A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer

Cynthia X. Ma, Cesar Sanchez, Feng Gao, Robert Crowder, Michael Naughton, Timothy Pluard, Allison Creekmore, Zhanfang Guo, Jeremy Hoog, Craig Lockhart, Austin Doyle, Charles Erlichman, Matthew J. Ellis

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

Purpose: PI3K/AKT pathway activation is an important endocrine resistance mechanism in estrogen receptor-positive (ER+) breast cancer. After promising preclinical modeling of MK-2206, an allosteric pan-AKT inhibitor, with either estrogen deprivation or fulvestrant, we conducted a phase I trial in patients with metastatic ER+HER2- breast cancer to determine the recommended phase II treatment dose (RPTD) of MK-2206 when combined with either anastrozole, fulvestrant, or anastrozole/ fulvestrant. Experimental Design: ER+ breast cancer cell lines were exposed in vitro to MK-2206 plus estrogen deprivation with or without fulvestrant and monitored for apoptosis. A standard 3+3 design was employed to first determine the maximum tolerated dose (MTD) of MK-2206 plus anastrozole based on cycle 1 toxicity. Each cycle was 28 days. The RPTD was determined on the basis of toxicities observed at MTD level during the first 3 cycles. Subsequent patients received MK-2206, at the RPTD determined above, plus fulvestrant or anastrozole/fulvestrant to define RPTD for these additional regimens. Results: MK-2206 induced apoptosis in parental ER+ but not in long-term estrogen-deprived cell lines, for which fulvestrant was required for apoptosis induction. Thirty-one patients enrolled. The RPTD was defined as MK-2206 150 mg orally weekly with prednisone prophylaxis for each combination. Grade 3 rash was dose limiting. 42% (95% CI, 23%-63%) patients derived clinical benefit without progression within 6 months. Response was not associated with tumor PIK3CA mutation. Conclusions: MK-2206 plus endocrine treatments were tolerable. MK-2206 in combination with anastrozole is being further evaluated in a phase II neoadjuvant trial for newly diagnosed ER+ HER2- breast cancer.

Original languageEnglish (US)
Pages (from-to)2650-2658
Number of pages9
JournalClinical Cancer Research
Volume22
Issue number11
DOIs
StatePublished - Jun 1 2016

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Fingerprint Dive into the research topics of 'A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer'. Together they form a unique fingerprint.

  • Cite this

    Ma, C. X., Sanchez, C., Gao, F., Crowder, R., Naughton, M., Pluard, T., Creekmore, A., Guo, Z., Hoog, J., Lockhart, C., Doyle, A., Erlichman, C., & Ellis, M. J. (2016). A phase I study of the AKT inhibitor MK-2206 in combination with hormonal therapy in postmenopausalwomenwith estrogen receptor-positive metastatic breast cancer. Clinical Cancer Research, 22(11), 2650-2658. https://doi.org/10.1158/1078-0432.CCR-15-2160