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

Background

Activation of the PI3K pathway is frequently observed in endometrial cancer. This study evaluated the safety and efficacy of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced endometrial cancer featuring activating mutations in the PI3K pathway.

Methods

We conducted a single-arm phase 2 trial using LY3023414 as monotherapy. Eligible patients had advanced endometrial cancer of any grade, had received 1-4 prior lines of cytotoxic therapy, and had PI3K pathway activation defined as a loss-of-function alteration in PTEN or activating mutations in PIK3CA, AKT1, PIK3R1, PIK3R2, or MTOR. The primary endpoint was the overall response rate (ORR) based on RECIST 1.1 criteria.

Results

A total of 28 patients were treated, with histological classifications including endometrioid (39%), carcinosarcoma (25%), serous (21%), and mixed (14%). Patients were heavily pretreated, with a median of 2 prior lines of cytotoxic therapy (range: 1-3). The most common genetic alterations were in PIK3CA (68%), PTEN (43%), and PIK3R1 (32%). Among the 25 patients evaluable for efficacy, the ORR was 16% (90% CI, 7%-100%), while the clinical benefit rate was 28% (90% CI, 16%-100%). Four patients achieved a confirmed partial response, with two responses lasting over 9 months. The median progression-free survival was 2.5 months (95% CI, 1.2-3.0) and overall survival was 9.2 months (95% CI, 5.0-15.9). The most common treatment-related adverse events included anemia (71%), hyperglycemia (71%), hypoalbuminemia (68%), and hypophosphatemia (61%). No correlation was found between molecular alterations and response.

Conclusion

In this study of heavily pretreated patients with advanced endometrial cancer selected for PI3K pathway mutations, LY3023414 demonstrated modest activity as a single agent and a manageable safety profile.