Cancer Sci. 2020 Oct 14. doi: 10.1111/cas.14686. Online ahead of print.
Trastuzumab deruxtecan (T-DXd: DS-8201a) is an anti-HER2 antibody drug conjugated with deruxtecan (DXd), a derivative of exatecan. The objective of this study was to characterize T-DXd-induced lung toxicity in cynomolgus monkeys. T-DXd was administered intravenously to monkeys once every 3 weeks for 6 weeks (10, 30, and 78.8 mg/kg) or for 3 months (3, 10, and 30 mg/kg). To evaluate the involvement of DXd alone in T-DXd-induced toxicity, DXd monohydrate was administered intravenously to monkeys once a week for 4 weeks (1, 3, and 12 mg/kg). Interstitial pneumonitis was observed in monkeys given T-DXd at ≥30 mg/kg. The histopathological features of diffuse lymphocytic infiltrates and slight fibrosis were similar to ILD/pneumonitis related to anticancer drugs in patients, with an incidence that was dose-dependent and dose-frequency-dependent. Monkeys receiving DXd monohydrate did not suffer lung toxicity, although the DXd exposure level was higher than that of DXd in the monkeys given T-DXd. HER2 expression in the monkey lungs was limited to the bronchial level, although the lesions were found at the alveolar level. Immunohistochemical analysis confirmed that T-DXd localization was mainly in alveolar macrophages, but not pulmonary epithelial cells. These findings indicate that monkeys are an appropriate model for investigating T-DXd-related ILD/pneumonitis. The results are also valuable for hypothesis generation regarding the possible mechanism of T-DXd-induced ILD/pneumonitis in which target-independent uptake of T-DXd into alveolar macrophages may be involved. Further evaluation is necessary to clarify the mechanism of ILD/pneumonitis in patients with T-DXd therapy.