A Phase II Study of Anti-EGFR Antibody-drug Conjugate (ADC) Combine With CDK4/6 Inhibitors Posterior Line in the Treatment of Recurrent/Metastatic CDKN2A Gene Variant Head and Neck Squamous Cell Carcinoma

Inclusion Criteria:

1. 18 years old ≤75 years old;

2. Patients with recurrent or metastatic head and neck squamous cell carcinoma (including oral cavity, oropharynx, hypopharynx, larynx, etc.) confirmed byhistology or cytology, recurrent patients cannot receive local treatment such assurgery or radiotherapy, and have failed to receive PD-1 (L1) inhibitors and/orplatinum drugs in the past, which can be first-line combination regimens orsequential administration. Progression after receiving PD-1 (L1) inhibitors and/orplatinum-based drugs;

3. Receive ≤2 lines of treatment;

4. ECOG score 0~1;

5. Lack of CDKN2A function;

6. At least one evaluable lesion according to RECIST (version 1.1) criteria;

7. Adequate organ function;

8. The expected survival time is greater than 3 months;

9. No serious organic heart disease or arrhythmia;

10. Women of childbearing age (15-49 years) must undergo a pregnancy study within 7 daysbefore starting treatment and the results are negative; Fertile men and women mustconsent to the use of effective contraception to ensure that they do not becomepregnant during the study period and for 3 months after stopping treatment;

11. Obtain the "informed consent" voluntarily signed by the patient.

Exclusion Criteria:

1. ≥ grade 2 peripheral neuropathy (according to CTCAE 5.0).

2. Surgery or any other form of systemic or local anti-tumor therapy, includingmaintenance therapy or radiotherapy for head and neck squamous cell carcinoma (including palliative care, except palliative care for non-target lesions), isexpected to be required during the study period.

3. Systematic chemotherapy was received within 3 weeks before the first administrationof the drug, small molecule targeted therapy was received within 2 weeks before thefirst administration or 5 half-lives (depending on the time), antitumor biotherapy,macromolecule targeted therapy or immunotherapy was received within 4 weeks beforethe first administration of the drug. Or major surgery (except minor surgeryperformed within 2 weeks and complete recovery); Radiotherapy was received within 14days prior to initial administration of the investigational drug (except for centralnervous system radiotherapy, which required a washout period of ≥28 days).

4. Known to have active central nervous system metastasis and/or cancerous meningitis.Patients with treated BMS may participate in the study if their condition is stableand they do not:

• Progressive or new neurological deficits, seizures, evidence of increasedintracranial pressure, vomiting, or headache;

• MRI shows evidence of enlargement at least 4 weeks before first dosing and atleast 14 days before study drug dosing Corticosteroids are required.

5. Residual toxic effects (except alopecia, fatigue and grade 2 hypothyroidism) causedby previous antitumor therapy (including immunotherapy, targeted therapy,chemotherapy or radiotherapy) or clinically significant laboratory test outliershigher than grade 1 (CTCAE v5.0).

6. Uncontrolled or poorly controlled heart disease, including a history of congestiveheart failure (CHF) ≥2 (CTCAE v5.0 or New York Heart Association rating), myocardialinfarction, unstable angina, ventricular tachycardia or tip twisting ventriculartachycardia, or arrhythmias requiring treatment within the 6 months prior toadmission, For example, men with QTcF > 450 ms and women with QTcF > 470 ms havecomplete left bundle branch block or third-degree atrioventricular block. QTcF= QT/ (RR^0.33).

7. Pulmonary embolism or deep vein thrombosis (except for catheter-derived thrombosisat infusion port or PICC) occurred within 3 months prior to the first administrationof the drug.

8. There is a known prior history of malignancy (except in patients with basal cellcarcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of theskin, carcinoma in situ, or papillary carcinoma of the thyroid who have undergoneradical surgery), unless the patient has received potentially curable therapy andhas been free of disease recurrence for 5 years since starting treatment. Note: The 5-year recurrence-free time requirement does not apply to head and neck squamouscell carcinoma in patients enrolled in this trial.

9. Any serious or uncontrolled systemic disease, including uncontrolled or poorlycontrolled hypertension (such as systolic blood pressure >160 mmHg or diastolicblood pressure >100 mmHg), glycosuria (glycated blood red and egg white (HbA1c) >8%), etc.

10. Patients with a history of active bleeding, clotting disorders, or receivingcoumarin anticoagulant therapy.

11. Known allergic reactions to any component or excipient of MRG003 (citric acidmonohydrate, sodium citrate dihydrate, trehalose dihydrate, sodium chloride andpolysorbate 80), or grade ≥3 allergic reactions to other prior anti-EGFR drugs (including investigational drugs) or to other monoclonal antibodies.

12. Known active hepatitis B or C. Active hepatitis B is defined as known HBsAg positiveand HBV DNA≥500 IU/mL. Active hepatitis C is defined as a known positive hepatitis Cantibody and a known quantitative hepatitis C virus HCV RNA result greater than thelower limit of detection. Other serious liver diseases are present, includingchronic autoimmune liver disease, primary biliary cirrhosis or sclerosingcholangitis, alcoholic liver disease, or non-alcoholic steatohepatitis (NASH).

13. Concurrent severe, uncontrolled infection or known human immunodeficiency virus (HIV) (HIV antibody positive) infection, or a diagnosis of acquired immunedeficiency syndrome (AIDS); Or uncontrolled autoimmune disease; Have previouslyreceived an allogeneic tissue/organ transplant, stem cell or bone marrow transplant,or have previously received a solid organ transplant.

14. Active bacterial, viral, fungal, rickettsial, or parasitic infections requiringsystemic anti-infective therapy (unless treatment is obtained and resolves prior toadministration of the investigational drug).

15. The live virus vaccine was administered within 30 days prior to the firstadministration of the investigational drug. Seasonal influenza vaccines or approvedCOVID-19 vaccines that allow the use of inactivated viruses must be at least oneweek from the time of first administration.

16. A history of interstitial pneumonia, severe chronic obstructive pulmonary diseasewith respiratory failure, severe pulmonary insufficiency, and symptomaticbronchospasm.

17. Immunological based treatment for any reason, including long-term use of a systemicsteroid equivalent to >10 mg/ day of prednisone within 7 days before the firstadministration of the study drug or at any time during study participation. Note:Inhaled or topical steroids or systemic corticosteroids equivalent to ≤10 mg/ day ofprednisone are permitted, as are short-term corticosteroids equivalent to >10 mg/day of prednisone (e.g., prodromal administration before contrast agentadministration).

18. Uncontrolled pleural, abdominal, pelvic or pericardial effusions require drainage ≥once a month.

19. Patients who have tested positive for pregnancy or are breastfeeding. Women and menwho do not plan to use adequate contraception during treatment and within 180 daysafter the last treatment.

20. Any other illness or clinically significant laboratory parameter abnormality,serious medical or psychiatric illness/condition, and substance abuse, includingalcohol abuse, that the investigator believes could compromise patient safety, studyintegrity, affect patient participation in the study or interfere with the purposeof the study and analysis of the results.