Tislelizumab Combined With Chemotherapy With or Without Bevacizumab in TKI-Resistant EGFR-Mutated Non-squamous NSCLC

Inclusion Criteria:

1. Histologically or cytologically confirmed, locally advanced (Stage IIIB/C) not amenable to curative surgery or radiotherapy, or metastatic (Stage IV) non-squamous NSCLC according to American Joint Committee on Cancer, 8th Edition.
2. Documentation of tumor EGFR sensitizing mutation before EGFR TKI treatment, including 19del, L858R, G719X, S786I and L861Q.
3. Disease progression after treatment with an EGFR TKI therapy: 1) Patients previously treated with 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib/icotinib) are required to provide specimens after PD to confirmed absence of EGFR T790M mutation; 2) Patients with confirmed acquired T790M mutation after 1st or 2nd generation EGFR TKI (e.g. erlotinib/afatinib/gefitinib/icotinib) are required to have 3rd generation EGFR TKI (e.g. osimertinib) treatment failure prior to enrollment; 3) Patients previously failed from 3rd generation EGFR TKI (e.g. osimertinib) treatment as 1st line therapy are eligible regardless of their EGFR T790M mutation status.
4. ECOG (Eastern Cooperative Oncology Group) performance status ≤ 1.
5. Life expectancy ≥ 3 months.
6. Adequate organ function
7. Able to provide written informed consent by the patient or by the patient's legally acceptable representative and can understand and agree to comply with the requirements of the study.
8. 18 to 75 years old on the day of signing the ICF (Informed Consent Form).

Exclusion Criteria:

1. Received prior therapies targeting PD-1, PD-L1, CTLA-4 or other immune checkpoints.
2. Received prior platinum-based chemotherapy for advanced disease.
3. Patients who have received prior systemic anti-vascular therapy (e.g., bevacizumab and small molecule VEGFR inhibitors) for advanced disease (Cohort 2)
4. Received EGFR TKI treatment within 2 weeks
5. Treatment with any approved systemic anti-cancer therapy or systemic immune-stimulatory agents (including but not limited to interferons, interleukin IL-2, and tumor necrosis factor) within 28 days prior to initiation of study treatment.
6. Clinically uncontrolled pleural effusion or ascites that requires pleurocentesis or abdominal tapping for drainage within 2 weeks prior to initiation of study treatment.
7. Active leptomeningeal disease or uncontrolled brain metastasis.
8. History of allergic reactions to any study drugs.
9. CrCl \< 45 mL/min
10. Patients with active viral hepatitis that requires treatment.
11. Active autoimmune diseases that requires treatment and may affect study treatment estimated by investigator.
12. Any condition that required systemic treatment with either corticosteroids or any other immunosuppressive medication that may affect study treatment estimated by investigator.
13. Severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy.
14. History of hemoptysis, i.e., coughing up at least one-half teaspoon of fresh blood, within 3 months prior to enrollment. (Cohort 2)
15. Imaging shows tumor invasion of a large vessel (e.g., pulmonary artery or superior vena cava) that the investigator determines is at risk for bleeding. (Cohort 2)
16. Had minor surgical procedures, such as tube placement, within 48 hours prior to first bevacizumab treatment. (Cohort 2)
17. Recently treated with a full dose oral or parenteral anticoagulant or thrombolytic agent. Prophylactic using anticoagulants is allowed. (Cohort 2)
18. History or test results indicating an inherited bleeding tendency or coagulation disorder that may increase the risk of bleeding (cohort 2)
19. uncontrolled hypertension (systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg) (cohort 2)
20. Clinically meaningful (e.g., active) cardiovascular disease that, in the judgment of the investigator, is intolerant to bevacizumab therapy (cohort 2)
21. Non-cured wound, peptic ulcer in active phase, or fracture (cohort 2)
22. History of abdominal fistula, gastrointestinal perforation, intra-abdominal abscess or thrombotic disease within 6 months judged by the investigator to be intolerant to bevacizumab treatment (Cohort 2)
23. With a history of interstitial lung disease, non-infectious pneumonitis, or uncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis, acute lung diseases, etc.
24. Have known human immunodeficiency virus (HIV) infection.
25. Any major surgical procedure requiring general anesthesia ≤ 28 days before initiation of study treatment.
26. Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that would be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs (Adverse Events) or result in insufficient or might impair compliance with study conduct.
27. Concurrent participation in another clinical study.
28. Pregnant or lactating women, or male and female patients who plan to have children during the study period. -