Trastuzumab deruxtecan kills skin and uveal melanoma in vivo by HER2-independent payload release

Background: HER2-directed CAR-T cells can eradicate melanoma despite low HER2 expression. We therefore asked whether melanoma would also respond to trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate targeting HER2. Patients and methods: T-DXd was evaluated in several patient-derived xenograft (PDX) models and as a compassionate use in one patient with metastatic uveal melanoma. We compared T-DXd with another ADC, trastuzumab emtansine (T-DM1), and examined ADC sensitivity and trastuzumab uptake in vitro, and expression of HER2 and cathepsin L (CTSL) in xenografts. Results: T-DXd inhibited all subcutaneous PDXs, while liver models were less sensitive. T-DM1 had limited activity. Unexpectedly, parental and ERBB2-knockout melanoma xenografts showed similar initial responses to T-DXd, although knockout tumors regrew earlier. Tumor-derived CTSL was detected outside melanoma cells in the xenografts. Melanoma cells were largely resistant to both ADCs in vitro and showed little trastuzumab uptake compared to HER2-amplified breast cancer cells. Conclusions: T-DXd has a substantial HER2-independent component of activity in the tested melanoma xenografts. Presence of extracellular CTSL, an enzyme known to cleave T-Dxd, provide a possibility that linker cleavage and payload release can occur outside of the tumor cells.