Anti-PD-1 Antibody Therapies of Camrelizumab in Combination With Pemetrexed and Carboplatin as First-line Treatment in Patients With Advanced or Metastatic Non-Squamous Non-Small Cell Lung Cancer

Inclusion Criteria:

1. Subject aged between 19-80 at the time of signing the informed consent form, male orfemale.
2. Histologically or cytologically confirmed non-squamous non-small cell lung cancer (NSCLC), Stage IIIB-IV (as per the International Association for the Study of LungCancer (IASLC) Staging Handbook in Thoracic Oncology, 8th Edition).
3. The site must provide documented information on EGFR mutation and ALK translocationand both must be negative. Subject cannot be randomized before receiving the sourcedocument for EGFR mutation and ALK translocation.
4. A tumor tissue specimen collected upon or after diagnosis of advanced or metastaticdisease, either fresh or archival (within 6 months prior to the first dose), must beprovided. At least 10 unstained slides can be generated from the formalin fixed,paraffin-embedded (FFPE) tumor tissue block for immunohistochemistry assay orbiomarker testing (or may be less than 10 slides as approved by the sponsor's medicalmonitor). Specimen obtained from fine needle aspiration, pleural fluid smear, or drillbiopsy are unacceptable. For bone lesions, specimen without soft tissue components ordecalcified bone tumor specimen is also unacceptable.
5. Subjects who have not previously received systemic chemotherapy foradvanced/metastatic NSCLC. Chemotherapy as neo-adjuvant/adjuvant therapy orchemoradiotherapy is permitted, as long as the treatment has been completed at least 12 months before the diagnosis of advanced or metastatic disease.
6. Radiographically measurable lesions via CT or MRI, as per RECIST 1.1. The tumorassessment of baseline should be performed within 28 days prior to the first dose.
7. ECOG PS score: 0-1.
8. Expected survival ≥ 3 months.
9. Subjects must undergo all screening laboratory tests as per the protocol within 14days prior to the first dose. Laboratory tests at screening must meet the followingcriteria:

1. Hematology: (without blood transfusion, G-CSF, or medication within 14 days prior toscreening)

1. Hemoglobin (HB) ≥ 90 g/L;
2. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L;
3. Platelet (PLT) ≥ 100 x 109/L;
4. White blood cell (WBC) ≥ 4.0 x 109/L and ≤ 15 x 109/L; 2) Biochemistry: (no blood oralbumin transfusion within 14 days prior to screening)
5. AST and ALT ≤ 1.5 x ULN (≤ 5 x ULN for liver metastasis);
6. ALP ≤ 2.5 x ULN (≤ 5 x ULN for bone metastasis);
7. TBIL ≤ 1.5 x ULN;
8. ALB ≥ 30 g/L;
9. Cr ≤ 1.5 x ULN, and creatinine clearance (CrCL) ≥ 60 mL/min (Cockcroft-Gaultequation);
10. APTT ≤ 1.5 x ULN, and INR or PT ≤ 1.5 x ULN (no anticoagulant therapy).
11. Female subjects of childbearing potential must have a negative serum pregnancytest within 3 days prior to the first dose. Female subjects of childbearing potentialand male subjects with partners of childbearing potential must agree to use adequatemethod of contraception during the study period and 180 days after the last dose ofstudy medication.
12. Subject has voluntarily agreed to participate by giving written informedconsent/assent.

Exclusion Criteria:

1. Exclusion criteria for the target indication
2. Subjects with other histological types besides non-squamous non-small cell lungcancer, including mixed carcinomas or NSCLC with small cell lung cancercomponents/neuroendocrine differentiation.
3. Subjects with EGFR mutation or ALK translocation.
4. Subjects without radiographically measurable lesions.
5. Subjects with carcinomatous meningitis and spinal cord compression.
6. Subjects with untreated central nervous system (CNS) metastasis. Subjects withpreviously treated CNS metastases may participate if the CNS metastasis islimited to the supraentorial and cerebellar regions, adequately treated, andclinically stable (by radiological tumor assessments, preferably enhanced MRI orCT) for at least 4 weeks, and if the subject's neurological symptoms can returnto NCI-CTCAE Grade ≤ 1 within 2 weeks prior to the first dose. In addition,subjects who are using corticosteroids for clinical symptoms are not eligible,unless the doses of corticosteroids stable or gradually reduced to prednisone ≤ 10 mg/day (or equivalent) -for at least 2 weeks.
7. Subjects who can be treated with surgical resection or radical radiotherapy.
8. Subjects who previously received treatment with any other anti-PD-1(L1) or CTLA4monoclonal antibodies.
9. Medical history and complications
10. Subjects with any active, known, or suspected autoimmune diseases. Subjects whoare clinically stable and do not require systemic immunosuppressants, such asthose with Type I diabetes, hypothyroidism requiring only hormone replacementtherapy, or skin diseases that do not require systemic treatment (for example,vitiligo, psoriasis or alopecia), or subjects in whom recurrence are not expectedwithout external triggers may be eligible.
11. Subjects with any complication that require systemic corticosteroids likeprednisone (> 10 mg/day or equivalent) or other immunosuppressants within 14 daysprior to the first dose. In the absence of active autoimmune disease, inhaled ortopical use of corticosteroids, and physiologic hormone replacement therapy foradrenal insufficiencylike prednisone > 10 mg/day or equivalent are permitted;
12. Subjects who received cancer vaccines or other immunostimulatory anti-canceragents (interferon, interleukin, thymosin, or immune cell therapy) within 1 monthprior to the first dose.
13. Subjects who are currently participating and receiving study therapy or hasparticipated in a study of an investigational agent and received study therapywithin 4 weeks (or 5 half-lives of the previous investigational agent) prior tothe first dose.
14. Subjects who are expected to require any other forms of anti-cancer treatment (including maintenance treatment with other drugs, radiotherapy, and/or surgicalresection) for NSCLC while on study.
15. Subjects who received major surgery within 4 weeks prior to the first dose,non-thoracic radiation therapy > 30 Gy within 4 weeks prior to the first dose,thoracic radiation therapy > 30 Gy within 24 weeks prior to the first dose, orpalliative radiation ≤ 30 Gy within 2 weeks prior to the first dose, and failedto recover from the toxicities and/or complications of these interventions toNCI-CTC AE Grade ≤ 1 (except for alopecia and fatigue). Palliative radiotherapyfor symptomatic control is permitted, but must be completed within 2 weeks priorto the first dose and no additional radiotherapy should be scheduled for the samelesion.
16. Subjects highly suspected of interstitial lung disease, or with conditions thatmay interfere with the testing or management of suspected treatment-relatedpulmonary toxicities, or other moderate to severe lung diseases that seriouslyaffect pulmonary function.
17. Subjects who require concomitant treatment for other active malignant tumors.
18. Subjects with a history of prior malignant tumors, except for basal cellcarcinoma, superficial bladder cancer, squamous cell carcinoma of the skin, orcervical carcinoma in situ with complete remission for at least 5 years prior toscreening and no additional treatment is required or expected while on study.
19. Subjects with Grade II or higher myocardial ischemia or myocardial infarction, orpoorly controlled arrhythmias. Subjects with NYHA Class III-IV cardiacinsufficiency or an LVEF (left ventricular ejection fraction) < 50% byechocardiography.
20. Subjects with significant hemoptysis or coughing a daily volume up to half ateaspoon (2.5 mL) or more of blood within 1 month prior to randomization.
21. Subjects with clinically significant hemorrhage or clear bleeding tendency within 1 month prior to randomization, such as GI bleeding, hemorrhagic gastric ulcer,or vasculitis.
22. Events of arterial/venous thrombosis within 3 months prior to randomization, suchas cerebrovascular accidents (including transient ischemic attacks, cerebralhemorrhage, brain infarction), deep vein thrombosis, and pulmonary embolism.
23. Subjects with active pulmonary tuberculosis (TB). Active TB should be ruled outin subjects suspected of such condition, by chest X-ray, sputum test, andexaminations of clinical symptoms and signs. Subjects with a history of active TBinfection within 1 year prior to the screening are excluded, despite beingtreated. Subjects with a history of active TB infection more than 1 year ago canbe enrolled if the course and type of TB treatment are appropriate.
24. Subjects with serious infection within 4 weeks prior to the first dose, includingbut not limited to infective complications, bacteremia and severe pneumonia thatrequire hospitalization. Subjects with any active infections are excluded,lymphangitic spread of the NSCLC is not exclusionary.
25. Subjects who prepare to receive or have previously received tissue/organtransplants.
26. Subjects who plan to receive or have received live vaccines within 30 days priorto the first dose.
27. Subjects with contraindications for platinum-based medications before the firstdose: gout, varicella, herpes zoster, and Grade ≥ 2 peripheral neuropathy.
28. It is not recommended to enroll subjects with uncontrolled tumor-related pain.Subjects requiring pain medication must have a stable regimen beforerandomization. Palliative radiotherapy for symptomatic lesions (such as bonemetastasis or perineural invasion) should be completed at least 2 weeks beforeenrollment. Loco-regional treatment should be considered before randomization, ifappropriate, for asymptomatic metastatic lesions where further growth may resultin functional deficits or intractable pain (e.g., epidural metastasis withoutspinal cord compression).
29. Physical examination and laboratory tests
30. Subjects have known history of human immunodeficiency virus (HIV) seropositivestatus or acquired immunodeficiency syndrome (AIDS).
31. Subjects with untreated active hepatitis. Hepatitis B: Hepatitis B surfaceantigen (HBV sAg) positive and HBV DNA greater than the upper limit of normal;Hepatitis C: HCV antibody (HCV Ab) positive and HCV RNA positive, and abnormalhepatic function; Hepatitis B and C coinfection.
32. Subjects with uncontrolled pleural effusion, pericardial effusion, or ascitesrequiring recurrent drainage procedures.
33. Allergies and adverse drug reactions
34. Severe allergic, anaphylactic, or other hypersensitivity reactions to othermonoclonal antibodies.
35. Allergy or intolerance during an infusion.
36. History of severe allergies to pemetrexed, carboplatin, or their premedications.
37. Subjects with mental illness, alcohol abuse, inability to quit smoking, and drug orsubstance abuse disorders that would interfere with cooperation with the requirementsof the trial.
38. Based on the investigator's opinion, subjects with a history or current evidence ofany condition, diseases, treatments, or laboratory abnormalities that may confound thestudy results, interfere with study procedures, or are not in the best interests ofthe subjects, should be excluded.