Pemetrexed injected into the spinal fluid for EGFR‑mutant lung cancer that has spread to the leptomeninges.

Inclusion criteria

* At least 20 years of age.
* Patients with metastatic non-squamous NSCLC harboring known EGFR activating mutation and with a diagnosis of probable or confirmed LM by the European Association of Neuro-Oncology-European Society for Medical Oncology (EANO-ESMO) guideline. \[5\] EGFR activating mutations include exon19 deletion, T790M, L858R, G719X, L861Q, or S768I.
* Intracranial disease progression after osimertinib use, proved by contrast-enhanced MRI
* Stable extra-cranial disease status, judged by investigators.
* Eastern Cooperative Oncology Group (ECOG) performance status 0-3 and a minimum life expectancy of 12 weeks
* Normal bone marrow and organ function as defined below:

  * Marrow: Hemoglobin ≥9gm/dL, ANC ≥1500/mm3 platelets ≥100,000/mm3
  * Hepatic: Serum total bilirubin ≤1.5 x upper limit of normal (ULN), ALT (SGPT) and AST (SGOT) ≤3 x ULN.
  * Renal: Creatinine clearance (Ccr) ≥45 mL/min.
* For female patients of childbearing potential, agreement (by patient and/or partner) to use a highly effective form(s) of contraception that results in a low failure rate (\< 1% per year) when used consistently and correctly, and to continue its use for 5 months after the last dose of IP. Such methods include: combined (estrogen and progestogen containing) hormonal contraception, progestogen-only hormonal contraception associated with inhibition of ovulation together with another additional barrier method always containing a spermicide, intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner (on the understanding that this is the only one partner during the whole study duration), and sexual abstinence.
* Ability to understand and willingness to sign an IRB approved written informed consent document.
* Willing to provide CSF and plasma samples for ctDNA analysis.

Exclusion criteria

* Uncontrolled extra-CNS disease which needs other systemic treatment than EGFR-TKI.
* Uncontrolled tumor-related pain
* Uncontrolled or symptomatic hypercalcemia (\> 1.5 mmol/L ionized calcium or Ca \> 12 mg/dL or corrected serum calcium \> ULN). Patients who are receiving denosumab prior to study enrollment must be willing and eligible to receive a bisphosphonate instead while in the study.
* Malignancies other than NSCLC within 5 years prior to study enrollment, with the exception of those with a negligible risk of metastasis or death (e.g., expected 5-year OS \> 90%) treated with expected curative outcome (such as adequately treated carcinoma in situ of the cervix, basal or squamous-cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent)
* On chronic systemic steroid therapy more than 20 mg prednisolone per day (or equivalent) or on any other form of immunosuppressive medication
* Has received a live-virus vaccination within 30 days of planned treatment start
* Systemic cytotoxic chemotherapy or major surgery within 2 weeks of the first dose of study medication
* Active infection requiring therapy
* History of Human Immunodeficiency Virus (HIV) infection.
* Hepatitis B carrier: Patients with HBV infection were required to be receiving effective antiviral therapy and have a viral load less than 100 IU/mL at screening
* Active Hepatitis C
* Has received intrathecal chemotherapy within 2 weeks before the start of IP
* Has received whole-brain radiotherapy (WBRT) within 2 weeks before the start of IP
* Uncontrolled epilepsy
* History of allergic reaction to intravenous pemetrexed.
* Severe coagulation abnormality (INR \> 2).
* Severe symptomatic hydrocephalus that requires other treatment modalities other than IP
* Bulky intra-cranial lesion that requires other treatment modalities other than IP