This is a Phase II study of anti-nectin-4 ADC combined with the EGFR monoclonal antibody and the PD-1 monoclonal antibody in participants with advanced head and neck squamous cell carcinoma.

This trial consists of two parts. Part 1 (Monotherapy Group) evaluates both SYS6002 monotherapy (stratified into two cohorts by dose levels and administration frequencies) and JMT101 monotherapy. Part 2 (Combination Therapy Group) comprises Stage 1 (dose escalation phase) and Stage 2 (proof-of-concept phase). Following completion of the dose escalation phase in Part 2 and evaluation of integrated efficacy and safety analyses of SYS6002 monotherapy in Part 1 of this study as well as other clinical studies involving participants with ≥2L HNSCC, the decision on progressing to Stage 2 of Part 2 will be made through discussion between the Sponsor and investigators.

Inclusion Criteria:

• Aged 18 years or older, regardless of gender.
• Able to understand and voluntarily sign a written informed consent form (ICF).
• Confirmed recurrent or metastatic HNSCC that is not curable with local treatments. Primary tumor must be located in the oral cavity, oropharynx, hypopharynx, or larynx.
• Able to provide well-preserved or fresh tumor tissue.
• According to the Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, at least one measurable lesion confirmed by CT or MRI.
• Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1.
• Life expectancy ≥ 3 months.
• Normal major organ function within 7 days prior to treatment.

Exclusion Criteria:

• Primary tumor located in the nasopharynx, nasal cavity, paranasal sinuses, salivary glands, thyroid or parathyroid glands, skin, or squamous cell carcinoma with an unknown primary site.
• Presence of leptomeningeal metastasis, spinal cord compression, symptomatic or progressive brain metastases.
• (Only for Stage 2 in Part 2) Prior systemic anti-tumor therapy for recurrent or metastatic HNSCC.
• Known allergy to any component of SYS6002, JMT101, or Enlonstobart injection.
• Participants who have previously received MMAE toxin ADC treatment (only for Part 1 and Stage 2 in Part 2).
• Adverse events related to prior anti-tumor treatment that have not resolved to ≤ Grade 1 according to NCI-CTCAE v5.0 (except for toxicities deemed low-risk by the investigator, such as Grade 2 alopecia).
• Washout period not met for anti-tumor medications or treatments.
• Any serious and/or uncontrolled comorbid conditions that may interfere with the participant's ability to participate in the study
• Pregnant or breastfeeding women; women of childbearing potential with a positive pregnancy test within 7 days before enrollment. Breastfeeding women may participate if they stop breastfeeding, but they cannot resume breastfeeding during the treatment and after the study ends.
• Any male or female participants of childbearing potential who refuse to use highly effective contraception during the study and for 6 months after the last dose of study drug.
• Unwilling or unable to comply with the study procedures and requirements, or deemed unsuitable for participation by the investigator.