EGFR-TKI Combined With Concurrent or Sequential Chemotherapy for Patients of Gradual Progression

Inclusion criteria：

1. Patients had to voluntarily join the study and give written informed consent for the study
2. Histologically documented, unresectable, inoperable, locally advanced, recurrent or metastatic stage IIIB or IV adenocarcinoma.
3. A cytologic diagnosis is acceptable (i.e., FNA or pleural fluid cytology)
4. Sensitive EGFR mutations (exon 19 deletion or L858R mutation in exon 21)
5. At least one measurable lesion meeting Response Evaluation Criteria in Solid Tumours (RECIST) criteria.
6. Patients achieved the gradual progression after first-line EGFR-TKI therapy.

The criteria of gradual progression:

1. disease control≥6 months with EGFR-TKI treatment;
2. compared with the previous assessment，no significant increment of tumor burden and progressive involvement of non-target lesions with a score ≤2;
3. symptom scored≤1. 7) Patients did not achieve acquired EGFR-T790M mutation assessed by ARMS, next-generation sequencing (NGS) or droplet digital PCR (ddPCR) after first-line EGFR-TKI therapy 8) Patients did not receive any chemotherapy previously 9) Able to comply with study and follow-up procedures 10) Age \>=18 years, ECOG PS: 0\~2, estimated survival duration more than 3 months； 11) Major organ function

Exclusion criteria：

1. Other types of non-small cell lung cancer except adenocarcinoma and Small cell lung cancer（including patients with mixed small cell lung cancer and non-small cell lung cancer）；
2. Evidence of other types of non-small cell lung cancer except adenocarcinoma, small cell, carcinoid, or mixed small cell/non-small cell histology
3. EGFR wild-type patients, or patients with rare EGFR mutations or complex EGFR mutations
4. Patients achieved the dramatic progression after first-line EGFR-TKI therapy. The criteria of dramatic progression
5. Patients achieved the local progression after first-line EGFR-TKI therapy. The criteria of local progression
6. Patients achieved acquired EGFR-T790M mutation assessed by ARMS, next-generation sequencing (NGS) or droplet digital PCR (ddPCR) after first-line EGFR-TKI therapy
7. Previously (within 5 years) or presently suffering from other malignancies
8. A in situ，non-melanoma skin cancers and superficial bladder cancer
9. Unstable systemic disease
10. History of other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that might affect the interpretation of the results of the study or render the patient at high risk from treatment complications
11. Gastrointestinal tract disease resulting in an inability to take oral medication or a requirement for intravenous (IV) alimentation, or prior surgical procedures affecting absorption
12. Pregnancy or lactation