Study of Fruquintinib (HMPL-013) in High Risk Patients With Advanced NSCLC

• Signed informed consent
• Histologically or cytological documented stage IIIB/IV non-squamous non-small cell lung cancer patients
• Epidermal growth factor receptor (EGFR) mutation wild type; or EGFR activating mutation and resistant / intolerant to related targeted therapies
• Anaplastic lymphoma kinase (ALK) mutation negative; or ALK mutation positive and resistant / intolerant to related targeted therapies
• Presence of at least one measurable tumor lesion in accordance with RECIST 1.1 criteria
• Expected survival > 12 weeks
• Queue 1: 1) Age > 75 years 2) Disease progression during or within 3 months after first-line systemic chemotherapy; or intolerable toxicity / intolerance during first-line systemic chemotherapy (excluding immunotherapy); or without systemic chemotherapy (rejected or intolerable), judged by investigators 3) Eastern Cooperative Oncology Group (ECOG) of 0-1
• Queue 2: 1) Age 18-75 years old (including 18 and 75 years old) 2) Disease progression during or within 3 months after first-line systemic chemotherapy; or intolerable toxicity / intolerance during first-line systemic chemotherapy (excluding immunotherapy); or without systemic chemotherapy (rejected or intolerable), judged by investigators 3) Eastern Cooperative Oncology Group (ECOG) of 2
• Queue 3: 1) Age 18-75 years old (including 18 and 75 years old) 2) without systemic chemotherapy 3) Eastern Cooperative Oncology Group (ECOG) of 0-1
• Queue 4: 1) Age 18-75 years old (including 18 and 75 years old) 2) Disease progression during or within 3 months after at least three lines systemic chemotherapy; or intolerable toxicity / intolerance during at least third-line systemic chemotherapy (excluding immunotherapy) 3) Eastern Cooperative Oncology Group (ECOG) of 0-1

Exclusion Criteria:

• Patients who have participated in another clinical trial or received systemic anti-neoplastic chemotherapy, biotherapy or immunotherapy within 3 weeks prior to administration of the study drug; or received target drugs treatment as EGFR - Tyrosine Kinase Inhibitors (TKIs), ALK inhibitors, within in 2 weeks; or received anti-neoplastic traditional Chinese medicine within 1 week; or received pleural infusion chemotherapy within 1 week.
• Patients who have received palliative radiotherapy within 1 week prior to administration of the study drug; or received radical / extensive radiotherapy within 3 weeks; or received brachytherapy within 60 days (as seed implantation)
• Patients who have previously received therapy with VEGFR inhibitors
• Patients who have previously received potent inhibitor and/or potent inducer of cytochrome P450 3A4 (CYP3A4) within two 2 weeks prior to administration of the study drug; receiving P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrate drugs within two 2 weeks prior to randomization
• Patients who have previously received major surgery or large invasive procedure within 60 days prior to administration of the study drug, or incomplete recovery from previous surgery/procedure, or incomplete healing of surgical incision/wound; no recovery of the toxicity from previous antitumor therapies (i.e., CTCAE grade > 1) (if applicable)
• Patients with brain metastasis
• Patients with spinal compression with no surgical therapy and/or radical radiotherapy; or previously treated spinal compression, however, no clinical evidence showing stable condition
• Radiological evidence showing tumor invading or encompassing major blood vessels of lungs (e.g., pulmonary artery, superior vena cava)
• Patients with other primary malignancies within the past 5 years except basal cell carcinoma of skin or carcinoma in situ of cervix
• Patients with uncontrolled active infections, e.g. acute pneumonia
• Patients with active hepatitis B or active hepatitis C, etc. (for patients with a history of hepatitis B, whether treated or not, hepatitis B virus (HBV) DNA ≥500copies or ≥ 100IU / ml)
• Patients with human immunodeficiency virus (HIV) infection
• Patients with dysphagia or known drug malabsorption
• Patients active duodenal ulcer, ulcerative colitis, intestinal obstruction and other gastrointestinal diseases or other conditions that may lead to gastrointestinal bleeding or perforation according to the investigators' judgment; or with a history of intestinal perforation or intestinal fistula

• Patients fulfilling any of the following criteria shall be excluded:

  1. Absolute neutrophil count (ANC) \<1.5×109/L, platelet \<100×109/L or hemoglobin \<9 g/dL within 2 week prior to administration of the study drug
  2. Serum total bilirubin > 1.5 × upper limit of normal (ULN), alanine transaminase and aspartate aminotransferase >2.5×ULN (according to reference range in each clinical study site); ALT and AST > 5×ULN in patients with liver metastasis
  3. Clinically significant electrolyte abnormality
  4. Blood creatinine > ULN and creatinine clearance \<50 ml/min
  5. Urine protein 2+ or more, or urine protein quantification ≥1.0 g/24 h
  6. Activated partial thromboplastin time (APTT) or/and INR and prothrombin time (PT) > 1.5×ULN (according to reference range in each clinical study site)
• Patients with uncontrolled hypertension, systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg after symptomatic treatment
• Cardiac function: left ventricular ejection fraction \<50% (by echocardiography); moderate or above mitral or tricuspid insufficiency; acute myocardial infarction, serious/unstable angina pectoris or coronary artery bypass grafting within 6 months prior to randomization; or New York heart association (NYHA) grade 2 or above cardiac insufficiency
• Patients who have a history of arterial thrombosis or deep venous thrombosis within 6 months prior to administration of the study drug; history or evidence of thrombosis or bleeding tendency regardless of the severity within 2 months; history of hemoptysis (i.e. coughing blood in bright red color at least 2.5ml or 1/2 teaspoon) within 2 weeks; history of liver hemangioma > 3 cm
• Patients who have a history of stroke and/or transient ischemic attack within 12 months prior to administration of the study drug
• Patients with skin wound, surgical site, wound site, severe mucosal ulcer or fracture without complete healing
• Pregnant or lactating women, or women of child bearing potential with positive pregnancy test result before the first dose; Patients with child bearing potential who or whose sexual partners are not willing to take contraceptive measures
• Patients with any clinical or laboratory abnormalities unsuitable for participating in this clinical trial according to the investigator's judgment
• Patients with serious psychological or psychiatric disorders which may affect subject compliance in this clinical study
• Patients who are allergic to analogue of Fruquintinib and/or its inactive ingredients.