This is a double-blind Phase 3 clinical trial evaluating the efficacy and safety of TRS003 and paclitaxel-carboplatin versus China-approved bevacizumab and paclitaxel-carboplatin in patients with unresectable, locally advanced, or metastatic non-squamous non-small cell lung cancer (NSCLC). Approximately 608 patients will be enrolled in this study from America, Europe, and Asia. Patients who sign the informed consent and meet the inclusion criteria, will be randomized (1:1) to receive either TRS003 in combination with paclitaxel and carboplatin or China-approved bevacizumab in combination with paclitaxel and carboplatin for 4 to 6 cycles.

This is a randomized, double-blind, multinational, multicenter, active-control, parallel two-group Phase 3 clinical trial evaluating the efficacy and safety of TRS003 plus paclitaxel-carboplatin versus China-approved bevacizumab plus paclitaxel-carboplatin in patients with unresectable, locally advanced, recurrent or metastatic non-squamous NSCLC. Approximately 608 subjects will be enrolled into this study from America, Europe and Asia. Patients who sign the informed consent and meet the inclusion criteria will be randomized (1:1) to receive either TRS003 or China-approved bevacizumab in combination with paclitaxel-carboplatin for 4 to 6 cycles. Patients will be stratified by region (Asia, Europe and America), gender, and cigarette smoking habit (previous smoker, smoker and non-smoker).

Patients will receive either TRS003 (Arm A), or China-approved bevacizumab (Arm B) first followed by the administration of paclitaxel and carboplatin. TRS003 or China-approved bevacizumab will be administered at 15 mg/kg by intravenous (IV) infusion on Day 1 of each cycle (every 3 weeks, Q3W). Paclitaxel will be administered at a dose of 200 mg/m^2 by IV infusion (over 3 hours) Q3W on Day 1 of each cycle and carboplatin will be administered at an area under the plasma concentration-time curve (AUC) 6 mg/mL/ min (the maximum dose capped at 900 mg) by IV infusion (over 15 - 30 minutes) Q3W on Day 1 of each cycle. Each cycle is 3 weeks. Treatments will continue until disease progression, death, intolerable toxicity, withdrawal of consent, investigator decision, or completion of 4-6 cycles of therapy. Maintenance therapy may be given at the discretion of the patient's primary oncologist.

Efficacy will be evaluated by the investigator per RECIST v1.1 (Eisenhauer et al., 2009). Efficacy evaluation will be performed at baseline and every 6 weeks ± 7 days during the 4-6 cycle combination treatment periods. After completion of combination treatments, efficacy evaluations will be performed every 9 weeks ± 7 days (if patients received maintenance therapy). The analysis of Investigator-determined objective response rate (ORR) (RECIST v1.1) will be based on information obtained prior to Week 19. Investigator-determined duration of response (DOR) and progression-free survival (PFS) will also be evaluated according to RECIST v1.1. Data on overall survival (OS) will be collected. Central radiology review will not be required. However, for the purpose of quality control, the Sponsor may elect to have some or all tumor assessments to be reviewed by an independent imaging vendor.

Safety will be evaluated throughout the study. Adverse events will be recorded from the time of informed consent. Safety will be assessed based on periodically physical examination findings, vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, laboratory variables (hematology, coagulation tests, serum chemistries, urinalysis and pregnancy tests), and electrocardiogram (ECG) findings. Adverse events and laboratories will be graded according to National Cancer Institute (NCI) CTCAE v5.0.

Immunogenicity will be assessed in all patients who received at least one dose of TRS003 or China-approved bevacizumab. Samples will be assessed for the development of antidrug antibodies to either TRS003, or China-approved bevacizumab. Neutralizing antibodies (NAb) will assessed in samples that are antidrug antibody (ADA) positive. Trough pharmacokinetics (PK) samples will be collected and will be analyzed for interpretation of immunogenicity data and exploratory analysis when needed.

Inclusion Criteria :

1. Male or female ≥ 18 years.

2. Signed and dated informed consent form.

3. Willing and able to comply with all study procedures.

4. Histologically or cytologically confirmed unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC; if the tumor shows multiple histologies, the main cellular phenotype will be used. Must provide archived tumor tissue obtained within 3 years for epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) testing. If archival tissue meeting this requirement is not available, patients will undergo biopsy to be eligible for study entry.

5. No previous systemic therapy targeting the primary tumor or sites of metastases. Adjuvant therapy should be completed at least 6 months prior to study entry. Patients may have received radiation therapy if this was completed at least 1 month prior to entry and if other sites of measurable disease (per RECIST v11) are present.

6. At least one measurable lesion per RECIST v1.1.

7. ECOG performance status score 0 or 1.

8. Life expectancy ≥ 6months.

9. Adequate hepatic function as evidence by meeting all the following requirements:

   1. Total bilirubin ≤ 1.5 × upper limit of normal (ULN).
   2. Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 3×ULN or ALT ≤ 5 × ULN if liver metastases are present.

10. Adequate renal function as evidence by meeting all the following requirements:

    1. Serum creatinine ≤ 1.5 × ULN and calculated creatinine clearance (CrCL) > 50 mL/min (Cockroft-Gault Equation) or estimated glomerular filtration rate (GFR) > 50 mL/min.
    2. Urine dipstick for proteinuria < 2+. If urine dipstick is greater than or equal to 2+, proteinuria must be less than 2 g in 24 hours or the urine protein/creatinine ratio < 2.

11. Hematological function defined as:

    1. Platelet count ≥ 100,000/μl without transfusion within 2 weeks prior to the study screening.
    2. Prothrombin time, international normalized ratio or activated partial thromboplastin time < 1.5 × ULN.
    3. Absolute neutrophil count ≥ 1,500/μl without any medical interventional treatment within two weeks prior to the study screening (ie, granulocyte-colony stimulating factors and/or herbal remedies).
    4. Hemoglobin (Hb) ≥ 9 g/dl without the need for transfusion within 2 weeks prior to the study screening.

Exclusion Criteria ：

1. Known sensitizing EGFR mutations or ALK rearrangements.
2. Squamous lung cancer, mixed small cell and non-small cell lung cancer or squamous cell-dominant adeno-squamous lung cancer.
3. Tumor cavitation, invading into large blood vessels or close to large vessels (such as pulmonary artery or Superior vena cava.
4. Significant thrombotic or hemorrhagic events within 6 months prior to the study screening e.g., hemoptysis > 2.5 mL of red blood, gastrointestinal bleeding, hematemesis, central nervous system hemorrhage, severe epistaxis or vaginal bleeding, etc.
5. Severe cardiovascular disease, including cerebrovascular accident (CVA), transient ischemic attack (TIA), myocardial infarction and significant vascular disease (including but not limited to aneurysm requiring surgical repair or recent artery thrombosis); unstable angina pectoris, New York Heart Association (NYHA) class III or IV heart failure and uncontrollable arrhythmia within 6 months prior to entry.
6. History of active gastroduodenal ulcer, abdominal fistula as well as non-gastrointestinal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to the study screening.
7. Central nervous system (CNS) metastases; Subjects with asymptomatic CNS metastases who are neurologically stable ≥ 4 weeks following CNS-directed therapy with no evidence of CNS disease progression ≥ 4 weeks, and on a stable or decreasing dose of corticosteroids may be eligible and should be discussed with the Medical Monitor.
8. Concurrent malignancy within 5 years other than adequately treated primary cervical cancer, skin-squamous or basal cell carcinomas, prostatic cancer following radical resection that does not require therapy, prostate cancer treated with active surveillance, ductal carcinoma in situ of the breast, or < T1 urothelial carcinoma.
9. Uncontrolled hypertension (systolic blood pressure >150 mmHg and diastolic blood pressure >100 mmHg at the study screening), or a history of hypertension crisis or hypertensive encephalophy.
10. Active hepatitis B or hepatitis C virus. Patients with evidence of infection with hepatitis B who have an undetectable viral load are eligible for study entry. Patients with evidence of infection with hepatitis C should have completed curative therapy.
11. Known to be positive for human immunodeficiency virus (HIV) and with an AIDS defining opportunistic infection within 12 months of study entry or a CD4 T cell count < 359 cells/μL.
12. Full dose anticoagulants, including oral or parenteral; Low dose anti-coagulation (not intended to achieve a therapeutic INR) for port patency is permitted. No Factor Xa inhibitors. No aspirin or other nonsteroidal anti-inflammatory drugs that can inhibit platelet within ten days prior to screening. No history of hemorrhagic or thrombotic disorders (e.g., hemophilia, protein C deficiency).
13. Thoracic radiotherapy within 4 weeks prior to screening or palliative radiotherapy for metastasis outside thoracic region within 2 weeks prior to screening.
14. Any major surgical procedure within 28 days prior to screening or anticipated elective surgery during the study. Any minor surgery such as deep vein catheterization within 48 hours prior to the first dose of the study drugs.
15. Evidence of pericardial or pleural effusion or ascites that requires intervention.
16. Treatment history of monoclonal antibodies or small molecule inhibitors against vascular endothelial growth factor (VEGF) or its receptor (VEGFR), including bevacizumab.
17. Clinically uncontrolled active infection requiring systemic therapy within 2 weeks prior to entry.
18. Subject has known sensitivity to any of the products to be administered during the study, including mammalian cell derived drug products.
19. Participation in any other clinical trial within 4 weeks prior to screening. Recipient of any anticancer therapy (other than hormones used to treat breast cancer) within 4 weeks prior to screening.
20. Women of childbearing potential who are pregnant or is breast feeding or who do not consent to use highly effective methods of birth control during treatment and for an additional 120 days after the last administration of the protocol specified treatment.
21. Men with a partner of childbearing potential who does not consent to use highly effective methods of birth control during treatment and for an additional 120 days after the last administration of the protocol specified treatment.
22. Any condition that the Investigator or primary physician believes may not be appropriate for participating the study.