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Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial

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Abstract

Introduction

The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I–III BC.

Materials and methods

Two doses of weekly oral MK2206 were administered at days − 9 and − 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls.

Results

Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06).

Conclusion

While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.

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Funding

Women at Risk funded this research. This work is also supported by contract N01-CM-62,204 to the New York Cancer Consortium (PI: Joseph A. Sparano) from the National Institutes of Health. In addition, this publication was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Number KL2 TR000081. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

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Authors and Affiliations

  1. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA

    K. Kalinsky, D. K. Marks, P. Mundi, K. D. Crew, M. A. Maurer & D. L. Hershman

  2. Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, Herbert Irving Pavilion, 161 Fort Washington Avenue, 10th Floor, Room 1069, New York, NY, 10032, USA

    K. Kalinsky, B. Taback, P. Mundi, E. Connolly, K. D. Crew, M. A. Maurer, H. Hibshoosh, S. Lee & D. L. Hershman

  3. Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, New York, USA

    J. A. Sparano

  4. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, USA

    X. Zhong, K. D. Crew, S. Lee & D. L. Hershman

  5. Weill Cornell Medicine, New York, USA

    E. Andreopoulou

  6. Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, USA

    B. Taback & L. Wiechmann

  7. Department of Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, New York, USA

    S. M. Feldman

  8. Department of Surgery, White Plains Hospital, New York, USA

    P. Ananthakrishnan

  9. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, USA

    A. Ahmad, S. Cremers, A. N. Sireci & H. Hibshoosh

  10. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, USA

    J. R. Cross

  11. Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, USA

    E. Connolly

Authors
  1. K. Kalinsky
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  2. J. A. Sparano
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  3. X. Zhong
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  4. E. Andreopoulou
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  5. B. Taback
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  6. L. Wiechmann
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  7. S. M. Feldman
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  8. P. Ananthakrishnan
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  9. A. Ahmad
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  10. S. Cremers
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  11. A. N. Sireci
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  12. J. R. Cross
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  13. D. K. Marks
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  14. P. Mundi
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  15. E. Connolly
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  16. K. D. Crew
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  17. M. A. Maurer
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  18. H. Hibshoosh
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  19. S. Lee
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  20. D. L. Hershman
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Corresponding author

Correspondence to K. Kalinsky.

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Conflicts of interest

The authors would like to report the following conflicts of interest: KK (Advisory: Biotheranostics, Lilly, Pfizer, Amgen, Novartis, Eisai) and MM (Stock and Employment: Bristol-Myers Squibb).

Research involving human participants

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Kalinsky, K., Sparano, J.A., Zhong, X. et al. Pre-surgical trial of the AKT inhibitor MK-2206 in patients with operable invasive breast cancer: a New York Cancer Consortium trial. Clin Transl Oncol 20, 1474–1483 (2018). https://doi.org/10.1007/s12094-018-1888-2

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  • DOI: https://doi.org/10.1007/s12094-018-1888-2

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