A Phase III Clinical Trial of Fruquintinib in Patients With Advanced Non-small Cell Lung Cancer

Inclusion Criteria:

1. Fully understand the study and sign the informed consent form voluntarily;
2. Histologically or cytologically diagnosed with local advanced and/or metastatic stage IIIB/IV non-squamous NSCLC;
3. Disease progressed or developed non-tolerable toxicity after 2 lines of systemic chemotherapy (not including TKI therapy); Notes: a. The first-line chemotherapy should be platinum-based doublets regimens; b. For each line of systemic therapy, at least one treatment cycle should be completed, and maintenance therapy using one of the doublets is considered as the same line of therapy; c. Previous adjuvant/neoadjuvant therapy is allowed. If disease progressed during the adjuvant/neoadjuvant therapy period or within 1 year after completion of the above treatment, it is considered that patient failed the first-line systemic chemotherapy;
4. Patients with EGFR genetic test negative; or positive with EGFR, test result but resistant or intolerable to related targeted therapies;
5. Patients with ALK test negative; or positive with ALK test result but resistant or intolerable to related targeted therapies;
6. Aged 18-75 years (inclusive);
7. Measurable disease (according to RECIST1.1);
8. ECOG Performance Status score 0-1;
9. Life expectancy \>12 weeks.

Exclusion Criteria:

1. Patients who have participated in another clinical trial or received systemic anti-neoplastic therapy, radiotherapy or biotherapy within 3 weeks prior to administration of the study drug; or received EGFR-TKI treatment in the past 1 week.
2. Patients who have previously received therapy with VEGFR inhibitors;
3. Patients who have not recovered from toxicity caused by previous anti-neoplastic treatment (CTCAE \> grade 1), or not completely recovered from previous surgery;
4. Patient with active brain metastasis (untreated with proper radiation therapy, showing clinical symptoms or symptom stable time less than 4 weeks, or indicated for symptomatic treatment for brain metastasis, etc.);
5. Patients with other primary malignancies within the past 5 years except basal cell carcinoma of skin or carcinoma in situ of cervix;
6. Patients with uncontrolled active infections, e.g. acute pneumonia, active hepatitis B or active hepatitis C, etc. (for patients with a history of hepatitis B, whether treated or not, HBV DNA ≥500copies or ≥ 100IU / ml);
7. Patients with dysphagia or known drug malabsorption;
8. 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;
9. 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 1 week prior to enrollment;

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 \<60 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);

10\. Patients with uncontrolled hypertension, systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mmHg after symptomatic treatment;

11\. Patients with left ventricular ejection fraction \<50% (echocardiography) in heart function evaluation;

12\. Patients with acute myocardial infarction, severe/unstable angina or coronary bypass surgery within 6 months prior to enrollment; cardiac insufficiency of NYHA II or above;

13\. Patients who have a history of arterial thrombosis or deep venous thrombosis within 6 months prior to enrollment, history or evidence of thrombosis or bleeding tendency regardless of the severity within 2 months prior to enrollment; history of hemoptysis (i.e. coughing blood in bright red color or at least 1/2 teaspoon) within 2 weeks prior to enrollment;

14\. Patients who have a history of stroke and/or transient ischemic attack within 12 months prior to enrollment;

15\. Patients with skin wound, surgical site, wound site, severe mucosal ulcer or fracture without complete healing;

16\. Pregnant or lactating women, or women of child bearing potential with positive pregnancy test result before the first dose;

17\. Patients with child bearing potential who or whose sexual partners are not willing to take contraceptive measures;

18\. Patients with any clinical or laboratory abnormalities unsuitable for participating in this clinical trial according to the investigator's judgment;

19\. Patients with serious psychological or psychiatric disorders which may affect subject compliance in this clinical study;

20\. Patients who are allergic to analogue of Fruquintinib and/or its inactive ingredients.