Capivasertib Combines with Trastuzumab Deruxtecan to Enhance Antitumor Activity in HER2-Positive and HER2-Low Tumors.

Trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate composed of an anti-HER2 antibody and a cytotoxic topoisomerase I inhibitor, is approved for the treatment of HER2-positive (HER2+) and HER2-low breast cancer as well as HER2-high gastric and HER2-mutant lung cancer tumors. The AKT inhibitor capivasertib is approved for the treatment of HER2- estrogen receptor-positive breast cancer with alterations in PIK3CA, PTEN, and AKT-1. The potential for the combination of T-DXd with AKT inhibition to enhance antitumor activity was explored in HER2+ or HER2-low preclinical models. In vitro, combination activity was observed in both HER2-high- and HER2-low-expressing breast cancer as well as in gastric, endometrial, and ovarian models, irrespective of HER2 expression level or PI3K-AKT status pathway alterations. The T-DXd-capivasertib combination effect translated in vivo with increased antitumor benefit in HER2-expressing, PI3K-AKT pathway-altered tumor xenografts when compared with the combination of trastuzumab and capivasertib. In cell lines sensitive to the combination, combining T-DXd with capivasertib targeted complimentary pathways which resulted in disruption of the cell cycle and increased cell death. These results suggest that T-DXd combined with capivasertib has the potential to be active in HER2+ as well as HER2-low tumors independent of PI3K pathway alteration status.