Abstract P2-13-23: Activity and tolerability of combination of trastuzumab deruxtecan with the pan-AKT inhibitor capivasertib in preclinical HER2+ and HER2-low breast cancer models
Authors: Bashi Azadeh Cheraghchi , Proia Theresa , Randle Suzanne , Anderton Mark , Rasheed Zeshaan , Pease J. Elizabeth , Barry Simon , Carroll Danielle , Mettetal Jerome 
Published: March 2022

Abstract
Background: Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor approved for HER2+ metastatic breast and gastric cancer. Clinically, T-DXd has demonstrated significant antitumor activity in both HER2+ and HER2-low (IHC 1+ & 2+/ISH-) breast cancer patients. The PI3K/AKT pathway is frequently activated in breast cancer, and mediates signals downstream of HER2. T-DXd has been shown to inhibit downstream AKT signaling driven by HER2. Capivasertib, a potent, selective inhibitor of all three AKT isoforms (AKT1/2/3) has shown clinical activity in breast cancer trials. Given the clinical activity of both agents, the anti-tumor activity of combined treatment with T-DXd with capivasertib, was explored preclinically in HER2+ and HER2-low models. Methods: The antiproliferative activity of the combination of T-DXd with capivasertib was assessed in a panel of 27 breast cancer cell lines using a 7 day viability assay. To determine whether the combination also translates in vivo, T-DXd (3 and 10mg/kg Q3W) and capivasertib (130mg/kg BID 4 days on/3 days off) were tested in KPL4 (HER2+). To determine whether the combination of T-DXd and capivasertib has a negative impact on normal tissue integrity, we further evaluated the combination in a human 2D in vitro bone marrow progenitor assay. Results: The combination treatment was more effective than each single agent in 6/27 of the models tested in vitro, resulting in increased cell kill in the viability assay. Two of these positive cell lines, HCC1569 (HER2+) and AU565 (HER2+) were PTEN altered, KPL4 (HER2+) and EFM19 (ER+) were mutant in PIK3CA, and HCC1419 (HER2+) and ZR-75-30 (ER+/HER2+) were neither PTEN or PIK3CA altered. In KPL4 xenografts, the combination of T-DXd and capivasertib showed modest increased activity over monotherapy T-DXd or capivasertib at 28d (Tumor Growth Inhibition (TGI) of T-DXd = 76%, capivasertib = 25%, and T-DXd+Capivasertib = 83%; p=0.3 combo vs. mono T-DXd) and more markedly at 46d (TGI of the combination vs T-DXd monotherapy was 65%). Importantly, the combination showed enhanced durability of response (stasis) in 100% mice while 38% (3/8) mice in the T-DXd mono therapy treatment group were actively re-growing at 46d. In the in vitro bone marrow assay, the combination demonstrated no increased interaction over monotherapy activity (average Loewe Synergy Score of -0.2). Conclusions: These results suggest combining T-DXd with capivasertib has potential to be active in breast cancer patients, with activity likely to be enriched in tumours with mutations in PIK3CA and PTEN, but also in tumours with no PI3K pathway activating mutations.
Citation Format: Azadeh Cheraghchi Bashi, Theresa Proia, Suzanne Randle, Mark Anderton, Zeshaan Rasheed, J. Elizabeth Pease, Simon Barry, Danielle Carroll, Jerome Mettetal. Activity and tolerability of combination of trastuzumab deruxtecan with the pan-AKT inhibitor capivasertib in preclinical HER2+ and HER2-low breast cancer models [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P2-13-23.