ctDNA-driven Adaptive Proton Craniospinal Irradiation in Non-Small Cell Lung Cancer With Leptomeningeal Metastasis After Resistance to Third-Generation TKIs in the Consolidation Phase

Inclusion Criteria:

1. Voluntary participation with written informed consent obtained prior to any study-specific procedures, and willingness and ability to comply with scheduled visits, the treatment plan, laboratory tests, and other study requirements.
2. Male or female patients aged between 18 and 75 years (inclusive) at the time of signing informed consent.
3. Primary tumour confirmed as non-small cell lung cancer (NSCLC) by cytology or histology, harbouring EGFR-sensitive mutations (including 19del and exon 21 L858R). Testing reports for EGFR mutation status must be available; if no prior report exists, submission of archived tissue or baseline biopsy for assessment is mandatory.
4. Leptomeningeal metastasis (LM) diagnosed according to the EANO-ESMO guidelines, based on cerebrospinal fluid (CSF) cytology and/or imaging evidence of leptomeningeal enhancement or ventriculomegaly.
5. Disease progression of LM documented after treatment with third-generation EGFR-TKIs (including osimertinib, almonertinib, or furmonertinib). Patients may continue their current EGFR-TKI therapy during the study, provided that extracranial disease remains stable.
6. The patient has had an Ommaya reservoir implanted or has undergone Ommaya reservoir placement prior to study entry, and is willing to undergo intrathecal injections via the reservoir throughout the study.
7. Extracranial disease is stable, defined as no progressive extracranial lesions (per RECIST v1.1) within 28 days prior to enrollment. Continuation of background systemic EGFR-TKI therapy is permitted.
8. Life expectancy ≥ 3 months as assessed by the investigator.
9. Karnofsky Performance Status (KPS) ≥ 70 at screening.
10. Medically fit to tolerate intrathecal pemetrexed and proton craniospinal irradiation (pCSI), as determined by the investigator.
11. Adequate organ and bone marrow function as defined below (within 14 days prior to initiation of study treatment), without having received blood transfusions, granulocyte colony-stimulating factor (G-CSF), or hematopoietic growth factors within 14 days prior to screening:

    * Hematology:

      * Haemoglobin (Hb) ≥ 90 g/L;
      * Absolute Neutrophil Count (ANC) ≥ 1.5 × 10⁹/L;
      * Platelets (PLT) ≥ 75 × 10⁹/L.
    * Blood Chemistry:

      * Total Bilirubin (TBIL) ≤ 2.0 × ULN (≤ 3.0 × ULN for patients with Gilbert's syndrome);
      * Alanine Aminotransferase (ALT) and Aspartate Aminotransferase (AST) ≤ 5.0 × ULN;
      * Serum Creatinine (Cr) ≤ 1.5 × ULN or Calculated Creatinine Clearance (CrCl) ≥ 50 mL/min (using the Cockcroft-Gault formula):
      * Male: CrCl = ((140 - age) × weight) / (72 × serum creatinine)
      * Female: CrCl = ((140 - age) × weight) / (72 × serum creatinine) × 0.85 (Note: Weight in kg; Serum creatinine in mg/dL)
    * Coagulation Function:

      * International Normalized Ratio (INR) ≤ 2.0 or Prothrombin Time (PT) ≤ 6 seconds above the upper limit of normal.
12. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 7 days prior to the first dose of study treatment. If the urine test cannot be definitively confirmed as negative, a serum pregnancy test must be performed, and the serum result will be considered definitive.
13. Female subjects of childbearing potential who are sexually active with unsterilised male partners must agree to use highly effective contraception starting at screening and continue for 180 days after the last dose of study treatment.
14. Sexually active male subjects who have not undergone sterilisation and who are sexually active with female partners of childbearing potential must agree to use effective contraception starting at screening and continue for 180 days after the last dose of study treatment. Decisions regarding cessation of contraception beyond this timeframe should be discussed with the investigator.
15. Subjects must be willing and able to comply with the study protocol, including scheduled visits, treatment administration, laboratory tests, imaging assessments, and CSF sample collections via the Ommaya reservoir.

Exclusion Criteria:

* Patients with concurrent primary tumors of the brain or spinal cord.
* Patients with severe central nervous system diseases (including severe cerebral herniation or coma).
* Patients with life-threatening or uncontrolled systemic diseases, such as uncontrolled hypertension or active bleeding tendency.
* Patients with other concurrent malignancies, except for basal cell carcinoma of the skin and carcinoma in situ.
* Patients who have previously received whole-brain radiotherapy or photon radiotherapy to involved fields of the brain and spinal cord.
* Patients judged by the investigator to be unsuitable for participation, or who have factors that may affect compliance with the protocol.
* Toxicity from prior treatment has not recovered to normal or to grade 1 per NCI-CTCAE version 6.0.
* Patients with drug allergy or metabolic disorders to the drugs used in this protocol.
* Pregnant or lactating women, or female patients who plan to become pregnant during the study period or within 6 months after the last dose.
* Patients who are concurrently participating in other clinical studies
* Patients with pre-existing cardiac dysfunction.