Molecular imaging predicts trastuzumab-deruxtecan (T-DXd) response in head and neck cancer xenograft models

Erb-b2 receptor tyrosine kinase 2 (ERBB2; also known as HER2) expression is observed in 25-40% of head and neck squamous cell carcinomas (HNSCC), yet there are no anti-HER2 therapies under evaluation for HNSCC, as conventional cytostatic anti-HER2 antibodies have had limited effectiveness and levels of HER2 overexpression are lower in HNSCC tumors compared to breast cancer. Trastuzumab-deruxtecan (T-DXd; Enhertu) is a HER2-targeting antibody-drug conjugate (ADC) comprising an anti-HER2 monoclonal antibody, a cleavable linker, and a potent topoisomerase I inhibitor payload, and has shown promising results in very low HER2-expressing tumors. We compare the efficacy of T-DXd, trastuzumab-emtansine (ADC comprising an anti-HER2 antibody and microtubule inhibitor, T-DM1; Kadcyla) and trastuzumab (Herceptin) therapy in HNSCC with low and absent HER2 expression in vitro and in vivo. In vitro treatment of a low HER2-expressing human HNSCC cell line (FaDu) with T-DXd resulted in dose-dependent cell death (IC50 values of 9856 ng·mL^-1). T-DXd treatment of FaDu and UMSCC-47 (low HER2-expressing cell line) mouse xenografts displayed antitumor activity (P = 0.0001 and 0.015 respectively). When comparing T-DXd to other approved anti-HER2 therapies, only FaDu mice treated with T-DXd showed a reduction in tumor growth (P = 0.0012). In UMSCC-1 cells (absent HER2 expression), the drug failed to accumulate in tumors and showed no measurable antitumor effect, in contrast to FaDu xenografts, where drug accumulation in the tumor correlated with a therapeutic response. T-DXd treatment yielded antitumor activity in FaDu and UMSCC-47 tumors, highlighting the potential for T-DXd efficacy in low HER2-expressing tumors.