Overview

Objective to compare the efficacy and safety of TQB2450 injection combined with anlotinib and chemotherapy, and TQB2450 injection combined with chemotherapy in the treatment of advanced non-small cell lung cancer subjects who failed to receive first-line chemotherapy combined with immunization, and to explore and evaluate biomarkers related to efficacy, mechanism of action / resistance mechanism, and safety.

Eligibility

Inclusion Criteria:

1. According to the International Association for the Study of Lung Cancer and the Joint Committee on the American Classification of Cancer, 8th edition TNM staging of lung cancer, patients with locally advanced (stage IIIB/IIIC), metastatic or recurrent (stage IV) NSCLC who are histologically proven to be inoperable and unable to undergo radical synchronous radiotherapy and chemotherapy.
2. 18 years old ≤ age ≤ 75 years old; No gender limit; ECOG score 0-1 points; The expected survival period is ≥ 3 months.
3. According to RECIST 1.1 standard, there should be at least one measurable lesion.
4. Tumor resistance has progressed after receiving first-line treatment with immune checkpoint inhibitors (including PD-1 or PD-L1 monoclonal or dual antibodies) combined with platinum based drugs in the past. For neoadjuvant/adjuvant chemotherapy or radiotherapy or concurrent radiotherapy and chemotherapy, if the disease progresses during treatment or within 6 months after discontinuation of treatment, it should be considered as a first-line treatment plan.
5. It is necessary to provide tumor tissue sections that have been diagnosed with advanced or metastatic NSCLC and have not undergone radiotherapy (at least 5 samples are required for PD-L1 testing of tumor tissue, but if testing has been conducted before the first line treatment, recognized test results from each participating center can be accepted.) Tumor tissue samples must be archived samples or freshly obtained samples within the first 12 months of randomization.
6. Except for patients with squamous NSCLC, enrolled patients need to demonstrate the absence of EGFR gene sensitive mutations, ALK fusion oncogenes, or ROS1 fusion oncogenes. If it is adenosquamous cell carcinoma, stratification needs to be determined based on the dominant tissue composition.
7. Good function of main organs
8. Women of childbearing age should agree to use effective contraceptive measures during the study period and within 6 months after the end of the study. Serum pregnancy or urine pregnancy tests should be negative within 7 days before enrollment in the study; Men should agree to use effective contraceptive measures during the study period and within 6 months after the end of the study period.
9. The subjects voluntarily joined this study, signed an informed consent form, and had good compliance.

   Exclusion Criteria:

   1. Tumor diseases and medical history:
      1. If there is a central nervous system metastasis before enrollment, enrollment can be made if all the following criteria are met: i. Previously received brain metastasis treatment and met all of the following criteria:

                  ① Only supratentorial and cerebellar metastases are allowed (i.e. transfer to the
                  midbrain, pons, medulla, or spinal cord is not allowed);
                  ② No imaging evidence of new or enlarged brain metastases was found;
                  ③ There are no symptoms of brain metastasis, and the subject must have stopped
                  using corticosteroids/dehydrating agents for at least 2 weeks before starting to
                  use the investigational drug.
                  Ii. Has not received brain metastasis treatment in the past and meets all of the
                  following criteria:
                    -  No more than 3 metastatic lesions; ② The total length and diameter of all
                       lesions ≤ 1.5cm;
                         -  There are no neurological symptoms caused by brain tissue compression;
                            ④ Before starting to use the investigational drug, the subject must
                            have stopped using corticosteroids/dehydrating agents for at least 2
                            weeks.
                            b) There were no active malignant tumors for ≤ 2 years before
                            randomization. c) Central type squamous cell carcinoma with a cavity
                            (primary in the main bronchus and around the hilum of the lungs).
                            d) Imaging shows that the tumor invades large blood vessels, or the
                            boundary between the tumor and the blood vessels is unclear, or the
                            researcher determines that the tumor is highly likely to invade
                            important blood vessels and cause fatal massive bleeding during
                            subsequent studies.
                            e) (1) Severe bone damage caused by tumor bone metastasis, including
                            pathological fractures of load-bearing bones (such as spinal vertebrae,
                            pelvis, femur, tibia, phalanges, calcaneus, etc.) and spinal cord
                            compression that occur within 6 months; (2) Imaging examination
                            suggests the presence of three or more multiple bone metastases in the
                            load-bearing bone.
                            f) Patients with serous cavity (pleural, abdominal, or pericardial)
                            effusion that requires repeated drainage to alleviate clinical symptoms
                            (as determined by the researcher), or those who have received serous
                            cavity effusion drainage for treatment purposes within 2 weeks prior to
                            treatment.
               2. Previous anti-tumor treatment:
                    1. Within 2 weeks before the start of the study treatment, he received
                       traditional Chinese patent medicines and simple preparations with anti-tumor
                       indications specified in the NMPA approved drug instructions.
                    2. I have previously used anti angiogenic drug systems such as arotinib,
                       apatinib, lenvatinib, sorafenib, sunitinib, regofinib, and furoquitinib to
                       treat locally advanced or metastatic NSCLC.
                    3. Previously received docetaxel for systematic treatment of locally advanced
                       or metastatic NSCLC.
                    4. Unacceptable toxicity after previous anti PD - (L) 1 treatment.
                    5. Patients who have received medication with immunomodulatory effects within
                       30 days before starting treatment.
                    6. Before randomization, there are any symptoms that require systemic treatment
                       with corticosteroids (prednisone or equivalent doses of similar drugs above
                       10 mg/d) or other immunosuppressive agents for ≤ 14 days.
                    7. Failure to recover from toxicity and/or complications of previous
                       intervention measures to CTCAE ≤ 1 level, except for peripheral neuropathy
                       with hair loss and ≤ 2 level.
               3. Concomitant diseases and medical history:
                  a) Decompensated cirrhosis (Child Pugh liver function rating B or C), active
                  hepatitis, and active COVID-19 infection.
                  b) Renal abnormalities: i. Renal failure requires hemodialysis or peritoneal
                  dialysis; Ii. Previous or existing nephrotic syndrome (excluding cured), chronic
                  nephritis.
                  c) Cardiovascular and cerebrovascular abnormalities: d) Gastrointestinal
                  abnormalities: i. Inability to take medication orally; Ii. History of
                  malabsorption syndrome or other diseases that can interfere with gastrointestinal
                  absorption, including a history of partial surgical removal of the stomach or
                  intestines (excluding appendectomy); Iii. Received treatment for active
                  gastrointestinal ulcers within the past 6 months.
                  e) History of Immunodeficiency: i. Having a history of immunodeficiency,
                  including HIV positive or suffering from other acquired or congenital
                  immunodeficiency diseases; Ii. A history of active autoimmune diseases or
                  autoimmune diseases, including but not limited to Crohn's disease, ulcerative
                  colitis, autoimmune hepatitis/enteritis/vasculitis/nephritis, etc; Iii. Prepare
                  to undergo or have previously received organ transplantation; f) Bleeding risk:
                  i. Suffering from bleeding, coagulation disorders, or using warfarin, aspirin,
                  and other antiplatelet agglutination drugs within 28 days prior to the start of
                  treatment (excluding preventive medication with aspirin ≤ 100 mg/d); Ii. Have a
                  history of hemoptysis within 28 days before the start of treatment; Iii.
                  Regardless of the severity, patients with congenital bleeding or coagulation
                  disorders, or those who are currently using anticoagulants for treatment; Iv.
                  Major surgical treatment or obvious traumatic injury received within 28 days
                  prior to the start of the study treatment; v. Long term uncured wounds or
                  fractures, excluding pathological fractures. g) Type I diabetes or II diabetes is
                  poorly controlled. h) Having experienced severe infection of level 4 or higher
                  within one year prior to the start of the study treatment; Subjects with 2-3
                  levels of active infection within 2 weeks prior to the start of study treatment;
                  Treponema pallidum antibody (TP Ab) positive; Or those who experience unexplained
                  fever of>38.0 ℃ during the screening period or before the first administration,
                  or who require medical intervention.
                  i) Previous or existing pneumoconiosis, interstitial pneumonia, non infectious
                  pneumonia requiring corticosteroid treatment, currently suffering from grade 2 or
                  other types of pneumonia, or objective evidence of severe impairment of lung
                  function confirmed by pulmonary function examination (FEV1 or DLCO or DLCO/VA
                  accounting for% of expected value<40%).
                  j) Patients with active tuberculosis within one year prior to enrollment. k)
                  Allergic constitution, or a history of severe allergies, or severe
                  hypersensitivity reactions after receiving other monoclonal antibody treatments,
                  or known allergies to the study drug excipients, or allergies to Tween 80.
                  l) Previous history of severe mental disorders. m) Individuals with a history of
                  drug abuse, alcohol or drug abuse.
               4. The end of previous clinical studies (last administration) is less than 4 weeks
                  or the 5 half-lives of the study drug, whichever is shorter.
               5. Vaccination history within the first 28 days of randomization or vaccination
                  during the planned study period.
               6. Pregnant or lactating female patients.
               7. According to the researcher's viewpoint, it may increase the risk associated with
                  participating in the study, or other reasons may make it unsuitable to
                  participate in this clinical study.