The CR1STAL-Adaptive study is a randomized, open-label, phase II multicenter interventional trial designed to evaluate the safety and efficacy of Ivonescimab (PD-1/VEGF bispecific antibody) combined with docetaxel versus standard treatment in patients with advanced NSCLC who have achieved long-term benefit from first-line immune checkpoint inhibitors (ICIs), but are ctDNA-MRD positive. Building upon insights from previous CR1STAL study (NCT05198154), the CR1STAL-Adaptive study supports the development of precision-guided, adaptive treatment strategies to delay progression and improve outcomes in NSCLC patients with a long-term response to immunotherapy. It represents a step forward in integrating dynamic molecular monitoring with individualized intervention strategies in the era of immunotherapy.

Inclusion Criteria:

1. Sign written informed consent prior to any study-related procedures, be willing and able to complete the visits, treatment regimen, and laboratory tests specified in the schedule, and comply with other requirements of the study;
2. Aged ≥18 and ≤75 years old;
3. ECOG PS score 0-1;
4. Expected survival time ≥ 12 weeks;
5. Patients with stage IIIB-IIIC and IV non-small cell lung cancer confirmed by histology or cytology that cannot be treated locally (TNM lung cancer staging of the 9th edition of the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer Classification);
6. There must be no EGFR gene-sensitive mutation, ALK gene fusion or ROS1 gene fusion in non-squamous carcinoma
7. Immunotherapy combined with platinum-containing doublet chemotherapy as a first-line standard treatment regimen;
8. Non-PD with PFS at screening enrollment is 11 to 15 months;
9. According to the Response Evaluation Criteria in Solid Tumors (RECIST version 1.1), it is recommended to have at least one measurable lesion, but patients without measurable lesions can still be included in the group (primary tumor recurrence or new metastatic lesions are considered PD).

Participants with brain metastases who are asymptomatic or whose symptoms are stable after local treatment are allowed to enroll, as long as the participants meet the following conditions:

1. There are measurable lesions outside the central nervous system
2. No central nervous system symptoms or no worsening of symptoms for at least 2 weeks
3. No need for glucocorticoid treatment, or glucocorticoid treatment was discontinued within 7 days before the first dose, or the glucocorticoid dosage was stable and reduced to less than 10mg/day prednisone (or equivalent dose) within 7 days before the first dose.

10. Meet the following laboratory indicators (within 14 days before the first treatment):

1. Routine blood test: absolute neutrophil count ≥1.5×109/L; platelet count ≥100×109/L; hemoglobin content ≥9.0 g/dL (no blood transfusion or erythropoietin-dependent administration within 7 days).
2. Liver function: total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN); for patients with liver metastasis or confirmed/suspected Gilbert's syndrome, TBIL ≤3×ULN; in the absence of liver metastasis, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5×ULN. For patients with liver metastasis, ALT or AST ≤5×ULN.
3. Renal function: serum creatinine (Cr) ≤ 1.5 times ULN or Cr clearance ≥ 50 mL/min (Cockcroft-Gault formula), and urine routine test results show urine protein (UPRO) <2+ or 24-hour urine protein quantification <1g.
4. Coagulation function: international normalized ratio (INR) ≤ 1.5 times ULN or partial thromboplastin time (PTT) or activated partial thromboplastin time (APTT) ≤ 1.5 times ULN; if the study participants are receiving anticoagulant therapy, as long as PT is within the range of the anticoagulant drug;
5. Cardiac function: left ventricular ejection fraction (LVEF) ≥ 50% 11. For female study participants of childbearing age, a urine or serum pregnancy test with a negative result should be performed within 3 days before the first dose of study drug (Day 1 of Cycle 1). If the urine pregnancy test result cannot be confirmed as negative, a blood pregnancy test is required. Women of non-childbearing age are defined as women who have been postmenopausal for at least 1 year, or have undergone surgical sterilization or hysterectomy; if there is a risk of pregnancy, all study participants (whether male or female) must use contraceptive measures with an annual failure rate of less than 1% throughout the treatment period until 120 days after the last dose of study drug (or 180 days after the last dose of study drug).

12. If an intact male study participant has sexual intercourse with a female partner of reproductive potential, the study participant must use effective contraception from screening until day 120 after the last dose. Whether to discontinue contraception after this time point should be discussed with the investigator.

Exclusion Criteria:

1. Concurrent participation in another interventional clinical study or receipt of another investigational drug, unless participating in an observational clinical study；

2. Systemic therapy with proprietary Chinese medicines with anti-tumor indications or immunomodulatory drugs (including thiopeptides, interferons, interleukins, except those used locally for the control of hydrothorax or ascites) within 2 weeks prior to the first dose；

3. No measurable lesions as defined by RECIST 1.1 due to prior radical treatment (e.g., surgery or radiotherapy)

4. Subjects who have received systemic antiangiogenic therapy;

5. Subjects who are enrolled in another clinical study at the same time, unless it is a non-interventional clinical study or the follow-up period of an interventional study (defined as the time between the first dose of this study and the last dose of the previous clinical study being more than 4 weeks or more than 5 half-lives of other study drugs, whichever is shorter);

6. During the screening period, imaging shows that the tumor surrounds important blood vessels or there is significant necrosis or cavity, and the investigator determines that entering the study will cause a risk of bleeding;

7. Imaging findings during the screening period show that the tumor invades important peripheral organs and blood vessels (such as the heart and pericardium, trachea, esophagus, aorta, superior vena cava, etc.) or there is a risk of developing esophagotracheal fistula or esophagopleural fistula;

8. Active autoimmune diseases requiring systemic treatment (such as treatment with disease-modifying drugs, corticosteroids, and immunosuppressants) within 2 years before the first dose (excluding irAEs caused by the use of PD-1/L1 inhibitors). Replacement therapy (such as thyroxine, insulin, or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a systemic treatment;

9. A history of major diseases within 1 year before the first dose, specifically:

   • Unstable angina, myocardial infarction, congestive heart failure (NYHA classification ≥ Class 2) or vascular diseases (such as aortic aneurysm with a risk of rupture) that require hospitalization within 12 months before the first dose, or other cardiac damage that may affect the safety evaluation of the study drug (such as poorly controlled arrhythmia, myocardial ischemia, etc.);
   • Hepatic encephalopathy, hepatorenal syndrome or Child-Pugh class B or more severe cirrhosis
   • Current hypertension with systolic blood pressure ≥150 mmHg or diastolic blood pressure ≥100 mmHg after oral antihypertensive therapy;
   • Hyperglycemia that cannot be controlled after treatment (fasting blood glucose > 10 mmol/L);
   • A history of esophageal and gastric varices, with severe ulcers and unresolved wounds, abdominal fistulas, intraabdominal abscesses, or acute gastrointestinal bleeding within 6 months before the first dose;
   • Any arterial thromboembolic events, venous thromboembolic events of grade 3 orabove as specified in NCI CTCAE 5.0, transient ischemic attacks, cerebrovascular accidents, hypertensive crises, or hypertensive encephalopathy that occurred within 6 months before the first dose;
   • Acute exacerbation of chronic obstructive pulmonary disease that occurred within 4 weeks before the first dose;
   • Active or prior history of inflammatory bowel disease (such as Crohn's disease, ulcerative colitis, or chronic diarrhea);

10. A history of gastrointestinal perforation and/or fistula, a history of gastrointestinal obstruction (including incomplete intestinal obstruction requiring parenteral nutrition), or extensive bowel resection (partial colon resection or extensive small bowel resection, with chronic diarrhea) within 6 months before the first dose;

11. Those who have received chest radiotherapy >30 Gy within 6 months before the first dose, non-chest radiotherapy >30 Gy within 4 weeks before the first dose, and palliative radiotherapy ≤ 30 Gy within 2 weeks before the first dose, and who have not recoveredfrom the toxicity and/or complications of these interventions to NCI-CTC AE ≤ grade 1 (excluding alopecia and fatigue). Palliative radiotherapy to control symptoms is allowed, but it must be completed at least 2 weeks before the first dose, and no additional radiotherapy is scheduled for the same lesion;

12. Those who have received live or live attenuated vaccines within 4 weeks before the first dose, or plan to receive live or live attenuated vaccines during the study period. The use of inactivated vaccines is allowed;

13. Severe infections within 4 weeks before the first dose, including but not limited to complications requiring hospitalization such as sepsis, or severe pneumonia; active infections that have received systemic anti-infective treatment within 2 weeks before the first dose (excluding antiviral treatment for hepatitis B or C);

14. Those with a history of severe bleeding tendencies or coagulation disorders; those with clinically significant bleeding symptoms within 4 weeks before the first dose, including but not limited to gastrointestinal bleeding, hemoptysis (defined as coughing up or vomiting up ≥ 1 teaspoon of blood or small blood clots, or only coughing up blood without sputum; those with blood in the sputum are allowed to be enrolled), nasal bleeding (excluding epistaxis and bloody nasal discharge); those who have received continuous antiplatelet or anticoagulant therapy (except for preventive use of anticoagulants, such as the use of anticoagulants to maintain venous patency) within 14 days before the first dose;

15. Those who have undergone major surgery or experienced severe trauma within 4 weeks before the first dose, or have a major surgery planned within 4 weeks after the first dose (as determined by the investigator);

16. Presence of clinically uncontrolled pleural effusion or ascites (subjects may be recruited who do not require drainage of the effusion or who do not have a significant increase in the effusion after 3 days of cessation of drainage)

17. Previous history of non-infectious pneumonia requiring systemic glucocorticoid treatment or current interstitial lung disease;

18. Those with a history of immunodeficiency; those with positive HIV antibody tests;

19. Known history of allogeneic organ transplantation and allogeneic hematopoietic stem cell transplantation;

20. Subjects with untreated active hepatitis B (HBsAg positive and HBV-DNA > 1000 copies/mL (200 IU/mL) or above the lower limit of detection, whichever is higher), for subjects with hepatitis B who are required to receive anti-hepatitis B virus treatment during the study treatment period; subjects with active hepatitis C subjects (HCV antibody positive and HCV-RNA levels above the lower limit of detection);

21. Known presence of active pulmonary tuberculosis (TB);

22. Known active syphilis infection;

23. Known allergy to any component of any study drug; a known history of severe hypersensitivity to other monoclonal antibodies

24. Those with a history of immunodeficienc; those who are currently receiving long-term systemic corticosteroids or other immunosuppressants;

25. A known history of mental illness, drug abuse, alcohol or drug addiction;

26. The toxicity of previous anti-tumor therapy has not been relieved, which is defined as the toxicity has not returned to grade 1 or below specified in NCI CTCAE 5.0, or the level specified in the inclusion/exclusion criteria, except for alopecia and fatigue;

27. Known symptomatic CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may be enrolled in the trial if they are clinically stable (no evidence of imaging progression for at least 4 weeks prior to the first dose of the experimental treatment, no evidence of new brain metastases or increase in size of pre-existing brain metastases as confirmed by repeat imaging) and do not require steroid therapy for at least 14 days prior to the first dose of the experimental treatment. This exception does not include carcinomatous meningitis, which should be excluded regardless of whether it is clinically stable.

28. History of other primary malignancies within 5 years, except：

    • malignancies that have been in complete remission for at least 2 years prior to enrolment and for which no other treatment was required during the study period.
    • adequately treated non-melanoma skin cancer or malignant nevus with no evidence of disease recurrence.
    • adequately treated carcinoma in situ without evidence of disease recurrence

29. Subjects who are pregnant or breastfeeding or plan to breastfeed during the study;

30. Other acute or chronic illnesses, psychiatric disorders, or abnormal laboratory test values that could increase the risks associated with study participation or study drug administration or interfere with the interpretation of study results and, in the investigator's judgment, render the patient ineligible for participation in the study.

31. Uncontrolled metabolic disorders, or local or systemic diseases due to non-malignant tumors, or diseases or symptoms secondary to the tumor, which may lead to higher medical risk and/or uncertainty in survival assessment, or diseases that the investigator considers unsuitable for enrollment;