Befotertinib and Icotinib for NSCLC With Uncommon EGFR Mutations

Inclusion Criteria: 1. 18 years of age or older. 2. Pathologically confirmed adenocarcinoma of the lung, with locally advanced or metastatic disease and not amenable to curative surgery or radiotherapy (stage IIIB, IIIC or IV disease based on the eighth edition of the American Joint Committee on Cancer (AJCC) TNM classification). Patients with mixed histology are eligible if adenocarcinoma is the predominant histology. 3. Patients must be treatment-naive for locally advanced or metastatic NSCLC systemic antitumor therapy. Prior adjuvant and neo-adjuvant therapy (except for EGFR-TKIs) is permitted if have been completed at least 6 months prior to initiation of disease progression. 4. Tissue or blood samples are confirmed by the central laboratory or research center as rare EGFR mutations, including exon 18 G719X, S768I in exon 20 and at least one of the L861Q mutations in exon 21; 5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. 6. Predicted survival ≥ 3 months. 7. At least 1 measurable tumor lesion without radiotherapy as per RECIST v1.1. 8. Agree to use effective contraception during the study period and for at least 3 months after completion of the study treatment. 9. Provision of informed consent prior to any study procedure. Exclusion Criteria: 1. Combined with other malignancy(except for clinically cured in situ cervix carcinoma, basal cell or squamous epithelial skin cancer,thyroid papillary carcinoma). 2. Prior treatment with any EGFR-TKIs. 3. Prior treatment with any systemic antitumor therapy for locally advanced or metastatic NSCLC. 4. Previous traditional chinese medicine with an antitumor indication within 2 weeks before the first dose of study drug. 5. Previous major surgery within 4 weeks before the first dose of study drug,or planing to have major surgery during study. 6. Symptoms or signs worsened within 2 weeks before the first dose of study drug. 7. Any unresolved toxicities from prior treatment greater than NCI CTCAE v4.03 grade 2 or higher. 8. Spinal cord compression,symptomatic or unstable central nervous system (CNS) metastases that require the use of steroids .Patients who have a stable CNS status for at least 4 weeks before treatment will be allowed to join the study. 9. Any clinical evidence of serious or uncontrolled systemic disease,including uncontrolled hypertension after drug treatment,active bleeding diatheses, previous or present thrombus,uncontrolled cardiovascular and cerebrovascular diseases. 10. Active infection including hepatitis B,hepatitis C,syphilis and human immunodeficiency virus (HIV). 11. Mean resting corrected QT interval (QTcF) ≥450 msec,obtained from 3 ECGs or any clinically important abnormalities in rhythm,conduction, morphology of resting ECG or left ventricular ejection fraction (LVEF) ≤ 50%,etc. 12. Previous history of interstitial lung disease(ILD),drug-induced interstitial lung disease,history of radiation-induced pneumonia requiring hormone therapy,or clinical evidence of active interstitial lung disease. 13. Any instance that affects the patient's ability to swallow drug or oral malabsorption. 14. Occur any laboratory indicator abnormalities as follow： * absolute neutrophil count(ANC)\<1,500/mcL * platelets\<100,000/mcL * hemoglobin\<9.0 g/dL * AST/ALT\>2.5 times the upper limit of normal (ULN)or \>5 times the ULN in the presence of liver metastases * total bilirubin(TBIL)\>1.5 times the ULN if no liver metastases or \> 3 times the ULN in the presence of liver metastases * serum creatinine(SCr) \>1.5 times the ULN or creatinine clearance ≥50 mL/min. 15. Patients with a known allergy or delayed hypersensitivity reaction to the any component of study drugs or their excipients. 16. Within 1 week before the first dose of study drug currently receiving or need concomitant medications known to be potent inhibitors or inducers of CYP3A, CYP2D6,CYPC8 and CYP2C19,sensitive substrate of CYP3A and CYP2C9. 17. Within 1 week before the first dose of study drug ongoing use of warfarin. 18. Previous therapeutic clinical trial within 4 weeks before the first dose of study drug.