Befotertinib is a third-generation EGFR-TKI independently developed in China. In first-line treatment of advanced non-small cell lung cancer (NSCLC) with EGFR mutations, it has demonstrated a median progression-free survival (PFS) of 22.1 months, representing the longest reported PFS data among currently available third-generation EGFR-TKIs. Building on the clinical advantages of this agent and addressing the unmet therapeutic needs in oligometastatic NSCLC, this study aims to conduct a prospective exploration by dynamically monitoring circulating tumor DNA (ctDNA) to guide the application of befotertinib combined with radiotherapy in patients with EGFR mutation-positive oligometastatic NSCLC.

Inclusion Criteria:

1. Age 18-75 years at the time of signing the informed consent form, both males and females are eligible;

2. Histologically confirmed newly diagnosed or treatment-naïve oligometastatic stage IV NSCLC (AJCC 9th edition) with ≤3 involved organs and ≤5 metastatic lesions. Regional lymph node involvement (regardless of number) is not counted as metastatic sites; non-regional lymph node involvement is classified as a metastatic lesion;

3. Presence of an EGFR sensitizing mutation (19Del or 21L858R);

4. At least one measurable lesion according to RECIST v1.1;

5. ECOG performance status 0-1;

6. Life expectancy ≥12 weeks;

7. No prior systemic anti-tumor therapy for advanced NSCLC, including standard chemotherapy, biologic therapy, targeted therapy, immunotherapy, or investigational drug treatment before starting the study drug. Patients who have received adjuvant or neoadjuvant therapy (chemotherapy and/or radiotherapy) are eligible if there has been no progression within 6 months after completion of such therapy;

8. Adequate organ function (no transfusion, growth factor support, or medical correction within 14 days before screening):

   Hematology:

   1. Hemoglobin (HB) ≥90 g/L;
   2. Absolute neutrophil count (ANC) ≥1.5 × 10⁹/L;
   3. Platelet count (PLT) ≥100 × 10⁹/L;
   4. White blood cell count (WBC) ≥4.0 × 10⁹/L and ≤15 × 10⁹/L.

   Blood biochemistry (no transfusion or albumin infusion within 14 days before screening):

   1. AST and ALT ≤1.5 × ULN (≤5 × ULN if liver metastases are present);
   2. Alkaline phosphatase (ALP) ≤2.5 × ULN;
   3. Total bilirubin (TBiL) ≤1.5 × ULN;
   4. Albumin (ALB) ≥30 g/L;
   5. Serum creatinine (Cr) ≤1.5 × ULN and creatinine clearance (CrCL) ≥60 mL/min (Cockcroft-Gault formula);
   6. Activated partial thromboplastin time (APTT) ≤1.5 × ULN, and INR or PT ≤1.5 × ULN.

9. Women of childbearing potential must agree to use effective contraception (e.g., intrauterine device, oral contraceptives, or condoms) during the study and for 6 months after study completion; a negative serum or urine pregnancy test within 7 days before enrollment is required, and the patient must not be breastfeeding. Male participants must agree to use contraception during the study and for 6 months afterward;

10. Voluntary participation in the study, provision of written informed consent, good compliance, and willingness to provide blood samples.

Exclusion Criteria:

1. Small cell lung cancer or non-small cell lung cancer mixed with histologic types such as small cell lung cancer or neuroendocrine carcinoma;
2. Confirmed EGFR exon 20 insertion mutation or non-classical mutations such as L861Q, G719X, or S768I;
3. Prior systemic anti-tumor therapy for advanced/metastatic NSCLC (e.g., standard chemotherapy, targeted therapy, biologic therapy, immunotherapy, etc.);
4. Patients with symptomatic brain metastases, carcinomatous meningitis, or spinal cord compression, or imaging (CT or MRI) findings of brain or leptomeningeal disease at screening (except those with previously treated brain metastases who have been stable and without progression for ≥4 weeks before enrollment, and confirmed by brain MRI, CT, or venography to have no evidence of intracranial hemorrhage);
5. Known history of hypersensitivity to the active or inactive excipients of Befotertinib or to drugs with similar chemical structures or classes;
6. Factors that significantly affect oral drug absorption, such as inability to swallow, chronic diarrhea, intestinal obstruction, etc.;
7. History of interstitial lung disease, drug-induced interstitial lung disease, or radiation pneumonitis requiring steroid treatment;
8. Any evidence of severe or uncontrolled systemic disease, including uncontrolled hypertension, diabetes, active bleeding, etc., that in the investigator's judgment would compromise patient participation or protocol compliance, or any active infection including uncontrolled hepatitis B, hepatitis C, or human immunodeficiency virus (HIV);
9. QTc prolongation >470 ms or any clinically significant arrhythmia;
10. Any condition that, in the investigator's judgment, would preclude participation in this study, including patients deemed unlikely to comply with study procedures, constraints, and requirements, or other situations at the investigator's discretion.