Sacituzumab Tirumotecan Combined With Immunotherapy in Advanced Thyroid Cancer

Inclusion criteria

Participants must meet all of the following criteria:

• Age ≥ 18 years at the time of informed consent. 2. Histologically confirmed unresectable, locally advanced, or metastatic:

• Anaplastic thyroid carcinoma (ATC), or
• Poorly differentiated thyroid carcinoma (PDTC), or
• Radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC), including papillary thyroid carcinoma or follicular thyroid carcinoma and variants.

• For ATC or PDTC:
• No BRAF V600E mutation, RET fusion, NTRK fusion, or ALK fusion;
• Or harboring such alterations but have failed prior standard first-line targeted therapy.

• For RAIR-DTC: Disease must be refractory to radioactive iodine (RAI), defined as at least one of the following:
• No RAI uptake in measurable lesions;
• Radiographic progression within 12 months after RAI therapy;
• Cumulative RAI dose >600 mCi (or iodine-equivalent);
• Fluorodeoxyglucose (FDG)-avid measurable disease;
• Failure of prior multi-target tyrosine kinase inhibitor (TKI) therapy. 5. At least one measurable lesion per RECIST version 1.1. 6. ECOG performance status 0-2. 7. Life expectancy ≥ 12 weeks. 8. Adequate hematologic function:
• Absolute neutrophil count ≥ 1.2 × 10⁹/L
• Platelet count ≥ 100 × 10⁹/L
• Hemoglobin ≥ 90 g/L 9. Adequate hepatic function:
• AST and ALT ≤ 2.5 × upper limit of normal (ULN)
• ≤ 5 × ULN if liver metastases present
• Total bilirubin ≤ 1.5 × ULN 10. Adequate renal function:
• Creatinine clearance ≥ 60 mL/min (Cockcroft-Gault formula)

• No active autoimmune disease requiring systemic therapy.
• No concurrent active malignancy requiring treatment.
• Willing and able to provide written informed consent.

Exclusion criteria

Participants meeting any of the following criteria will be excluded:

• Prior therapy targeting TROP2.
• Prior treatment with any topoisomerase I inhibitor antibody-drug conjugate.
• Prior immune checkpoint agonists (e.g., ICOS, CD40, CD137, GITR, OX40) or immune cell therapy.
• Another malignancy within 3 years prior to first dose, except adequately treated localized cancers (e.g., basal cell carcinoma, squamous cell carcinoma of the skin, carcinoma in situ of the cervix).
• Uncontrolled or symptomatic central nervous system metastases.

• Patients with treated and stable CNS disease for ≥4 weeks and off corticosteroids for ≥2 weeks may be eligible.
• Significant uncontrolled comorbidities including, but not limited to:

• Uncontrolled hypertension
• Severe diabetes mellitus
• Active infection
• History of interstitial lung disease (ILD) or non-infectious pneumonitis requiring steroids, or current suspected ILD.
• Unresolved toxicities from prior anti-cancer therapy greater than Grade 1 (CTCAE v5.0), except alopecia or other clinically insignificant toxicities.
• Active autoimmune disease requiring systemic treatment within the past 2 years (excluding hormone replacement therapy such as levothyroxine or physiologic corticosteroids).
• Systemic corticosteroid use >10 mg/day prednisone equivalent within 10 days prior to first dose (except inhaled, topical, or physiologic replacement doses).
• Known HIV infection or AIDS. Active syphilis infection.
• History of allogeneic organ transplantation or hematopoietic stem cell transplantation.
• Known severe hypersensitivity to study drugs or components.
• Chemotherapy, radiotherapy, immunotherapy, biologic therapy, TKI, or systemic immune stimulation within protocol-defined washout period prior to first dose.
• Pregnant or breastfeeding women.
• Severe ocular disorders that may interfere with corneal healing (e.g., severe dry eye syndrome, severe meibomian gland disease).