This is a prospective, single-center, Phase II clinical study designed to explore the efficacy and safety of ivonescimab plus third-generation EGFR-TKIs in patients with advanced EGFR-mutant non-small cell lung cancer who developed slow progression or potential progression after prior EGFR-TKI therapy.

This is a prospective, single-center, Phase II clinical study. The study plans to enroll a total of 36 patients, all diagnosed with advanced NSCLC who developed slow progression or potential progression after failure of EGFR-TKI therapy. The objective of this study is to investigate the efficacy and safety of ivonescimab combined with EGFR-TKIs in patients with advanced NSCLC presenting with the specific progression patterns after prior EGFR-TKI therapy.

The study design is divided into two stages: The first stage is the safety lead-in phase, which plans to enroll 6 subjects. All subjects will receive ivonescimab in combination with their original EGFR-TKI regimen. After the last enrolled subject completes at least 21 days of observation following their first dose of study treatment, investigators will conduct a safety assessment and decide whether to enter the expansion phase with the current dose regimen. If the safety and tolerability profile is unacceptable, investigators will decide to revise or terminate the study, and may adjust the dosing regimen of ivonescimab and/or EGFR-TKIs. A total of 30 subjects are planned to be enrolled in the expansion phase.

All enrolled patients will receive ivonescimab in combination with their original EGFR-TKI regimen, with every 3 weeks constituting one treatment cycle. Treatment will continue until disease progression, intolerable toxicity, investigator-initiated discontinuation, patient withdrawal of informed consent, or meeting other treatment discontinuation criteria specified in the protocol, whichever occurs first. During treatment, investigators will determine disease progression (PD) based on tumor response evaluated per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), and decide whether the patient may continue study treatment. If the patient's performance status remains stable and the investigator judges that the patient can benefit from continued treatment, the patient may continue on study treatment. During the study, clinical tumor imaging assessment will be performed by investigators per RECIST v1.1 in accordance with routine clinical practice. For patients who discontinue treatment for reasons other than disease progression, follow-up of disease status will continue whenever possible until the patient initiates other anti-tumor therapy, develops disease progression, withdraws informed consent, dies, or the study concludes, whichever occurs first.

Investigators will assess the safety of ivonescimab in this study population. All adverse events (AEs) will be graded using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v5.0), and the causal relationship between adverse events and study treatment will be determined.

Inclusion Criteria:

• 1. Voluntarily signed written informed consent form; 2. Age ≥ 18 years; 3. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1; 4. Expected survival ≥ 3 months; 5. Histologically or cytologically confirmed locally advanced (stage IIIB/IIIC) or metastatic (stage IV) non-squamous non-small cell lung cancer (NSCLC), which is unresectable for complete surgical resection and not eligible for radical concurrent/sequential chemoradiotherapy, staged per the 8th edition TNM Staging for Lung Cancer released by the Union for International Cancer Control (UICC) and American Joint Committee on Cancer (AJCC); 6. Positive EGFR sensitive activating mutation confirmed by tumor histology, cytology or hematology testing before enrollment, including exon 19 deletion (19Del) and exon 21 point mutation (L858R); patients with EGFR T790M mutation are also eligible for enrollment; 7. Developed slow progression or potential progression during EGFR-TKI therapy: 8. Presence of at least one measurable lesion; 9. Normal function of major organs, meeting all the following criteria:

Routine blood test results meet the requirements (no blood transfusion, no use of hematopoietic growth factors, no drug correction within 14 days before testing):

a. Absolute neutrophil count (ANC) ≥ 1.5×10⁹/L (1,500/mm³); b. Platelet count (PLT) ≥ 90×10⁹/L (90,000/mm³); c. Hemoglobin (HB) ≥ 90 g/L; 10. Biochemical test results meet the following criteria:

1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5×ULN;
2. Serum albumin (ALB) ≥ 28 g/L;
3. Serum creatinine (sCr) ≤ 1.5×ULN; urine protein < 2+ or 24-hour urinary total protein quantification < 1.0 g (creatinine clearance calculated per Cockcroft-Gault formula); Coagulation function meets the requirements: International Normalized Ratio (INR) ≤ 1.5×ULN and activated partial thromboplastin time (APTT) ≤ 1.5×ULN;

Exclusion Criteria:

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