Sequential pemetrexed + carboplatin followed by befotertinib for EGFR‑mutant NSCLC after resistance to third‑generation EGFR inhibitors

Inclusion Criteria:

1. Age ≥18 years;
2. Histologically or cytologically confirmed advanced or metastatic non-squamous NSCLC; and prior resistance to third-generation EGFR TKIs, with EGFR-sensitive mutations confirmed via tissue or blood samples (defined as: 19 Del or 21 L858R);
3. Exclusion of small cell lung cancer (SCLC) or squamous cell carcinoma (SqCC) transformation, and known NSCLC with clear targetable mutations for targeted therapy, such as HER2, MET amplification (GCN ≥ 5), KRAS G12C mutation, BRAF V600E mutation, RET fusion mutation, ALK fusion mutation, NTRK fusion mutation, etc.;
4. ECOG performance status (PS) score of 0-2;
5. Life expectancy of at least 12 weeks;
6. Ability to swallow oral medications;
7. Adequate organ system function, defined as follows and determined based on investigator judgment:

   1. Absolute neutrophil count (ANC) ≥ 1.5 x 10⁹/L
   2. Platelets ≥ 100 x 10⁹/L;
   3. Hemoglobin ≥ 9 g/dL (≥ 90 g/L). Note: Blood transfusions are permitted to achieve the required hemoglobin level;
   4. Total bilirubin ≤ 1.5 times the upper limit of normal (ULN);
   5. If no liver metastases: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN; if liver metastases present: ≤ 5 × ULN;
   6. Creatinine ≤1.5 × ULN. If ≥1.5 × ULN, patients remain eligible if the Cockcroft-Gault-calculated creatinine clearance ≥50 mL/min (0.83 mL/s);
8. Female subjects of childbearing potential must have a negative serum pregnancy test within 3 days prior to study drug initiation and agree to use a medically approved highly effective contraceptive method (e.g., intrauterine device, oral contraceptives, or condoms) during the study and for 3 months after the last study drug administration; Male subjects with female partners of childbearing potential must be surgically sterilized or agree to use an effective method of contraception during the study period and for 3 months after the last study dose.
9. Voluntarily agree and be capable of adhering to the trial and follow-up procedures.
10. Be able to understand the nature of the trial and complete the written informed consent form.

Exclusion Criteria:

1. Rare EGFR mutations;
2. Prior treatment with pemetrexed and platinum-based chemotherapy regimens;
3. Advanced and/or symptomatic brain metastases (measurable or non-measurable) and/or leptomeningeal metastases;
4. Active hepatitis B (serum HBV DNA ≥10⁴ copies/mL \[i.e., 20,000 IU/mL\]), hepatitis C virus antibody positive, HIV antibody positive, or treponema pallidum antibody positive;
5. Women of childbearing potential with a positive serum pregnancy test within 7 days prior to treatment initiation, pregnant or lactating women, or male and female subjects not using effective contraception or planning pregnancy during treatment and for 3 months post-treatment;
6. Patients who used or require concomitant use of the following drugs within 14 days prior to the first dose or during treatment: drugs associated with QTc prolongation and/or risk of torsades de pointes ventricular tachycardia; strong CYP3A inhibitors or inducers;
7. Patients who underwent major surgery or immunotherapy within 4 weeks prior to the first dose; patients who received radiotherapy within 2 weeks prior to the first dose.
8. Imaging (CT or MRI) demonstrating tumor invasion of major vessels, or a high likelihood of tumor invasion into critical vessels causing fatal hemorrhage during the study period;
9. History of interstitial lung disease, drug-induced interstitial disease, or any clinically evident active interstitial lung disease; presence of idiopathic pulmonary fibrosis identified on baseline CT scan;
10. Other severe acute or chronic medical conditions, including uncontrolled diabetes, medical or psychiatric disorders, or laboratory abnormalities, that in the investigator's judgment may increase study-related risks or interfere with interpretation of study results;
11. Other conditions deemed by the investigator to be unsuitable for participation in this trial.