Given the high unmet clinical need in patients with CNS metastases, established intracranial activity of T-DXd, the biological implication of HER3 overexpression in CNS tumors and the preliminary evidence of CNS activity of HER3-DXd, we performed the prospective, international, multicenter, single-arm phase 2 TUXEDO-3 trial (NCT05865990) to investigate CNS activity of HER3-DXd in active breast and lung cancer BMs and LMD of various tumor types. Here, ERBB3 is linked to central nervous system neoplasm.