K Kalinsky1,2, J A Sparano3, X Zhong4, E Andreopoulou5, B Taback6,7, L Wiechmann7, S M Feldman8, P Ananthakrishnan9, A Ahmad10, S Cremers10, A N Sireci10, J R Cross11, D K Marks12, P Mundi12,6, E Connolly6,13, K D Crew12,6,4, M A Maurer12,6, H Hibshoosh6,10, S Lee6,4, D L Hershman12,6,4. 1. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA. kk2693@columbia.edu. 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. kk2693@columbia.edu. 3. Department of Medicine, Albert Einstein College of Medicine, Montefiore Medical Center, New York, USA. 4. Department of Biostatistics, Mailman School of Public Health, Columbia University, New York, USA. 5. Weill Cornell Medicine, New York, USA. 6. 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. 7. Department of Surgery, College of Physicians and Surgeons, Columbia University, New York, USA. 8. Department of Surgery, Albert Einstein College of Medicine, Montefiore Medical Center, New York, USA. 9. Department of Surgery, White Plains Hospital, New York, USA. 10. Department of Pathology and Cell Biology, College of Physicians and Surgeons, Columbia University, New York, USA. 11. Donald B. and Catherine C. Marron Cancer Metabolism Center, Memorial Sloan-Kettering Cancer Center, New York, USA. 12. Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, USA. 13. Department of Radiation Oncology, College of Physicians and Surgeons, Columbia University, New York, USA.
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.
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.
Entities:
Keywords:
AKT inhibitor; Breast cancer; MK-2206; Phase 0; Pre-surgical
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