This is an open-label, multicenter, Phase II clinical study designed to evaluate the safety and efficacy of JSKN033 in the treatment of patients with advanced NSCLC. The study is divided into two phases: Part 1 (Dose Selection) and Part 2 (Cohort Expansion). Enrolled subjects are patients with locally advanced (Stage IIIB/IIIC) or metastatic (Stage IV) NSCLC who are not eligible for curative treatment. Part 1 (Dose Selection): It consists of two dose groups, with a maximum of 20 subjects enrolled in each group. Part 2 (Cohort Expansion): It consists of two cohorts, with a maximum of 60 subjects enrolled in each cohort.

Inclusion Criteria:

1. Subjects can understand the informed consent form,voluntarily participate in the study, and sign the informed consent form.
2. Subjects are≥18 years old on the day of signing the informed consent form, regardless of gender.
3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.
4. Expected survival time ≥3 months.
5. Histologically or cytologically confirmed locally advanced or metastatic NSCLC (per AJCC 8th Edition Lung Cancer TNM Staging) that is not eligible for curative surgery and/or curative radiotherapy.
6. NSCLC confirmed to be no other known driver gene alterations for which first- line targeted therapy has been approved.
7. For Part 1(Dose Selection): Enrolled subjects are those with advanced unresectable or metastatic NSCLC who have failed or are intolerant to standard previous treatments, and have HER2 mutation or HER2 expression in tumor tissue.
8. For Part 2 (Cohort Expansion): Enrolled subjects are those with locally advanced or metastatic NSCLC who have not received prior systemic anti-tumor treatment for their advanced disease.
9. Per RECIST 1.1 criteria,subjects have at least one extracranial measurable lesion at baseline.
10. Subjects must provide tumor tissue samples.
11. Sufficient organ function.
12. Female subjects of childbearing potential or male subjects whose partners are of childbearing potential agree to use highly effective contraceptive measures from the time of signing the informed consent form until 24 weeks after the last dose.

Exclusion Criteria:

1. Presence of any small cell carcinoma component in the histological pathology.
2. History of other malignant tumors within 5 years prior to the first dose administration.
3. History of brainstem, meningeal, or spinal cord metastases/compression, or carcinomatous meningitis; presence of active brain metastases.
4. Imaging during the screening phase shows tumor invasion, compression, or location in surrounding vital organs.
5. Sufficient washout period from previous treatments prior to the first dose.
6. Presence of the following lung diseases or medical history leading to severe respiratory impairment.
7. Presence of risk factors related to interstitial lung disease (ILD) or non-infectious pneumonia.
8. Presence of cardiovascular and cerebrovascular diseases or risk factors.
9. Presence of uncontrolled infections.
10. Toxicity from previous anti-tumor treatment has not recovered to grade≤1 (per CTCAE v5.0).
11. Previous history of allogeneic bone marrow or organ transplantation.
12. Known allergy to any component of the study drug.
13. Pregnant and/or lactating women, or women planning to become pregnant during the study.