The aim of this study is to investigate the efficacy and safety of intercalated combination of erlotinib and radiotherapy for patients with EGFR-mutant, unresectable, locally advanced NSCLC, and to explore a new treatment strategy for this subset. After Induction by erlotinib, local radiotherapy is intercalated, and followed by 24-week erlotinib maintenance.

Chemoradiation therapy is the standard treatment for unresectable, locally advanced NSCLC, but its efficacy reaches a platform, and treatment-related life threatening toxicity limits its use. The EGFR tyrosine kinase inhibitors (TKIs) produce a dramatic response in patients carrying EGFR activating mutations in the metastatic setting. Multiple prospective trials show that EGFR-TKIs have a better tolerability when compared with chemotherapy.

Inclusion Criteria:

1. Males or females aged ≥18 years.
2. ECOG performance status 0-2.
3. Pathologically diagnosed of non-small cell lung cancer, and staged as unresectable IIIA/IIIB according the TNM staging system (2009).
4. EGFR activating mutations in exon 18, 19 or 21were detected in tumor tissue or plasma.
5. Measurable disease must be characterized according to RECIST 1.1 criteria.
6. Life expectancy ≥12 weeks.
7. Adequate pulmonary function: FEV1.0 >50% of the normal predicted value, or DLCO >40% of the normal predicted value.
8. Adequate liver function: Total bilirubin ≤ 1.5 x upper limit of normal (ULN); Aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 3.0 x ULN in subjects without liver metastases; ≤ 5 x ULN in subjects with liver metastases.
9. Adequate renal function: serum creatinine ≤ 1. 5 x ULN, and creatinine clearance ≥ 45 ml/min.
10. Adequate hematological function: Absolute neutrophil count (ANC) ≥1.0 x 109/L, and Platelet count ≥75 x 109/L, and Hemoglobin ≥8 g/dL.
11. Female subjects should not be pregnant or breast-feeding.
12. Written informed consent provided.
13. Able to comply with the required protocol and follow-up procedures, and able to receive oral medications.

Exclusion Criteria:

1. Histologically mixed with small-cell lung cancer.
2. Mutations in EGFR exon 20 are detected.
3. Exposure to prior chest irradiation before the enrollment.
4. Patients with prior chemotherapy or agents directed at the HER axis (e.g. erlotinib, gefitinib, cetuximab, trastuzumab).
5. History of another malignancy in the last 5 years with the exception of the following: Other malignancies cured by surgery alone and having a continuous disease-free interval of 5 years are permitted; Cured basal cell carcinoma of the skin and cured in situ carcinoma of the uterine cervix are permitted.
6. Any unstable systemic disease (including active infection, uncontrolled hypertension, unstable angina, congestive heart failure, myocardial infarction within the previous year, serious cardiac arrhythmia requiring medication, hepatic, renal, or metabolic disease).
7. Existence of interstitial lung disease.