SYHX2011 in Combination With Carboplatin and Enlonstobart as First-Line Therapy for Squamous Non-Small Cell Lung Cancer

This is a multicenter, open-Label, phase II/III study in patients with squamous non-small cell lung cancer. Phase II will adopt a single-arm study design. The first 12 enrolled patients will be designated as the safety run-in cohort. Upon completion of safety observation after the first dose administration, the recommended dose will be selected for the expansion phase based on the safety and efficacy outcomes of the safety run-in phase.If the Phase II study results demonstrate that the combination therapy at the recommended dose is tolerable and has a favorable safety profile in trial participants, with preliminary evidence of anti-tumor activity, the investigators will determine whether to initiate the Phase III study. The current guideline-recommended first-line treatment regimen is planned to be selected as the control arm, and a randomized, controlled, open-label study design will be adopted. Participants will receive the study regimen (experimental arm) or the control regimen in accordance with the randomization results.

Inclusion criteria

• Age: ≥18 years old
• Histologically or cytologically confirmed locally advanced or metastatic squamous non-small cell lung cancer (Stage IIIB, IIIC, or IV according to the IASLC 9th Edition TNM Staging System), ineligible for radical surgery and/or radical radiotherapy
• Confirmed negative for driver genes (including EGFR mutation, ALK fusion, ROS1 fusion, etc.)
• Tumor cell PD-L1 expression in tumor tissue ≥1% (TPS ≥1%)
• No prior systemic anti-tumor therapy for Stage IIIB/IIIC and IV NSCLC, including chemotherapy, targeted therapy, biological therapy, immunotherapy, immunomodulatory drugs, Chinese herbal medicines or proprietary Chinese medicines, and other investigational drugs for tumor control
• ECOG PS score 0~1
• At least one measurable lesion according to the RECIST 1.1 criteria
• Adequate bone marrow and other organ functions:(1)Hematology: No significant signs of hematological disease; absolute neutrophil count (ANC) ≥1.5×10^9/L, platelet count (PLT) ≥75×10^9/L, hemoglobin (Hb) ≥90 g/L at screening. For patients with hematological indicators at the critical value who fail to meet the above criteria, the investigator will determine eligibility based on the patient's physical condition. (2)Coagulation function: International Normalized Ratio (INR) ≤1.5 × upper limit of normal (ULN); activated partial thromboplastin time (APTT) ≤1.5 × ULN. (3)Hepatic and renal function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) both ≤2.5 × ULN; for patients with hepatic metastasis, both AST and ALT ≤5 × ULN. Total bilirubin (TBiL) ≤1.5 × ULN; for patients with known Gilbert's disease: serum total bilirubin level ≤3 × ULN. Serum creatinine (Cr) ≤1.5 × ULN
• Expected survival ≥3 months
• Able to understand the study details; the patient and/or legal guardian voluntarily consents to participate in the study and signs the informed consent form

Exclusion criteria

• History of or current with other malignant tumors (excluding non-melanoma skin cancer, in situ breast cancer, in situ cervical cancer, and superficial bladder cancer that have been effectively controlled within the past 5 years)
• Active leptomeningeal disease or poorly controlled, untreated brain metastases (excluding patients with brain metastases that are well-controlled with local therapy)
• Interstitial lung disease (ILD), drug-induced interstitial pneumonitis, or non-infectious pneumonitis (including radiation pneumonitis, pulmonary fibrosis, acute lung disease requiring steroid therapy), and patients with severe impairment of pulmonary function
• Active autoimmune disease or a history of autoimmune disease (e.g., ulcerative colitis, Crohn's disease, etc.). However, participants with the following conditions are eligible for further screening: well-controlled type 1 diabetes mellitus; well-controlled hypothyroidism requiring only hormone replacement therapy; dermatological diseases not requiring systemic therapy (e.g., vitiligo, psoriasis, alopecia); or participants with diseases not expected to relapse in the absence of external triggers
• Peripheral neuropathy of Grade ≥2 per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 6.0
• Pleural effusion, peritoneal effusion, or pericardial effusion requiring clinical intervention within 2 weeks prior to the first administration of the study drug
• History of severe cardiovascular disease within 6 months prior to the first administration of the study drug, including but not limited to:(1)Severe cardiac rhythm or conduction abnormalities (e.g., ventricular arrhythmias requiring clinical intervention, third-degree atrioventricular block, etc.); Fridericia-corrected QT interval (QTcF) > 480 ms (Fridericia formula: QTcF=QT/RR^0.33, where RR=60/heart rate);(2)History of myocardial infarction, unstable angina pectoris, angioplasty, or coronary artery bypass graft surgery;(3)Heart failure of New York Heart Association (NYHA) Functional Class Ⅱ or higher; left ventricular ejection fraction (LVEF) < 50% as detected during screening
• Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection: Hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody (anti-HBc) positive, with HBV DNA copy number ≥ 1×10^4 copies/mL (or ≥ 2000 IU/mL); Hepatitis C virus antibody (anti-HCV) positive, with HCV RNA level exceeding the lower limit of quantification (LLOQ) of the applied analytical method
• Severe infection occurring within 4 weeks prior to the first study drug administration (including but not limited to bacteremia requiring hospitalization, severe pneumonia, active pulmonary tuberculosis, etc.); active infection requiring systemic antibiotic therapy within 2 weeks prior to the first study drug administration
• Lactating or pregnant females; females of childbearing potential with a positive blood pregnancy test within 7 days before study enrollment; all male and female patients of childbearing potential who decline to use highly effective contraceptive methods throughout the study period and for 6 months after the last drug administration
• Known hypersensitivity or anaphylaxis to any study drug, or a history of other severe hypersensitivity reactions
• History of immunodeficiency (including positive human immunodeficiency virus (HIV) test results, other acquired or congenital immunodeficiency diseases); a history of allogeneic stem cell or organ transplantation; other conditions that the investigator deems unsuitable for study participation (e.g., psychiatric disorders, uncontrolled or poorly controlled hypertension and diabetes mellitus, etc.)