SRT Combined With Envafolimab and Endostar in the First-line Treatment of Advanced NSCLC

This prospective multi-center single-arm phase II trial focuses on unresectable stage IV NSCLC patients with negative driver genes and positive PD-L1 expression (TPS ≥1%). Eligible subjects are treatment-naive patients or recurrent cases after adjuvant chemotherapy. Patients will receive stereotactic body radiation therapy targeting 1 to 5 metastatic lesions with a dose of 30-50 Gy in 5-10 fractions. Within 1 to 7 days after radiotherapy, patients will receive 300 mg envafolimab subcutaneously on day 1 and 210 mg endostar continuous intravenous pumping on days 1-3 of each 3-week cycle. The overall clinical efficacy and safety profiles of this combined regimen will be systematically observed.

Inclusion criteria

• Subjects voluntarily participate in this study, sign the written informed consent form, and demonstrate good compliance.
• Aged 18-80 years old at the time of signing informed consent, male or female.
• Histologically confirmed stage IV non-small-cell lung cancer (NSCLC) according to the 8th IASLC/AJCC TNM staging system, with negative actionable driver gene alterations (EGFR/ALK/ROS1), and no prior systemic anti-cancer treatment.
• Provide archived tumor tissue samples or newly obtained core/excisional biopsy specimens from tumor lesions which have not received prior anti-tumor therapy or radiotherapy. Formalin-fixed paraffin-embedded (FFPE) tissue blocks are preferred over slides; newly-obtained biopsy samples are preferred over archived tissues. PD-L1 expression ≥1% is confirmed by immunohistochemistry. For subjects without newly-obtained tissue, 5-8 slices of 3-5 μm paraffin sections of archived tissue collected within 2 years before enrollment are acceptable.
• Have at least one radiologically measurable lesion per RECIST version 1.1: target lesion with longest diameter ≥10 mm on CT/MRI, or pathologically enlarged lymph node with short-axis diameter ≥15 mm on CT scan.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.
• Expected survival time ≥ 3 months.
• Treatment-naive patients without previous systemic anti-tumor therapy (including radiotherapy, chemotherapy, targeted or immunotherapy), or patients with disease recurrence more than 6 months after completion of postoperative adjuvant chemotherapy.
• Adequate organ and bone marrow function confirmed by laboratory tests obtained within 7 days before enrollment. No blood product transfusion, growth factors, albumin or other corrective medications are permitted within 14 days prior to laboratory assessment:

• Hematology: absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count (PLT) ≥75×10⁹/L, hemoglobin (HGB) ≥90 g/L (no transfusion or erythropoietin-dependency within 14 days); 2) Liver function: total bilirubin (TBIL) ≤2×ULN; alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) ≤5×ULN; serum albumin ≥28 g/L; alkaline phosphatase (ALP) ≤5×ULN; 3) Renal function: serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance ≥50 mL/min using Cockcroft-Gault formula; urine protein <2+ on urinalysis. For baseline urine protein ≥2+, 24-hour urine protein quantification must be <1 g.

• Coagulation function: international normalized ratio (INR) or prothrombin time (PT) ≤1.5×ULN. For subjects receiving anticoagulants, INR within the therapeutic target range of anticoagulation is acceptable.

• For women of child-bearing potential, negative urine or serum pregnancy test within 3 days prior to first study drug administration.

• Tissue samples must be available for biomarker (e.g. PD-L1) analysis. Newly-obtained specimens are preferred; archived paraffin sections obtained within 2 years before enrollment are allowed if fresh tissue cannot be acquired.

Exclusion criteria

• Tumor invades major blood vessels on CT/MRI, or judged to carry high risk of invading critical vessels and causing fatal hemorrhage during study treatment.
• Currently participating in another interventional clinical trial, or received investigational drug/device within 4 weeks before first study drug administration.
• Received anti-tumor Chinese patent medicine or immunomodulatory agents (such as thymosin, interferon, interleukin) within 2 weeks prior to first dose; or underwent major surgical operation within 3 weeks before first dose.
• Active hemoptysis requiring clinical intervention, active diverticulitis, intra-abdominal abscess, gastrointestinal obstruction, or peritoneal metastasis.
• Any bleeding diathesis regardless of severity; any bleeding/hemorrhagic event ≥ CTCAE grade 3 within 4 weeks before enrollment; unhealed wound, ulcer or fracture.
• New York Heart Association (NYHA) class III-IV congestive heart failure, or uncontrolled clinically significant arrhythmia.
• History of arterial thrombosis, embolism or ischemic events within 6 months before study entry, such as myocardial infarction, unstable angina, cerebrovascular accident or transient ischemic attack.
• Known hypersensitivity to any study drug.
• Require chronic systemic corticosteroid therapy. Intermittent bronchodilators, inhaled corticosteroids for COPD/asthma, or local corticosteroid injection are permitted.
• Symptomatic central nervous system (CNS) metastases. Patients with asymptomatic or treated-stable brain metastases may be enrolled only if all of the following criteria are met: measurable extracranial lesion; no midbrain, pons, cerebellum, meningeal, medulla oblongata or spinal cord metastasis; clinically stable for at least 2 weeks; systemic steroid discontinued at least 3 days before first study drug dose.
• Active infection requiring treatment, or systemic anti-infective medication administered within 1 week before first dose. Subjects have not sufficiently recovered from toxicity/complications induced by prior interventions (≤ grade 1 or return to baseline, excluding fatigue and alopecia).
• Known human immunodeficiency virus (HIV-1/2 antibody positive).
• Untreated active hepatitis B (HBsAg positive with HBV-DNA above local laboratory upper limit of normal). Subjects with HBV viral load <1000 copies/mL (200 IU/mL) are eligible and should receive anti-HBV prophylaxis during study therapy to prevent viral reactivation. Anti-HBc positive, HBsAg negative, anti-HBs negative and HBV-DNA negative subjects do not require prophylactic anti-HBV therapy but need close monitoring for viral reactivation.
• Active hepatitis C infection (HCV-Ab positive with HCV-RNA above assay lower limit).
• Received live-attenuated vaccine within 30 days before Cycle 1 Day 1. Seasonal inactivated injectable influenza vaccine within 30 days before first dose is allowed; intranasal live-attenuated influenza vaccine is prohibited.
• Pregnant or breastfeeding women.
• Medical history, disease condition, treatment or laboratory abnormality that may interfere with study results or prevent full participation in the trial; or other conditions judged by the investigator to render the subject unsuitable for enrollment or associated with potential safety risks.