Phase II Neoadjuvant Study of Garsorasib Followed by Ivonescimab Plus Chemotherapy in Resectable Stage IIA-IIIB KRAS G12C-Mutant NSCLC (GIVEN Study)

An Exploratory Phase II Clinical Study Protocol of Perioperative Treatment With Glesorasib Sequentially Combined With Ivonescimab and Chemotherapy for Resectable, Stage IB-IIIB, KRAS G12C-Mutant NSCLC

This study is a multicenter, prospective, open-label clinical trial. It enrolls previously untreated patients with resectable stage IB-IIIB KRAS G12C mutation-positive NSCLC to evaluate the efficacy and safety of glesorasib sequentially combined with ivonescimab and chemotherapy as perioperative treatment for this patient population.

Inclusion Criteria:

1. Age Range: Males or females aged 18 years or older.

2. Diagnosis and Stage: Patients with histologically or cytologically confirmed resectable IB-IIIB NSCLC, staged according to the International Association for the Study of Lung Cancer Staging Manual in Thoracic Oncology, 9th Edition.

3. Informed Consent: Patients must voluntarily participate in the study, provide written informed consent, and be willing to comply with follow-up procedures.

4. Prior Therapy: No prior systemic therapy for locally advanced or metastatic NSCLC (including adjuvant chemo/radiotherapy, neoadjuvant chemo/radiotherapy, definitive chemoradiotherapy, chemotherapy, radiotherapy, immune checkpoint inhibitors, targeted therapy, or anti-angiogenic therapy for locally advanced disease).

5. Mutation Status: KRAS G12C mutation positivity must be confirmed by next-generation sequencing (NGS) or polymerase chain reaction (PCR) testing.

6. Measurable Disease: At least one measurable target lesion as per RECIST v1.1. Lesions previously treated with radiotherapy or other local-regional therapies cannot be considered target lesions unless clear progression has been documented post-radiotherapy. At baseline, the lesion must be ≥10mm in the longest diameter (≥15mm in short axis for lymph nodes) on CT or MRI and be suitable for accurate repeated measurement per RECIST v1.1.

7. Performance Status: Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1.

8. Adequate Organ Function: Must meet the following criteria within 14 days prior to relevant tests, without transfusion or use of hematopoietic growth factors:

   1. Platelets (PLT) ≥90 × 10^9/L
   2. Hemoglobin (HGB) ≥90 g/L
   3. Absolute Neutrophil Count (ANC) ≥1.5 × 10^9/L
   4. Serum creatinine ≤1.5 × ULN or Creatinine Clearance (CrCl) ≥50 mL/min (calculated using the Cockcroft-Gault formula)
   5. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST) ≤2.5 × ULN (≤5 × ULN if liver metastases are present)
   6. Total Bilirubin (TBIL) ≤1.5 × ULN (≤3 × ULN for patients with Gilbert's syndrome)
   7. International Normalized Ratio (INR) or Prothrombin Time (PT) ≤1.5 × ULN, and Activated Partial Thromboplastin Time (APTT) ≤1.5 × ULN, or patients assessed by the investigator as having controlled bleeding tendency.
   8. Urinalysis showing urine protein <2+ or 24-hour urinary protein quantification <1g.

9. Life Expectancy: Expected survival time ≥3 months.

10. Contraception: Fertile female subjects must agree to use effective contraception (e.g., IUD, oral contraceptives, condoms) during the study and for 6 months after study completion; have a negative serum pregnancy test within 7 days before enrollment; and must not be breastfeeding. Male subjects must agree to use effective contraception during the study and for 6 months after study completion.

Exclusion Criteria:

1. Prior Anti-Tumor Therapy:

   1. Previous receipt of any anti-tumor therapy for lung cancer (including adjuvant chemoradiotherapy, neoadjuvant chemoradiotherapy, chemotherapy, radiotherapy, immune checkpoint inhibitors, targeted therapy, anti-angiogenic therapy, etc.).
   2. Treatment with any other investigational drug within 28 days prior to the first dose in this study.
   3. Treatment within 2 weeks prior to the first dose with NMPA-approved Chinese patent medicines explicitly indicated for anti-tumor purposes in their drug说明书 (e.g., Compound Banmao Capsules, Kang'ai Injection, Kanglaite Capsules/Injection, Aidi Injection, Yadanzi Oil Injection/Capsules, Xiaoaiping Tablets/Injection, Huachansu Capsules, etc.).

2. Recent Surgery: Any surgery within 4 weeks prior to screening examinations.

3. Concurrent Primary Malignancy: Patients with a concurrent primary malignancy (except for adequately treated basal cell carcinoma of the skin, carcinoma in situ of the cervix, etc.).

4. Abnormal Organ Function: Meeting any of the following at screening:

   1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) ≥ 1.5 times the upper limit of normal (ULN).
   2. Creatinine clearance rate (CrCl) > ULN.

5. Hematological Abnormalities: Total white blood cell (WBC) count > 10.0 × 10^9/L or < 1.0 × 10^9/L at screening.

6. Significant Comorbidities: History of immunodeficiency diseases (e.g., HIV), other active cancers or malignancy history, autoimmune diseases, severe cardiovascular or cerebrovascular diseases, or any other diseases that may significantly reduce life expectancy.

7. Conditions Affecting Compliance: Any history of conditions that may affect protocol compliance (e.g., severe psychiatric disorders, cognitive dysfunction, drug abuse or addiction).

8. Pregnancy, Lactation, and Contraception: Pregnant or lactating women, or subjects of childbearing potential unwilling or unable to use effective contraception.

9. Allergy: Known allergy to any component of the study drug(s).

10. Recent Trial Participation: Participation in any drug clinical trial within 6 months prior to screening.

11. Investigator's Discretion: Any condition considered by the investigator as unsuitable for study participation.

12. Other Driver Mutations: Non-small cell lung cancer with other standard-therapy-eligible driver gene mutations (e.g., EGFR, ALK, BRAF V600E, HER-2, MET Exon 14, ROS1, RET, or NTRK1/2/3).

13. Central Nervous System (CNS) Metastases:

    1. Symptomatic or progressive CNS metastases or carcinomatous meningitis.
    2. Subjects with a history of brain metastases may be considered if they are clinically stable: no neurological symptoms, no corticosteroid treatment required, no indication for radiotherapy, and the largest diameter of the largest metastatic lesion on recent imaging is ≤ 1.5 cm.
    3. Asymptomatic CNS metastases newly discovered during screening are allowed.
    4. Subjects with a history of asymptomatic CNS metastases require confirmation of no progression via imaging scans performed at least 2 weeks apart.
    5. Subjects with symptomatic CNS metastases may be considered if clinically stable after radiotherapy and/or surgery.
    6. Subjects who underwent surgery for CNS metastases must have an interval of at least 4 weeks before the first study dose.
    7. Asymptomatic subjects after CNS radiotherapy must have discontinued corticosteroids for at least 2 weeks prior to the first dose.

14. Cardiovascular Disease: Any of the following:

    1. Congestive heart failure of New York Heart Association Class II or above.
    2. Severe arrhythmia requiring medication.
    3. Acute myocardial infarction, severe or unstable angina, coronary or peripheral artery bypass graft within 6 months prior to enrollment.
    4. Left ventricular ejection fraction (LVEF) < 50%.
    5. Prolonged QTcF interval ( > 470 ms for females, > 450 ms for males) or risk factors for Torsades de Pointes.
    6. Uncontrolled hypertension (systolic BP ≥ 150 mmHg and/or diastolic BP ≥ 100 mmHg after antihypertensive therapy).

15. Thromboembolic Events: Arterial/venous thrombotic events within 6 months, hypertensive crisis, or hypertensive encephalopathy.

16. History of Epilepsy: Previous history of epilepsy.

17. Superior Vena Cava Syndrome: Presence of superior vena cava syndrome.

18. Pulmonary Disease: Active non-infectious interstitial lung disease, radiation pneumonitis, etc., active tuberculosis, pneumoconiosis, ≥ Grade 2 other pneumonias, or severely impaired pulmonary function at screening.

19. Severe Bone Lesions: Existing or potential severe bone damage from metastases, or uncontrolled bone pain.

20. Active Infection: Active or uncontrolled severe infection, or unexplained fever > 38.5°C.

21. Third-Space Fluid: Poorly controlled or drainage-requiring pleural effusion, ascites, or pericardial effusion. Subjects stabilized after treatment may be enrolled.

22. Tumor Invading Major Vessels: Imaging shows tumor invading or with unclear boundaries to major blood vessels.

23. Bleeding Risk: Evidence or history of bleeding tendency within 2 months before the first dose; history of hemoptysis, or unhealed wounds/ulcers/fractures within 2 weeks before the first dose.

24. Gastrointestinal Diseases: Known GI impairment or diseases significantly affecting drug absorption/metabolism, or major GI surgery affecting absorption.

25. Recent Live Vaccination: Administration of a live attenuated vaccine within 4 weeks before the first dose.

26. Severe Hypersensitivity to mAbs: History of severe hypersensitivity reaction to other monoclonal antibodies.

27. Autoimmune Disease: Active autoimmune disease requiring systemic treatment within 2 years before the first dose.

28. Immunosuppressive Therapy: Receiving systemic corticosteroids or other immunosuppressive therapy.

29. Viral Infections: Positive HIV antibody, or active viral hepatitis.

    1. Active Hepatitis B or active Hepatitis C.
    2. Carriers require antiviral therapy and monitoring during the study.

30. Active Syphilis.

31. Renal Failure: Requiring hemodialysis or peritoneal dialysis.

32. Poorly Controlled Diabetes: Fasting blood glucose > 10 mmol/L.

33. Organ Transplant: History of or planned organ transplantation.

34. Recent Major Surgery/Trauma: Major surgery or significant trauma within 4 weeks before the first dose.

35. Recent Radiotherapy: Palliative radiotherapy within 2 weeks before the first dose.

36. Residual Toxicity from Prior Therapy: Toxicities from previous anti-cancer therapy not recovered to Grade ≤1.

37. Other: Any other clinically significant abnormality or disease deemed by the investigator to pose risk or interfere with the study.