This is an open label, multi-center, randomized control phase II trial, to compare the
efficacy and safety of sintilimab combined with anlotinib versus standard platinum-based
chemotherapy as a first-line treatment in advanced NSCLC patients without driven-gene
This is an open label, multi-center, randomized control study comparing the combination of
sintilimab and anlotinib with standard platinum-based chemotherapy in treat-naïve advanced
(unresectable stage IIIB, IIIC and IV patients without driven-gene mutations) NSCLC patients.
Eligible subjects are 1:1 randomized into the experimental group (sintilimab combined with
anlotinib) or the control group (standard platinum-based chemotherapy).
1. Signed written informed consent before initiation of any study procedures
2. Age ≥ 18 years and ≤ 75 years
3. Histologically or cytologically confirmed NSCLC, with unresectable local advanced or
metastatic disease (stage IIIB-IV according to NSCLC staging version 8)
4. Epidermal Growth Factor Receptor (EGFR)/ Anaplastic Lymphoma Kinase (ALK) wild type
non-small cell lung cancer
5. Sufficient qualified tumor tissue or Paraffin-embedded slides are provided to detect
the expression of PD-L1 (TPS, 22C3 antibody).
6. At least 1 measurable disease according toRECIST 1.1
7. None previous chemotherapy or targeted therapy. Adjuvant chemotherapy, neoadjuvant
chemotherapy or neoadjuvant chemotherapy plus adjuvant were assessed for eligibility,
and the last treatment time must be more than 6 months before enrollment
8. Expected survival over 3 months
9. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
10. Brain metastasis patients with no symptoms or stable symptoms after local treatment
are eligible, provided they meet all of the following conditions:
1) measurable lesions outside the central nervous system 2) no central nervous system
symptoms or no aggravation of symptoms for at least 2 weeks 3) patients who did not require
glucocorticoid therapy or who discontinued glucocorticoid therapy within 3 days before the
first study drug administration 11. Patients are allowed to receive palliative radiotherapy
(including craniocerebral radiotherapy for symptomatic brain metastases) at least 1 week
prior to enrollment and return to less than or equal to 1 degree of radiosurgery toxicity
(CTCAE 5.0, excluding alopecia).
12. Adequate hematologic and organ function defined by the following laboratory results
obtained within 14 days prior to randomization: 13. For female patients of childbearing
age, a urine or serum pregnancy test should be administered within 3 days prior to the
first study drug administration (day 1 of cycle 1) and results should be negative. If a
urine pregnancy test does not confirm a negative result, a blood pregnancy test is
required. Non-childbearing female were defined as those who had been postmenopausal for at
least 1 year or who had undergone surgical sterilization or hysterectomy.
14. If pregnancy is potential, all patients (male and female) are required to use
contraception with an annual failure rate of less than 1% for the entire treatment period
up to 120 days after the last study drug administration (or 180 days after the last
chemotherapy drug administration).
1. Squamous cell carcinoma (including adenosquamous carcinoma); Small cell lung cancer
(including small cell cancer and non-small cell mixed lung cancer).
2. Patients with cavernous squamous cell carcinoma or imaging suggesting
infiltration/invasion of large blood vessels or other high bleeding risk factors
evaluated by the investigators.
3. Active hemoptysis within 2 weeks before first drug administration (at least 1/2
teaspoon blood spilt at one time);
4. Received radiotherapy before administration of the first study drug, which met one of
the following conditions:
1) ≥30% of bone marrow had received radiotherapy within 14 days before treatment 2)
received radiotherapy for lung lesions within 6 weeks before treatment with >30Gy dose
(enrolled subjects must recover from the toxicity of previous radiotherapy to level 1 or
below, do not need glucocorticoid treatment and have no history of radiation pneumonia) 3)
the end time of palliative radiotherapy should be within 7 days before the first study drug
administration 5. Major surgical treatment within 3 weeks of the first study drug
administration (except for biopsy surgery) 6. Have Participated in other clinical studies
or less than 4 weeks before the end of treatment in the previous clinical study 7.
Previously diagnosis as other malignant tumors within 5 years prior to the first dose of
study treatment, with the exception of: skin basal cell carcinoma or squamous cell
carcinoma with radical treatment, and/or carcinoma in situ underwent radical resection 8.
Prior treatment with PD-1 inhibitor, PD-L1 inhibitor, CTLA4 inhibitor, or anti- angiogenic
9. A history of active autoimmune disease requiring systemic treatment (e.g. using drugs
for disease remission, corticosteroids or immunosuppressor) within 2 years prior to the
first dose of study treatment. Substitution therapy (e.g. thyroxine, insulin or
physiological corticosteroids for treating adrenal or pituitary dysfunction) is not
considered as a systemic treatment.
10. Received a traditional Chinese medicine with anti-tumor effect, or an immunomodulatory
drug (thymosin, interferon, interleukin) within 2 weeks before the first dose, or received
major surgery within 3 weeks before the first dose 11. Systemic steroid therapy or any
other form of immunosuppressive therapy performed within 7 days prior to the first dose of
study (physiologic dose is allowed).
12. The presence of clinically uncontrollable pleural effusion/peritoneal effusion 13. Have
received a physical organ or blood system transplant 14. allergic to the active ingredients
or excipients of the drugs studied, such as sintilimab, pemetrexed, gemcitabine,
carboplatin, cisplatin, etc.
15. Patients with multiple factors that affect oral medications (such as inability to
swallow, gastrointestinal resection, chronic diarrhea, and intestinal obstruction) 16.
Patients with bleeding tendencies (such as active gastrointestinal ulcers) or treated with
anticoagulants or vitamin K antagonists such as warfarin, heparin or their analogues; Small
doses of warfarin (≤1mg/d), small doses of heparin (≤ 12,000 U/d) or small doses of aspirin
(≤100mg/d) are allowed for prophylactic purposes, provided that the international
standardized ratio of prothrombin time (INR) ≤1.5 17. Patients with severe arteriovenous
thrombosis, such as cerebrovascular accident (including temporary ischemic attack), deep
vein thrombosis and pulmonary embolism, which occurred within 6 months before the first
treatment 18. Not fully recovered from toxicity and/or complications resulting from any
intervention prior to initiation of treatment (i.e., ≤1 or baseline, excluding fatigue or
hair loss); 19. A history of human immunodeficiency virus (HIV) infection (ie, HIV 1/2
antibody positive) is known.
20. Untreated active hepatitis B; 21. Active HCV-infected subjects (HCV antibody positive
and HCV-RNA levels above the lower limit of detection) 22. Vaccination of live vaccine
within 30 days before the first dose (1st cycle, 1st day); 23. Pregnant or lactating women
24. Any serious or uncontrolled systemic diseases 25. Any medical history or evidence of
disease that may interfere with the outcome of the study, or other conditions that the
investigator considers inappropriate for the study.