Phase 2 trastuzumab deruxtecan (HER2 ADC; topoisomerase I payload) + lovastatin (HMG‑CoA inhibitor)

Washington University School of Medicine is running this Phase 2 study testing whether short “priming” with lovastatin—an HMG‑CoA reductase inhibitor used for cholesterol lowering—can modulate membrane biology (via proposed CAV‑1 effects) to increase functional HER2 availability and thereby improve tumor uptake and activity of trastuzumab deruxtecan (T‑DXd). T‑DXd (Enhertu; Daiichi Sankyo and AstraZeneca) is a HER2-directed antibody–drug conjugate that delivers a deruxtecan topoisomerase I inhibitor payload after binding/internalization. The design includes a safety lead-in followed by standard-dose combination treatment; a subset undergoes paired pre-/on-treatment biopsies for pharmacodynamic readouts of the hypothesized “HER2 upshift” mechanism. Eligible patients have unresectable locally advanced or metastatic breast cancer with HER2-low or HER2-ultralow expression. Today, many patients with HR-positive, HER2-low/ultralow metastatic disease cycle through endocrine therapy + targeted partners (for endocrine-sensitive disease) and then move to sequential single-agent chemotherapy and/or ADCs (including T‑DXd per label in appropriate settings), so the commercial/scientific angle here is a low-cost, readily available small-molecule strategy to potentially expand depth/durability of an already category-defining ADC.