A Prospective, Single-Arm, Multicenter, Phase II Clinical Study of Chidamide Combined With Ivonescimab in the Treatment of Advanced Non-Small Cell Lung Cancer With Acquired Resistance to Immunotherapy and High YAP Protein Expression

Exclusion Criteria

• •1. Have a history of severe bleeding tendency or coagulation disorders; have significant clinical bleeding symptoms within 4 weeks before enrollment, including but not limited to gastrointestinal bleeding, hemoptysis (defined as coughing or expectorating ≥ 1 teaspoon of fresh blood or small blood clots or only coughing blood without sputum, subjects with blood in sputum are allowed to enroll), nasal bleeding (excluding epistaxis and retracted nasal blood); continuous antiplatelet or anticoagulant therapy within 14 days before the first dose;
• •2. History of gastrointestinal perforation and/or fistula, gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), esophagogastric varices, severe ulcers, unhealed wounds, abdominal fistulas, intra-abdominal abscesses, or acute gastrointestinal bleeding within 6 months before the first dose; extensive intestinal resection (partial colectomy or extensive small bowel resection complicated by chronic diarrhea);
• •3. Hypersensitivity to any study drug or its components;
• •4. Exclusion of central squamous cell lung cancer invading large blood vessels;
• •5. Patients who experienced Grade 3 or above immune-related adverse reactions with prior immunotherapy drugs, and investigators assess that immunotherapy has safety concerns with risks outweighing benefits;
• •6. Any arterial thromboembolic event, Grade 3 or above venous thromboembolic event as specified by NCI CTCAE 5.0, transient ischemic attack, cerebrovascular accident, hypertensive crisis, or hypertensive encephalopathy within 6 months before the first dose;
• •7. Acute exacerbation of chronic obstructive pulmonary disease within 4 weeks before the first dose;
• •8. Complicated with severe uncontrolled concurrent infections or other severe uncontrolled comorbidities, moderate or severe renal impairment (e.g., progressive infection, uncontrolled hypertension, diabetes mellitus, etc.);
• •9. Active hepatitis B or C infection (hepatitis B surface antigen positive and hepatitis B virus DNA \> 1 × 10³ copies/mL; hepatitis C virus RNA \> 1 × 10³ copies/mL);
• •10. Human Immunodeficiency Virus (HIV) infection (HIV antibody positive);
• •11. Clinically significant active infection, active pulmonary tuberculosis;
• •12. Past or current clinically active interstitial lung disease; current active pneumonia; current radiation pneumonitis requiring hormone therapy;
• •13. Evidence of severe or uncontrolled systemic diseases (e.g., severe mental or neurological diseases, epilepsy, or dementia not stably controlled by drugs; unstable or decompensated respiratory, cardiovascular, hepatic, or renal diseases; uncontrolled hypertension \[i.e., hypertension ≥ CTCAE Grade 3 despite drug treatment\]; hyperglycemia \[fasting blood glucose \> 10 mmol/L\]);
• •14. Clinically significant ventricular arrhythmia within 12 months before the first dose, atrial fibrillation not stably controlled by drugs, unstable angina pectoris, congestive heart failure, chronic heart failure with New York Heart Association (NYHA) classification ≥ Grade 2, or vascular diseases (e.g., aortic aneurysm at risk of rupture), or other cardiac impairments that may affect the safety evaluation of study drugs (e.g., uncontrolled arrhythmia, myocardial ischemia, etc.);
• •15. Past or current concurrent other malignant tumors (except for well-controlled non-melanoma cutaneous basal cell carcinoma, in situ breast/cervical cancer, and other malignant tumors that have been well-controlled without treatment for the past five years);
• •16. Tumor invasion of large vascular structures (e.g., pulmonary artery, superior vena cava, or inferior vena cava) detected at screening, or obvious necrosis/cavitation, which is judged by investigators to have a high risk of bleeding;
• •17. Active bleeding or taking therapeutic doses of anticoagulant drugs with a tendency to major bleeding;
• •18. Clinically uncontrolled pleural effusion/ascites/pericardial effusion;
• •19. Currently participating in interventional clinical study treatment, or receiving other study drugs or study devices within 2 weeks before the first dose;
• •20. Systemic treatment with Chinese patent medicines indicated for lung cancer or immunomodulatory drugs (including thymopeptides, interferons, interleukins, excluding local use for controlling pleural effusion) within 2 weeks before the first dose;
• •21. History of solid organ or hematopoietic stem cell transplantation;
• •22. Diagnosis of autoimmune disease and receiving systemic glucocorticoid therapy or any other form of immunosuppressive therapy within 7 days before the first dose of the study. Note: Physiological doses of glucocorticoids (≤ 20 mg/day prednisone or equivalent) are allowed;
• •23. Failure to fully recover from toxicity and/or complications caused by any intervention before the start of treatment (i.e., ≤ Grade 1 or return to baseline, excluding fatigue or alopecia);
• •24. Vaccination with live vaccines within 30 days before the first dose (Cycle 1, Day 1). Note: Inactivated viral vaccines for seasonal influenza administered by injection are allowed within 30 days before the first dose; however, intranasal attenuated live influenza vaccines are not allowed;
• •25. Pregnant or lactating women, and fertile patients unwilling to use contraceptive measures;
• •26. Concurrent other malignant tumors requiring treatment;
• •27. Patients judged by investigators to be unsuitable for participating in the study.