MRG003 Added to Ongoing Treatment After Progression in EGFR-Positive Advanced Thyroid Cancer

This study will evaluate whether adding MRG003 to an ongoing treatment regimen can produce confirmed tumor shrinkage in patients with EGFR-positive advanced thyroid cancer whose cancer initially benefited from that regimen and later progressed. The study will also evaluate the safety of the combinations. Cohort A will include patients with anaplastic or poorly differentiated thyroid carcinoma who previously benefited from lenvatinib plus an anti-PD-1 inhibitor and subsequently progressed. They will continue lenvatinib and the same anti-PD-1 inhibitor, with MRG003 added. Cohort B will include patients with radioactive iodine-refractory differentiated thyroid carcinoma who previously benefited from lenvatinib and subsequently progressed. They will continue lenvatinib, with MRG003 added. MRG003 will be given intravenously at 2.0 mg/kg every 3 weeks. The study plans to enroll 39 participants: 24 in Cohort A and 15 in Cohort B. The first 3 participants in each cohort will undergo an initial 6-week safety assessment before further enrollment is allowed. If additional safety assessment is needed, up to 6 participants who can be evaluated for dose-limiting toxicity will be assessed within the planned cohort enrollment. The main outcome is the proportion of patients in each cohort whose tumors shrink or disappear within 12 weeks after MRG003 starts, with the response confirmed at least 4 weeks later and by Week 18. Scans obtained before MRG003 is added provide the new baseline. Disease control is assessed at Week 12. Other response and survival outcomes are followed for up to 12 months after MRG003 starts. Safety follow-up continues during study treatment and for 90 days after the last study treatment dose, with longer follow-up of unresolved events as needed.

Inclusion Criteria: 1. Aged 18 to 80 years, regardless of sex； 2. Histologically or cytologically confirmed advanced anaplastic thyroid carcinoma (ATC) or poorly differentiated thyroid carcinoma (PDTC) for Cohort A, or radioactive iodine-refractory differentiated thyroid carcinoma (RAIR-DTC) for Cohort B； 3. EGFR-positive tumor confirmed by immunohistochemistry (IHC)； 4. Documented prior clinical benefit (complete response, partial response, or sustained stable disease) followed by RECIST 1.1 disease progression on the relevant ongoing regimen: lenvatinib plus an anti-PD-1 inhibitor for Cohort A, or lenvatinib for Cohort B. Continuing the prior regimen must remain clinically appropriate and tolerable. Cohort A must continue the same anti-PD-1 inhibitor； 5. A minimum washout period of at least 4 weeks (or at least 5 half-lives, whichever is shorter) between the last dose of other chemotherapy/targeted therapy and the first MRG003 dose. This washout requirement does not apply to the ongoing lenvatinib in either cohort or the same ongoing anti-PD-1 inhibitor in Cohort A, which are continued as the study treatment backbone； 6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1； 7. Life expectancy ≥ 3 months； 8. At least one measurable target lesion assessable by computed tomography (CT) or magnetic resonance imaging (MRI) according to RECIST 1.1. A new pretreatment imaging baseline must be obtained within 28 days before the first MRG003 dose； 9. Laboratory test results meeting the following criteria: (1) Bone marrow function: hemoglobin (Hb) ≥ 90 g/L; white blood cell count (WBC) ≥ lower limit of normal (LLN); absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L; platelet count ≥ 100 × 10⁹/L. (2) Renal function: serum creatinine (Cr) ≤ 1.5 × upper limit of normal (ULN); creatinine clearance rate (Ccr) ≥ 55 mL/min. (3) Liver function: total bilirubin ≤ 1.5 × ULN; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN. (4) Coagulation function: international normalized ratio (INR) for prothrombin time ≤ 1.5 × ULN, and activated partial thromboplastin time (aPTT) within the normal range； 10. Absence of severe complications, such as active gastrointestinal bleeding, perforation, jaundice, gastrointestinal obstruction, or non-neoplastic fever \> 38°C； 11. For female patients of childbearing potential: agreement to use contraception during the study period and for 6 months following study completion; a negative serum or urine pregnancy test within 7 days prior to study enrollment; and non-lactating status. For male patients: agreement to use contraception during the study period and for 6 months following study completion； 12. Ability to understand the study protocol and voluntary provision of written informed consent； 13. Patients are expected to have good compliance and be capable of adhering to the protocol for follow-up assessments of treatment efficacy and adverse events. Exclusion Criteria: 1. Diagnosis of any other malignancy within the past 5 years, excluding cured in situ carcinoma and basal cell carcinoma； 2. Presence of symptomatic or untreated known brain metastases or other central nervous system (CNS) metastases. Completely resected and/or post-radiotherapy CNS metastases with documented stability or improvement are not exclusion criteria, provided that computed tomography (CT) demonstrates stability for at least 4 weeks prior to screening, with no evidence of cerebral edema and no requirement for glucocorticoids or anticonvulsants for management of CNS metastases； 3. Subjects with psychiatric or neurological disorders who are unable to comply with the study protocol； 4. Prior treatment with an antibody-drug conjugate (ADC) with a monomethyl auristatin E (MMAE) payload； 5. Subjects preparing to undergo or having previously undergone organ or bone marrow transplantation； 6. Administration of a live vaccine within 30 days prior to the first dose of study treatment (injectable seasonal influenza vaccines are permitted, as they are inactivated vaccines)； 7. Uncontrolled clinically significant cardiac symptoms or diseases, such as New York Heart Association (NYHA) Class III-IV heart failure, unstable angina pectoris, myocardial infarction within 6 months, or severe arrhythmia； 8. Active infection (e.g., active hepatitis B virus \[HBV\], hepatitis C virus \[HCV\], or human immunodeficiency virus \[HIV\] infection) or active autoimmune disease requiring systemic therapy； 9. History or evidence of interstitial lung disease or active non-infectious pneumonitis； 10. Presence of other diseases rendering the subject unsuitable for enrollment, such as immunodeficiency, active pulmonary tuberculosis, hepatitis B (subjects are eligible for enrollment if HBV-DNA titer is \