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Uterine serous carcinoma (USC) is an uncommon subtype of endometrial cancer with a poor prognosis. USCs have genomic alterations in the PI3K pathway. A prior phase II study of AKT inhibitor MK-2206 (an allosteric AKT inhibitor, primarily affecting AKT1 and AKT2) in endometrial cancers resulted in progression-free survival (PFS) of ≥6 months in five out of seven patients with USC. To further assess the activity of MK-2206 in USC, we designed a phase II, single-stage assessment of MK-2206 in patients with advanced or recurrent high-grade serous endometrial cancer, who had received up to two lines of prior therapy. MK-2206 (135 mg) was administered orally once per week, in continuous 28-day cycles. Fourteen patients received treatment. The most common treatment-related adverse events were diarrhea (36%), acneiform rash (36%), nausea (29%), fatigue (29%), and hyperglycemia (21%); most events were grade 1-2. One confirmed partial response was observed in a patient who was also alive and progression-free at 6 months. One additional patient was alive and progression-free at 6 months. The clinical benefit rate was 14.3% (95% CI: 1.8 to 42.8). Five patients had stable disease (35.7%) and seven had progressive disease (50%); one was unevaluable. Median PFS was 2 months (95% CI: 1.6 to 4.4) and median overall survival was 6.4 months (95% CI: 5.1 to not reached). In summary, MK-2206 had limited activity in USC, although a few patients achieved sustained progression-free intervals in this study and in the previously reported phase II trial of MK-2206. Further investigations are needed to identify features associated with response., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The authors declare that they have no competing interests relevant to this study. For completeness, the following conflicts of interest disclosure is provided: A.P.M. is a full-time employee of Novartis. V.M. has participated in advisory boards for Novartis, Iteos, Eisai, Merck, Karyopharm, Clovis, and GSK. R.D. has been a consultant for Repare Therapeutics and Mersana Therapeutics, and is a founding member and has a financial interest in VOC Health. J.F.L. has received institutional funding for clinical trials from 2X Oncology, Aravive, Arch Oncology, AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, CytomX Therapeutics, GlaxoSmithKline, Regeneron, Surface Oncology, Tesaro, and Vigeo Therapeutics; and has participated in advisory boards for AstraZeneca, Clovis, Eisai, EpsilaBio, Genentech, GSK/Tesaro, and Regeneron Pharmaceuticals. F. M.-B. has received research support from Aileron Therapeutics, Inc. AstraZeneca, Bayer Healthcare Pharmaceutical, Calithera Biosciences Inc., Curis Inc., CytomX Therapeutics Inc., Daiichi Sankyo Co. Ltd., Debiopharm International, eFFECTOR Therapeutics, Genentech Inc., Guardant Health Inc., Klus Pharma, Takeda Pharmaceutical, Novartis, Puma Biotechnology Inc., and Taiho Pharmaceutical Co.,; has been a consultant for AbbVie, Aduro BioTech Inc., Alkermes, AstraZeneca, DebioPharm, eFFECTOR Therapeutics, F. Hoffman-La Roche Ltd., Genentech Inc., IBM Watson, Infinity Pharmaceuticals, Jackson Laboratory, Kolon Life Science, Lengo Therapeutics, OrigiMed, PACT Pharma, Parexel International, Pfizer Inc., Samsung Bioepis, Seattle Genetics Inc., Tallac Therapeutics, Tyra Biosciences, Xencor, and Zymeworks; has received honoraria from Chugai Biopharmaceuticals; and has participated in advisory boards for Black Diamond, Biovica, Eisai, Immunomedics, Inflection Biosciences, Karyopharm Therapeutics, Loxo Oncology, Mersana Therapeutics, OnCusp Therapeutics, Puma Biotechnology Inc., Seattle Genetics, Silverback Therapeutics, Spectrum Pharmaceuticals, and Zentalis. C.A. has received institutional funding for clinical trials from Abbvie, Clovis, Genentech, and AstraZeneca; has been a consultant for Eisai/Merck, Mersana Therapeutics, Roche/Genentech, Abbvie, AstraZeneca, Merck, and Repare Therapeutics; and has served on an advisory board for Blueprint Medicines. R.C. has received research support from AstraZeneca, Merck, Clovis, Genmab, Roche/Genentech, Janssen, Immunogen, and Genelux; and has been a consultant for AstraZeneca, GSK, Clovis, Genmab, Roche/Genentech, Janssen, Agenus, Regeneron, OncoQuest, Immunogen, Genelux, Onxerna, Onxeo, Deciphera, and Alkermes. G.B.M. has received funding for clinical trials from AstraZeneca, Genentech, GSK,and Eli Lilly; has been a consultant and/or advisory board member for Amphista, AstraZeneca, Chrysallis Biotechnology, GSK, ImmunoMET, Ionis, Lilly, PDX Pharmaceuticals, Signalchem Lifesciences, Symphogen, Tarveda, Turbine, and Zentalis Pharmaceuticals; and has a financial interest in Catena Pharmaceuticals, ImmunoMet, SignalChem, and Tarveda. L.C.C. has been a consultant for Novartis. U.A.M. has been a consultant for Merck, Novartis, and Astrazeneca; and has served on an advisory board for Symphogen. S.N.W. has received research funding from AstraZeneca, Bayer, Bio-Path, Clovis Oncology, GSK, Mereo, Novartis, OncXerna, Roche/Genentech, Zentalis; and has been a consultant for Agenus, AstraZeneca, Clovis Oncology, Eisai, ERQX, GSK, ImmunoGen, Merck, Mereo, Novartis, Pfizer, Roche/Genentech, Vincerx, and Zentalis. P.A.K. has been a consultant for Alkermes, AstraZeneca, Bayer, GSK, Merck, Pfizer, Tesaro, Mersana, Repare Therapeutics, and Kadmon., (© 2022 The Authors.)