This is a prospective, single-arm, single-center, phase II trial designed to evaluate the efficacy and safety of bevacizumab combined with a double dose of icotinib as a first-line treatment for patients with advanced non-squamous non-small cell lung cancer (NSCLC) harboring an EGFR Exon 21 L858R mutation. Patients will receive bevacizumab and icotinib (250 mg, administered orally three times per day ) until disease progression or unacceptable toxicity. The primary endpoint is progression-free survival (PFS). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), overall survival (OS), and toxicity profile. The hypothesis is that the combination therapy will provide improved outcomes for this patient population, which typically has a poorer response to standard EGFR-TKI therapy.

Inclusion Criteria

Patients must meet ALL of the following criteria to be eligible for study enrollment:

1. Voluntary provision of written informed consent prior to any study-specific procedures.

2. Age ≥ 18 and ≤75 years at the time of signing informed consent.

3. Willing and able to comply with the study protocol, as judged by the investigator.

4. Histologically or cytologically confirmed, unresectable, locally advanced (Stage IIIB, not amenable to radical chemoradiotherapy), metastatic (Stage IV), or recurrent non-squamous non-small cell lung cancer (NSCLC) per the American Joint Committee on Cancer staging manual, eighth edition

5. Documented EGFR exon 21 L858R mutation, as centrally confirmed by a high-sensitivity PCR-based test on tumor tissue. Results from direct sequencing are also acceptable.

6. Performance Status: Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1.

7. Life expectancy of ≥ 12 weeks.

8. Prior Therapy:

   • No prior systemic cytotoxic chemotherapy for advanced or metastatic disease.
   • Prior intra-cavitary cytotoxic agent administration for pleurodesis is excluded.
   • Prior neoadjuvant or adjuvant chemotherapy is permitted if completed ≥ 6 months prior to enrollment.

9. Prior radiotherapy is allowed provided:

   • No thoracic radiotherapy within 28 days prior to enrollment.
   • For radiotherapy outside the thorax, a washout period of ≥ 28 days from the last dose to enrollment is required. (For palliative radiotherapy to bone metastases within 2 weeks prior to enrollment, patients must have recovered from all related toxicities.)

10. At least one measurable lesion as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Previously irradiated lesions cannot be considered as target lesions.

11. Adequate Hematological Function:

    • Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L
    • Platelet count ≥ 100 × 10⁹/L
    • Hemoglobin ≥ 9.0 g/dL (transfusion allowed to achieve this level)

12. Adequate Hepatic Function:

    • Total bilirubin ≤ 1.5 × the upper limit of normal (ULN)
    • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (or ≤ 5 × ULN in the presence of liver metastases)

13. Adequate Renal Function:

    • Serum creatinine ≤ 1.5 × ULN OR calculated creatinine clearance ≥ 45 mL/min (using Cockcroft-Gault formula)
    • Urine dipstick for proteinuria < 2+. If dipstick reading is ≥ 2+, a 24-hour urine collection must demonstrate ≤ 1 g of protein per 24 hours.

14. Coagulation Parameters: International normalized ratio (INR) ≤ 1.5 and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN within 7 days prior to enrollment.

15. For women of childbearing potential: agreement to remain abstinent or use highly effective contraceptive methods (failure rate < 1% per year) during the treatment period and for at least 6 months after the last dose of study drug. For men: agreement to remain abstinent or use a condom plus an additional effective contraceptive method, and to refrain from sperm donation, during the treatment period and for at least 6 months after the last dose of study drug.

Exclusion Criteria

Patients who meet ANY of the following criteria will be excluded from the study:

1. History of mixed adenosquamous histology with predominant squamous component.
2. Presence of any other concomitant EGFR mutation (e.g., exon 19 deletion, T790M) as detected by high-sensitivity testing (e.g., digital PCR).
3. History or evidence of symptomatic or untreated central nervous system (CNS) metastases. Patients with previously treated CNS metastases are eligible if they are clinically stable and radiologically stable (without evidence of progression) for ≥ 28 days after CNS-directed therapy prior to enrollment.
4. History of significant hemoptysis (> 2.5 mL of bright red blood per episode) within 3 months prior to enrollment.
5. Radiological evidence of tumor invasion or encasement of major blood vessels (e.g., pulmonary artery, superior vena cava).
6. Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to enrollment, or anticipation of the need for major surgery during the study.
7. Core biopsy or other minor surgical procedure (excluding placement of a vascular access device) within 7 days prior to the first dose of study treatment. Placement of a vascular access device must be completed at least 2 days prior to treatment initiation.
8. Current or recent (within 10 days prior to initiation of bevacizumab) use of full-dose aspirin (> 325 mg/day) or other NSAIDs known to inhibit platelet function.
9. Current or recent (within 10 days prior to initiation of bevacizumab) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic purposes. Prophylactic use of low-dose anticoagulants is permitted.
10. Known hereditary or acquired bleeding diathesis or coagulopathy with a high risk of bleeding.
11. Poorly controlled hypertension (systolic blood pressure > 150 mmHg and/or diastolic blood pressure > 100 mmHg).
12. History of hypertensive crisis or hypertensive encephalopathy.
13. Significant cardiovascular disease within 6 months prior to enrollment, including but not limited to: cerebrovascular accident/transient ischemic attack, myocardial infarction, unstable angina, New York Heart Association (NYHA) Class II or greater congestive heart failure, or severe cardiac arrhythmia requiring medication that may interfere with the regularity of study treatment.
14. Severe peripheral vascular disease (e.g., aortic aneurysm requiring surgical intervention, recent arterial thrombosis) within 6 months prior to enrollment.
15. Non-healing wound, active peptic ulcer, or untreated bone fracture.
16. History of gastrointestinal perforation, abdominal fistula, or intra-abdominal abscess within 6 months prior to enrollment.
17. Pregnancy, lactation, or intention to become pregnant during the study period.
18. Treatment with any other investigational agent or participation in another clinical trial within 28 days prior to enrollment.
19. Known hypersensitivity to any component of the bevacizumab formulation, Chinese hamster ovary cell products, icotinib, or its excipients.
20. Active infection requiring systemic intravenous antibiotic therapy at the time of enrollment.
21. Presence of a tracheo-esophageal fistula.
22. Any prior systemic anti-cancer therapy (including chemotherapy, monoclonal antibodies, tyrosine kinase inhibitors, EGFR inhibitors, VEGF inhibitors) for advanced (Stage IIIB/IV) or recurrent NSCLC. (Note: Adjuvant/neoadjuvant therapy completed ≥ 6 months prior to enrollment is allowed.)
23. Inability to swallow oral medications, malabsorption syndrome, or any condition significantly affecting gastrointestinal function that would impair the absorption of icotinib.
24. Presence of severe dry eye syndrome, severe keratitis, keratoconjunctivitis, or any other ocular surface condition that may increase the risk of epithelial damage. Use of contact lenses during the study is not recommended.
25. History of other active malignancies within 5 years prior to enrollment, except for adequately treated carcinoma in situ of the cervix, basal cell or squamous cell carcinoma of the skin, localized prostate cancer, or ductal carcinoma in situ of the breast treated with curative intent.
26. Any condition that may interfere with study results, compromise subject safety, or preclude full participation as judged by the investigator.