Phase 2 study of LY3023414 in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway

Background PI3K pathway activation is common in endometrial cancer. We evaluated the safety and efficacy of the dual PI3K/mTOR inhibitor, LY3023414, in patients with advanced endometrial cancer harboring activating mutations in the PI3K pathway. Methods We conducted a single‐arm phase 2 study of monotherapy LY3023414. Eligible patients had advanced endometrial cancer of any grade, prior management with 1‐4 cytotoxic lines, and PI3K pathway activation prospectively defined as a loss‐of‐function PTEN alteration or activating alteration in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary objective was best overall response rate (ORR) per RECIST 1.1. Results Twenty‐eight patients were treated; histologies included endometroid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior cytotoxic lines (range, 1‐3). The most common alterations involved PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). In the 25 efficacy‐evaluable patients, the ORR was 16% (90% CI, 7%‐100%), and the clinical benefit rate was 28% (90% CI, 16%‐100%). Four patients had a confirmed partial response, and 2 responses lasted for >9 months. The median progression‐free survival and overall survival were 2.5 months (95% CI, 1.2‐3.0) and 9.2 months (95% CI, 5.0‐15.9), respectively. The most common all‐grade treatment‐related adverse events were anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation between molecular alterations and response was observed. Conclusion In patients with heavily pretreated advanced endometrial cancer prospectively selected for tumors with activating PI3K pathway mutations, LY3023414 demonstrated modest single‐agent activity and a manageable safety profile. The authors conducted a single‐arm phase 2 study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer who were prospectively selected to have activating PI3K pathway mutations. LY3023414 was tolerable and had a modest clinical response (overall response rate, 16% [90% CI, 7%‐100%]).