Sacituzumab Tirumotecan in Recurrent/Metastatic Adenoid Cystic Carcinoma and Papillary Thyroid Carcinoma (STRAP)

\<Background and Rationale\>

Adenoid cystic carcinoma (ACC) and papillary thyroid carcinoma (PTC) are uncommon malignancies that present distinct clinical challenges in the recurrent or metastatic setting. Although their biological behaviors differ, both diseases share a lack of well-established, effective systemic treatment options once standard therapies have failed.

ACC is a rare epithelial malignancy arising most frequently from the salivary glands. It is characterized by slow initial growth, perineural invasion, and a high propensity for distant metastasis, particularly to the lungs and bones. Despite its relatively indolent nature, ACC is ultimately associated with poor long-term outcomes due to relentless disease progression and resistance to conventional cytotoxic chemotherapy. No systemic therapy has been established as a standard of care for patients with unresectable or metastatic ACC, and treatment decisions are often based on limited evidence derived from small, single-arm studies.

PTC is the most common subtype of thyroid cancer and generally has a favorable prognosis following surgery and radioactive iodine (RAI) therapy. However, a subset of patients develops recurrent or metastatic disease that is refractory to RAI and other standard treatments. In this population, disease control becomes increasingly difficult, and available systemic therapies may offer limited efficacy or be associated with cumulative toxicity. Patients with progressive disease after multiple lines of therapy represent an area of significant unmet medical need.

Trophoblast cell-surface antigen 2 (TROP2) is a transmembrane glycoprotein involved in cell signaling, proliferation, and survival. Overexpression of TROP2 has been reported across a wide range of epithelial malignancies and is associated with tumor aggressiveness and poor clinical outcomes. These biological features make TROP2 an attractive therapeutic target.

Sacituzumab tirumotecan (sac-TMT) is an antibody-drug conjugate composed of a humanized IgG1 monoclonal antibody directed against TROP2, linked via a cleavable linker to a potent topoisomerase I inhibitor payload (KL610023). Upon binding to TROP2-expressing tumor cells, sac-TMT is internalized through the endosomal-lysosomal pathway, releasing the cytotoxic payload intracellularly. This results in DNA damage, cell cycle arrest in the S or G2/M phase, and apoptosis. In addition to direct cytotoxicity, sac-TMT exhibits antibody-dependent cell-mediated cytotoxicity and a bystander effect, potentially extending antitumor activity to neighboring tumor cells with lower or heterogeneous TROP2 expression.