A Study of Chidamide Combined With Ivonescimab in the Treatment of Advanced Non-Small Cell Lung Cancer (NSCLC) With Acquired Resistance to Immunotherapy and High Yes-associated Protein (YAP) Expression (NSCLC， YAP)

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

This is a prospective, single-arm, multi-center, phase II clinical trial to evaluate the efficacy and safety of Chidamide in combination with Ivonescimab in the treatment of advanced non-small cell lung cancer with secondary immune resistance and high YAP protein expression.

Study Overview

• Status: Not yet recruiting
• Conditions: Non-Small Cell Lung Cancer
• Intervention / Treatment: Drug: Chidamide in combination with Ivonescimab

Detailed Description

Not provided

• Study Type: Interventional
• Enrollment (Estimated): 32
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Qing Zhou, MD; Phone Number: +86 02083827812; Email: gzzhouqing@126.com
• Study Contact Backup: Name: Yi-chen Zhang, MD; Phone Number: 86 19128287863

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510080
      • Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Southern Medical University, Guangzhou, China
      • Contact: Qing Zhou; Phone Number: +86 02083827812; Email: gzzhouqing@126.com
      • Contact: Yi-Chen Zhang; Phone Number: +8619128287863
  • Hubei
    • Wuhan, Hubei, China, 430030
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science & Technology
      • Contact: Liu Huang; Phone Number: +86 1520710850; Email: huangliu017@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Written informed consent must be signed before implementing any trial-related procedures;
2. Age ≥18 years old;
3. Have histologically or cytologically confirmed locally advanced (IIIB/IIIC stage), metastatic or recurrent (IV stage) non-small cell lung cancer (NSCLC) that is not operable and not suitable for radical concurrent chemoradiotherapy, as classified by the 9th edition of the TNM staging system of the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer;
4. Previously received first-line PD-1/PD-L1 inhibitor monotherapy or combination therapy, with a progression-free survival (PFS) of ≥ 6 months under the initial PD-1/PD-L1-containing treatment regimen;
5. Previously received only first-line systemic treatment;
6. Able to provide 15 pieces of biopsied tumor tissue or tumor tissue sections after PD-1/PD-L1 treatment resistance, pathologically confirmed as non-small cell lung cancer, and centrally laboratory-confirmed high YAP protein expression. Eligible subjects voluntarily provide 5-15 sections of tumor tissue samples from initial diagnosis. (YAP immunohistochemical staining intensity is graded as 0 (negative), 1+ (weak), 2+ (moderate), and 3+ (strong); the proportion of positive tumor cells is graded as 0 (0-5%), 1+ (6-25%), 2+ (26-50%), 3+ (51-75%), and 4+ (>75%). The YAP IHC score is calculated by multiplying the staining intensity by the proportion of positive tumor cells: YAP IRS = Staining Intensity (A) × Proportion of Positive Tumor Cells (B). A YAP IHC score < 6 indicates low YAP expression, and ≥ 6 indicates high YAP expression);
7. Asymptomatic brain metastasis patients are eligible for enrollment;
8. Palliative radiotherapy completed within 2 weeks before study enrollment is allowed, and radiotherapy-related toxicity has recovered to ≤ Grade 1 (CTCAE 5.0). Radiated lesions are not considered evaluable lesions unless there is evidence of progression after radiotherapy;

9. No prior use of any traditional Chinese medicine (TCM) with anti-tumor effects, or prior use of TCM with anti-tumor effects no more than 3 times (one dose counts as one time), and discontinuation of such TCM for ≥ 2 weeks before the start of study drug treatment.

   Patients must meet the following laboratory test requirements at screening:

10. Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L without the use of growth factors in the past 14 days;
11. Platelet count ≥ 80 × 10⁹/L and hemoglobin ≥ 80 g/L without blood transfusion in the past 14 days;
12. Aspartate Aminotransferase (AST) and Alanine Aminotransferase (ALT) ≤ 2.5 × Upper Limit of Normal (ULN) (patients with liver metastasis are allowed to have ALT or AST ≤ 5 × ULN);
13. Total bilirubin ≤ 1.5 × ULN (patients with liver metastasis or biliary obstructive tumors are allowed to have ≤ 2.5 × ULN);
14. Serum creatinine ≤ 1.5 × ULN and creatinine clearance rate (calculated by the Cockcroft-Gault formula) ≥ 45 ml/min;
15. ECOG performance status score of 0-1;
16. Good coagulation function, defined as International Normalized Ratio (INR) or Prothrombin Time (PT) ≤ 1.5 × ULN;
17. Expected survival time > 12 weeks;
18. Negative pregnancy test (applicable only to women of childbearing potential).

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: The combination of Chidamide plus Ivonescimab(AK112); Participants will take 20 mg of Chidamide by month every 3-4 days on a twice weekly (BIW) schedule and Ivonescimab (AK112) 20 mg/kg intravenously (IV) Q3W.	Drug: Chidamide in combination with Ivonescimab; Chidamide 20mg/dose orally BIW; Ivonescimab 20mg/kg intravenously (IV) Q3W; Other Names: CS055; Tucidinostat; AK112

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Progression Free Survival(PFS) per Response Evaluation Criteria in Solid tumors (RECIST) v1.1	PFS is measured from the start of treatment until progression or death, whichever is first met	From the start of treatment until disease progression or death (assessed up to 24 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Overall Survival(OS) was measured from the date of first dose of study drug until date of death from any cause. Participants who were lost to follow-up and the participants who alive at the date of data cutoff was censored at the date the participant was last known alive, whichever came earlier.	From the date of first dose of study drug until date of death from any cause (up to approximately 5 years).
Adverse Events	The incidence of hematological and non-hematological adverse events, events will be classified according to CTCAE v5.0	From first dose until 30 days after the last dose, up to approximately 2 years
Object Response Rate (ORR)	ORR is defined as percentage of participants with Complete Response(CR) and Partial Response(PR), assessed by the investigators according to the RECIST 1.1.	Every 6 weeks (RECIST 1.1) until progression(up to 24 months)
Disease Control Rate(DCR)	DCR based on RECIST 1.1 assessed by the investigators, the proportion(%) of patients with at least one visit response of CR or PR, or SD.	From the first dose of study drug to the first date of documentation of disease progression or death whichever occurred first, up to approximately 2 years
Duration of Response(DOR)	DOR is defined as the time from the first documentation of CR or PR to the date of first documentation of PD or death (whichever occurred first) in participants with confirmed CR or PR based on RECIST 1.1 assessed by investigators.	From date of first documented confirmed CR or PR until date of first documentation of PD or death whichever occurred first, up to approximately 2 years

Collaborators and Investigators

• Sponsor: Guangdong Association of Clinical Trials
• Collaborators: Innovent Biologics, Inc.; Akesobio

Study record dates

Study Major Dates

• Study Start (Estimated): May 15, 2026
• Primary Completion (Estimated): March 31, 2028
• Study Completion (Estimated): March 31, 2029

Study Registration Dates

• First Submitted: February 9, 2026
• First Submitted That Met QC Criteria: February 9, 2026
• First Posted (Actual): February 17, 2026

Study Record Updates

• Last Update Posted (Actual): May 8, 2026
• Last Update Submitted That Met QC Criteria: May 5, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Keywords: YAP protein; Acquired immune resistance
• Additional Relevant MeSH Terms: Neoplasms by Site; Neoplasms; Respiratory Tract Diseases; Lung Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Carcinoma, Non-Small-Cell Lung; N-(2-amino-5-fluorobenzyl)-4-(N-(pyridine-3-acrylyl)aminomethyl)benzamide
• Other Study ID Numbers: CTONG 2505

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No