This is an open-label, multicenter, randomized, phase II clinical trial, which aims to evaluate the effectiveness and safety of gefitinib versus combination of gefitinib and doublet chemotherapy or apatinib in advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) activating mutation (exon 19 deletion or exon 21 L858R point mutation), accompanied with Bim deletion or low activating EGFR mutation abundance.

BIM (bcl-2 interacting mediator of cell death) deletion polymorphism and low EGFR mutation abundance were poor clinical response markers to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients who had EGFR mutations.This is a phase II clinical trial to investigate the efficacy of combination treatment for patients harboring above risk factors.

Advanced EGFR mutated NSCLC Patients with Bim deletion or EGFR low mutation abundance were randomized divided into following three treatment groups:

A: gefitinib 250mg Qd combined with doublet chemotherapy: pemetrexed (500mg/m²，day 1 ，intravenously) plus carboplatin (AUC=5,day 1,intravenously) every 21 days.

B: gefitinib 250mg Qd combined with apatinib 250mg/d intravenously per 21 days. C: gefitinib 250mg Qd

Inclusion Criteria:

1. Volunteered for attending the study, and signed informed consent form (ICF)to participate in the study.

2. Cytologically and Histologically documented, locally advanced or recurrent or metastatic (stage IIIb, IIIc, IV) non-small cell lung cancer patients .

3. EGFR mutation (exon 19 deletion or exon 21 L858R) with Bim deletion or low abundance for EGFR mutation.

4. Age range: 18 years to 75 years.

5. Patients must have measurable lesion according to the RECIST (version 1.1) criteria.

6. Life expectancy of ≥ 12 weeks

7. ECOG (Eastern Cooperative Oncology Group) performance status of ≤ 1.

8. Patients hadn't received past system treatment, including cytotoxic drugs; For patients who have received adjuvant or neoadjuvant chemotherapy appears recurrence or metastasis more than 6 months from accepting the last dose of chemotherapy drugs

9. Adequate organ function as defined by the following criteria:

   • Bone marrow function: absolute neutrophil count ≥ 1,500,000,000/L and platelet count ≥100,000,000,000/L and hemoglobin ≥9g/dL.
   • Liver function: Total bilirubin ≤ 1.5 ULN (upper limit of normal). AP (alkaline phosphatase), AST ( aspartate aminotransferase) and ALT (alanine transaminase) ≤ 3 ULN in the absence of liver metastases or up to 5 ULN in case of liver metastases.
   • Renal function: creatinine clearance ≥ 60 ml/min. (based on modified Cockcroft-Gault formula).
   • INR （international normalized ratio）≤ 1.5, and partial thromboplastin time (PTT) or activated partial thromboplastin time (aPTT) ≤ 1.5 ULN.

10. For all females of childbearing potential a negative serum/urine pregnancy test must be obtained within 48 hours before enrollment. Postmenopausal women must have been amenorrhoeic for at least 12 months to be considered of non-childbearing potential.

11. Fertile men and women must use effective contraception.

Exclusion Criteria:

1. Histology confirmed for squamous carcinomas, including mixed gland scale cancer, small cell lung cancer.
2. Poor controlled hypertension, it means systolic pressure ≥140 mmHg and/or diastolic pressure ≥90 mmHg after drug therapy.
3. There are imaging evidence of tumor invading or closing to the pulmonary vessels (e.g., pulmonary artery, superior vena cava).
4. Thrombosis in 6 months before enrollment, including pulmonary thrombosis or deep venous thrombosis., or patient had medical evidence or history of thrombosis or bleeding tendency regardless of the severity.
5. Patients with medical history of hemoptysis (defined as about 2.5ml bright blood) 2 weeks before the enrollments.
6. Proteinuria ≥++, or 24h proteinuria ≥1.0g.
7. A uncontrolled clinical infection, activity, including but not limited to acute pneumonia.
8. Patients with known liver disease: the hepatitis B virus (HBV) infection and hepatitis b virus DNA (HBV DNA) ≥ 500 copy number or ≥100 IU/ml; or more; or hepatitis C virus (HCV) infection; or liver cirrhosis, etc.
9. Patients who are at risk of human immunodeficiency virus (HIV) or syphilis infection.
10. Patients who have a difficulty in swallowing or drug absorption.
11. There are diseases of alimentary canal such as active duodenal ulcer, the ulcerous colitis, intestinal obstruction or other conditions which can cause gastrointestinal bleeding or perforation in the investigator's opinion; or patient has a history of intestinal perforation, intestinal fistula.
12. Evaluation of cardiac function: left ventricular ejection fraction < 50% (echocardiography); Moderate or above disorders of mitral valve and tricuspid shut down;, serious/unstable angina or acute myocardial infarction coronary artery bypass surgery in 6 months before enrollment; patients with class 2 and above cardiac dysfunction according to New York heart association (NYHA) classification
13. Stroke and transient ischemic in 12 months before enrollment.
14. severe ulcer in the skin wound, trauma and mucosa or fractures have been not fully healed.
15. Patients received CYP3A4 strong inhibitor and/or inducer in 2 weeks before enrollment; Patients received P-gp and breast cancer resistance protein (BCRP) substrates drug in 2 weeks before enrollment.
16. Patients received other anti-tumor treatment at the same time.
17. Patients exist serious psychological or mental abnormalities, so patient compliance is not sufficient.
18. Poorly controlled serous cavity effusion, including but not limited to malignant pleural effusion, malignant pericardial effusion and malignant peritoneal effusion.
19. Patients have a weight loss (≥10%) within 6 weeks before enrollment.
20. The pregnancy of female patients test is positive or lactation women.
21. Patients haven't been diagnosed other malignant disease, except the basal cell carcinoma and cervical carcinoma.