American Association for Cancer Research
10780432ccr152160-sup-155003_2_supp_3286377_nzz949.pptx (711.25 kB)

Suppl. Figure 1 from A Phase I Study of the AKT Inhibitor MK-2206 in Combination with Hormonal Therapy in Postmenopausal Women with Estrogen Receptor–Positive Metastatic Breast Cancer

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posted on 2023-03-31, 18:11 authored by Cynthia X. Ma, Cesar Sanchez, Feng Gao, Robert Crowder, Michael Naughton, Timothy Pluard, Allison Creekmore, Zhanfang Guo, Jeremy Hoog, A. Craig Lockhart, Austin Doyle, Charles Erlichman, Matthew J. Ellis

This supplementary figure shows the appearance of the rash and the histology of the skin biopsy. This needs to be a colored figure.


Breast Cancer Research Program, Fashion Footwear Association of New York, Mayo PIIC




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. Clin Cancer Res; 22(11); 2650–8. ©2016 AACR.See related commentary by Jansen et al., p. 2599

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