributions

All authors contributed to the conception and design, acquisition of data, analysis and interpretation of data, editing, and final approval. VP, HB, DGS, BR contributed to the drafting of the article. The critical revision of the article was performed by DGS and BR.

Corresponding author

Correspondence to Daniel G. Stover.

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Authors have no conflicts of interest related to the current analyses.

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Daniel G. Stover, Bhuvaneswari Ramaswamy equally directed the work.

This work was presented at the 2024 Annual Meeting of the American Association of Cancer Research; San Diego, CA, USA.

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Prasath, V., Boutrid, H., Wesolowski, R. et al. Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer. Breast Cancer Res Treat (2024). https://doi.org/10.1007/s10549-024-07551-z

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