BACKGROUND The AKT inhibitor MK‐2206 at a dose of 60 mg every other day was evaluated in gastric/gastroesophageal junction cancers. METHODS Patients who had progressed after first‐line treatment were eligible. Pertinent eligibility criteria included adequate organ function, a fasting serum glucose level ≤ 150 mg/dL, and less than grade 2 malabsorption or chronic diarrhea. MK‐2206 was given orally (60 evaluable patients required). The primary endpoint was overall survival, and a median survival of 6.5 months (power, 89%; significance level, 0.07) was considered encouraging for further investigation. RESULTS Seventy patients were included in the final analyses. The median age was 59.8 years (range, 30.4‐86.7 years); 70% were male, 89% were white, and 7% were Asian. There were 2 deaths possibly related to the study drug (cardiac arrest and respiratory failure). Grade 4 adverse events included hyperglycemia, anemia, and lung infection (1 each). Grade 3 adverse events occurred in < 5% of patients except for fatigue (6%). Other adverse events (all grades) included anemia (17%), anorexia (30%), diarrhea (26%), fatigue (50%), hyperglycemia (30%), nausea (40%), vomiting (22%), dry skin (19%), maculopapular rash (30%), and acneiform rash (13%). The response rate was 1%, the median progression‐free survival was 1.8 months (95% confidence interval, 1.7‐1.8 months), and the median overall survival was 5.1 months (95% confidence interval, 3.7‐9.4 months) CONCLUSIONS MK‐2206 as second‐line therapy was well tolerated by an unselected group of patients with gastric/gastroesophageal junction cancers, but it did not have sufficient activity (response rate, 1%; overall survival, 5.1 months) to warrant further testing in this population. Cancer 2015;121:2193–2197. © 2015 American Cancer Society. MK‐2206 is well tolerated in patients with gastric/gastroesophageal junction cancers, and there is some evidence of activity, but overall survival (5.1 months) is less than anticipated (6.5 months).