A phase II study of MK-2206, an allosteric inhibitor of AKT as second-line therapy for advanced gastric and gastroesophageal junction (GEJ) cancer: A SWOG Cooperative Group trial (S1005).

4041 Background: The PI3K/AKT/MTOR pathway is frequently activated in gastric/GEJ cancers. This study evaluated the activity of single agent MK-2206 at the dose of 60 mg every other day in this tumor type. Methods: Eligible patients (pts) had gastric /GEJ adenocarcinoma with measurable disease, who had had progression after first-line treatment, or recurrence within six months after adjuvant therapy. Other pertinent eligibility criteria included a Zubrod performance status of 0-1, a fasting serum glucose ≤150 mg/dL, and < Grade 2 malabsorption or chronic diarrhea. Adequate hematologic, renal, hepatic, and cardiac function were required. Prior treatment with a PI3, AKT, or mTOR inhibitor was not allowed. MK-2206 (60 mg every other day) was given until progression or intolerable toxicity. Primary endpoint was overall survival (OS), secondary endpoints were safety, progression free survival (PFS) and response rate (RR). The study required 60 evaluable pts and a median OS of 6.5 months (mo) (power of 89%, significance level 0.07) to be considered encouraging for further investigation. Results: Seventy-five pts were enrolled between 1/1/11 to 5/1/13. Eight pts were ineligible and one pt withdrew; 66 pts were included in the analyses. Median age is 60.7 yrs (range 30.4-86.7), Males 70%, White 89% and Asian 6%. There were 2 deaths possibly related to study drug (cardiac arrest and respiratory failure). Gr 4 adverse events (AEs) were hyperglycemia, anemia and lung infection (1 each). Gr 3 AEs were infrequent and < 5% except for fatigue (6%). Other all Gr AEs included anemia 15%, anorexia 27%, diarrhea 24%, fatigue 48%, hyperglycemia 29%, nausea 40%, vomiting 20%, maculopapular rash 30%, and acneiform rash 8%. The RR is 2%, median PFS is 1.8 mo. (95% CI of 1.7- 1.8) and median OS is 5 mo (95% CI 4 - 10 mo). Conclusions: MK-2206 as 2nd line therapy in an unselected group of gastric/GEJ cancers was well tolerated with some evidence of activity (RR 2%, OS 5.0 mo) and in the range of other second line agents (irinotecan, docetaxel, ramucirumab). The primary study endpoint of 6.5 mo was not met. (Support: NIH/NCI cooperative group grants CA32102 and CA38926). Clinical trial information: NCT01260701.

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