SKB264 Plus Glecirasib in Advanced KRAS G12C-Mutant NSCLC: A Phase II Study

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.