This is a multicenter, single-arm, phase II (Simon two-stage) prospective interventional clinical study. The primary objective is to evaluate the efficacy and safety of SKB264 in combination with Glecirasib (a KRAS G12C inhibitor) as first-line treatment in patients with KRAS G12C-mutated locally advanced or metastatic non-squamous non-small cell lung cancer (NSCLC). Specifically, the primary endpoint is the objective response rate (ORR) assessed by investigators per RECIST 1.1 to verify the core antitumor activity of the combination regimen. Secondary objectives include comprehensive evaluation of overall efficacy via disease control rate (DCR), duration of response (DoR), time to response (TTR), progression-free survival (PFS), and overall survival (OS). Safety will be monitored in accordance with NCI CTCAE 5.0, including the incidence and severity of adverse events (AEs) and serious adverse events (SAEs), to characterize the safety profile of the combination and the feasibility of dose modifications. This study aims to provide scientific evidence for the use of this combination regimen as first-line therapy for KRAS G12C-mutated advanced NSCLC and to explore a more optimal treatment option for this patient population.

Inclusion Criteria:

• Voluntarily participate in the study and sign the informed consent form (ICF).
• Male or female subjects aged ≥18 years and ≤75 years at the time of signing the ICF.
• Expected survival time of ≥3 months.
• Histologically or cytologically confirmed non-squamous non-small cell lung cancer (NSCLC) with unresectable locally advanced stage (Stage ⅢB/ⅢC), metastatic or recurrent stage (Stage Ⅳ) that is not eligible for radical concurrent chemoradiotherapy, in accordance with the 8th edition of the TNM --Staging System for Lung Cancer by the International Association for the Study of Lung Cancer (IASLC) and the American Joint Committee on Cancer (AJCC).

Confirmed KRAS G12C mutation-positive by a qualified laboratory (CAP/CLIA or nationally accredited) using next-generation sequencing (NGS) or an equivalent method; positivity in either tissue samples or plasma circulating tumor DNA (ctDNA) is acceptable. If plasma testing is negative and tissue testing is feasible, supplementary tissue testing is recommended.

• Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 to 1.
• Definition for first-line systemic therapy of advanced disease: No prior systemic anti-tumor therapy for metastatic/advanced disease. For subjects who previously received radical post-surgical therapy, chemoradiotherapy or immunotherapy alone, enrollment is permitted only if the interval from the last dose to disease recurrence is ≥6 months.
• Presence of at least one measurable lesion in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1; measurable lesions within a prior radiotherapy field or after local treatment may be selected as target lesions if disease progression is documented.
• Sufficient organ and bone marrow function, including the following:

Adequate hematopoietic function: Absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count ≥100×10⁹/L, hemoglobin ≥9 g/dL. No blood transfusion or treatment with granulocyte colony-stimulating factor (G-CSF), thrombopoietin (TPO), erythropoietin (EPO) or other similar agents is allowed within 14 days prior to blood routine testing.

• Adequate liver function: Total bilirubin (TBIL) <1.5×upper limit of normal (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <2.5×ULN; for subjects with Gilbert's syndrome, TBIL <2×ULN is acceptable; for subjects with liver metastases from tumor, AST and ALT <5.0×ULN is required; for subjects with extrahepatic obstruction confirmed by direct bilirubin (DBIL) testing, TBIL <3.0×ULN is permitted.
• Adequate renal function: Serum creatinine (Cr) ≤1.5×ULN, or if Cr >1.5×ULN, creatinine clearance (CrCl) ≥60 mL/min calculated by the Cockcroft-Gault formula.
• Adequate coagulation function: Prothrombin time (PT)/activated partial thromboplastin time (APTT) <1.5×ULN, and international normalized ratio (INR) <1.5 or within the target range for anticoagulant therapy.

Serum magnesium level within the normal range.

• Toxic effects from prior anti-tumor therapy must have recovered to baseline levels (excluding residual alopecia) or grade ≤1 at enrollment (grade ≤2 neurotoxicity is acceptable). For immune-related adverse events (irAEs) involving the endocrine system caused by prior immunotherapy (e.g., immune-related hypothyroidism), subjects with well-controlled symptoms under stable-dose hormone replacement therapy or physiological-dose corticosteroid therapy may be enrolled if the investigator assesses that the treatment does not interfere with the administration of study drugs and safety evaluation.
• Female subjects of childbearing potential and male subjects whose partners are of childbearing potential must adopt effective contraceptive measures from the time of signing the ICF until 6 months after the last dose of study drug. Female subjects of childbearing potential must have a negative blood pregnancy test result within 7 days (inclusive) prior to the first dose of study drug. If a urine pregnancy test result is inconclusive, a blood pregnancy test is required.
• The investigator judges that the subject is capable of effective communication, complying with scheduled follow-up visits and completing the study in accordance with the protocol requirements.

Exclusion Criteria:

• Prior treatment with a KRAS G12C inhibitor or TROP2-ADC; any prior systemic anti-tumor therapy (chemotherapy, immunotherapy, targeted therapy, etc.) for advanced non-small cell lung cancer (NSCLC).
• Positive for other clinically approved first-line targetable oncogenic drivers: classic sensitizing EGFR mutations (19del/L858R), ALK/ROS1/RET/NTRK fusions, BRAF V600E mutation, MET exon 14 skipping mutation, and other mutations for which guideline-recommended approved first-line targeted therapies are available (to avoid conflict with current standard of care); concurrent mutations such as KRAS combined with STK11/KEAP1 are not exclusion criteria.
• Histologically or cytologically confirmed mixed NSCLC with small cell carcinoma components or predominantly squamous cell carcinoma components.
• Significant cardiovascular and cerebrovascular diseases, including:

A confirmed major cardiovascular adverse event within 6 months, such as myocardial infarction, angina pectoris, heart failure, severe arrhythmia, or receipt of angioplasty, vascular stenting, coronary artery bypass grafting, or other similar procedures; -Clinically significant prolonged QT/QTcF interval on electrocardiogram (QTcF >470 ms in females or QTcF >450 ms in males); A confirmed major cerebrovascular adverse event within 3 months, such as intracerebral hemorrhage or cerebral infarction.

Uncontrolled central nervous system (CNS) disease: active CNS metastases requiring urgent local therapy; meningeal carcinomatosis.

-Interstitial lung disease (ILD)/drug-induced pneumonitis: active ILD/pneumonitis or a history of ILD/pneumonitis requiring systemic corticosteroid therapy; baseline chest imaging showing active ILD-like changes.