Pembrolizumab Plus Bevacizumab and Chemotherapy for Non-Squamous NSCLC Patients

Inclusion Criteria: According to the 8th edition of the AJCC/UICC TNM staging system for NSCLC, patients with locally advanced (stage III B/III C), metastatic or recurrent (stage IV) nonsquamous NSCLC confirmed by histology or cytology who are unable to undergo surgery and radical concomitant radiochemotherapy and are confirmed to have at least one measurable lesion according to RECIST 1.1. Patients harboring exon 20 insertions detected by ARMS or NGS or other approved methods. Age ≥18 years and ≤75 years. ECOG PS score: 0 to 1 Have a life expectancy of at least 3 months. Have not received prior systemic treatment including chemotherapy, checkpoint inhibitors, TKIs, and anti-angiogenesis agents for their advanced/metastatic NSCLC. Subjects who received adjuvant or neoadjuvant therapy including immunotherapy are eligible if the adjuvant/neoadjuvant therapy was completed at least 12 months prior to the development of advanced/metastatic disease. Palliative radiotherapy must be completed 7 days before the first dose of study drugs and participants must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis. Have adequate organ function as defined in the following： (1) Adequate bone marrow function Absolute neutrophil count(ANC) ≥ 1500/uL; Platelets≥10x104/uL; Hemoglobin ≥9.0g/dL or ≥5.6 mmol/L; (2) Adequate kidney function Creatinine≤ 1.5 x upper normal limit (ULN), OR Measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≥30 mL/min for the participant with creatinine levels >1.5 × institutional ULN (3) Adequate liver function Total bilirubin ≤ 1.5 x upper normal limit (ULN) OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN; Aspartate Aminotransferase (AST) (SGOT) ≤ 2.5 xULN (≤ 5.0 x ULN if hepatic metastases); Alanine Aminotransferase (ALT) (SGPT) ≤ 2.5 x ULN (≤ 5.0x ULN if hepatic metastases); (4) Coagulation function International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless the participant is receiving anticoagulant therapy as long as PT or aPTT is within the therapeutic range of intended use of anticoagulants. A male participant must agree to use contraception during the treatment period and plus an additional 90 days (a spermatogenesis cycle) for study treatments after the last dose of study treatment and refrain from donating sperm during this period; A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: a. Not a woman of childbearing potential (WOCBP) as defined in Appendix 3 OR b. A WOCBP who agrees to follow the contraceptive guidance in Appendix 3 during the treatment period and plus 30 days (a menstruation cycle) for study treatments after the last dose of study treatment. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial. Archival tumor tissue sample or newly obtained [core, incisional, or excisional] biopsy of a tumor lesion not previously irradiated has been provided. Formalin-fixed, paraffin-embedded (FFPE) tissue blocks are preferred to slides. Newly obtained biopsies are preferred to archived tissue. For hepatitis B-positive subjects: (1) Participants who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have an undetectable HBV viral load prior to enrollment. (2) Participants should remain on anti-viral therapy throughout the study intervention and follow local guidelines for HBV anti-viral therapy post-completion of the study intervention. (3) Participants with a history of HCV infection are eligible if HCV viral load is undetectable at screening. (4) Participants must have completed curative anti-viral therapy at least 4 weeks prior to enrollment. Exclusion Criteria: Small cell lung cancer (including mixed small cell and non-small cell lung cancer); Patients who have received systemic treatment for advanced/metastatic disease especially have received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g, CTLA-4, OX 40, CD137); Patients concurrently with 19del or 21L858R or other mutation types located in exon 18-21 Patients who are known to have active brain metastases diagnosed by CT or MRI at the time of screening, however, participants with previously treated brain metastases may participate provided they are radiologically stable, i.e. without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without the requirement of steroid treatment for at least 14 days prior to the first dose of the study intervention.; Patients with severe and/or uncontrolled diseases, such as: (1) Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction within 6 months before randomization, severe uncontrolled arrhythmias; uncontrolled blood pressure (systolic blood pressure > 140 mmHg, diastolic blood pressure > 90 mmHg); (2) Active or uncontrolled serious infection; (3) Liver diseases such as cirrhosis, decompensated liver disease, acute or chronic active hepatitis; (4) Not completely controlled eye inflammation or eye infection, or any condition that may lead to the above-mentioned ocular diseases (5) Poorly controlled diabetes (fasting blood glucose (FBG) > 10mmol/L); (6) Routine urine test result indicates that urine protein ≥++, and 24-hour urine protein quantitation is confirmed to be > 1.0 g; (7) Active tuberculosis, etc.; (8) Uncontrolled hypercalcemia (> 1.5 mmol/L calcium ion or calcium > 12 mg/dL or corrected serum calcium > ULN), or symptomatic hypercalcemia requiring continued diphosphate therapy; (9) Long-term unhealed wounds or fractures; 6. Patients who have a history of psychotropic drug abuse and cannot abstain from it or have mental disorders; 7. Patients who are known to have severe allergies (≥ grade 3) to active ingredients and any excipients of pembrolizumab 8. Patients who have other malignant tumors (except radical cervical carcinoma in situ, non-melanoma skin cancer, etc.) at the same time; patients who are evaluated by the investigator to have concomitant diseases that seriously endanger the safety of the patients or affect the patients completing the study. 9. The subjects or their sexual partners cannot or refuse to take effective contraceptive measures during the clinical trial 10. Pregnant or breast-feeding women 11. Patients in other situations who are evaluated by the investigator to be ineligible to be enrolled; 12. Has received a live vaccine or live-attenuated vaccine within 30 days before the first dose of the study intervention. Administration of killed vaccines is allowed (such as COVID-19 vaccines). 13. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study drug. 14. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with the use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. 15. Has a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis/interstitial lung disease. 16. Has a known history of Human Immunodeficiency Virus (HIV) infection. 17. Has a history or current evidence of any condition, therapy, laboratory abnormality, or other circumstance that might confound the results of the study, interfere with the participant's participation for the full duration of the study, such that it is not in the best interest of the participant to participate, in the opinion of the treating investigator. 18. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 19. Has had an allogeneic tissue/solid organ transplant. 20. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks prior to administration of pembrolizumab. 21. Patients who have contraindications of antiangiogenic therapy, including the presence of cavities, and bleeding tendencies judged by the treating physician.