Primary End-point - Post-LMS OS
Secondary End-point - CSF WBC, CEA improvement (50% decrease of baseline), Neurologic symptom improvement by RANO-LM criteria, Progression free survival, CSF response rate(CSF response rate is defined as the percentage of LM patients who have at least 1 CSF response (100% clearance of tumor cells from CSF) prior to any evidence of progression)
Background and Rationale: Non-small cell lung cancer with leptomeningeal metastases to the brain causes neurologic complications, impairs quality of life, and has a poor prognosis with a median survival of 1-4 months. Brain metastases and leptomeningeal metastases occur in EGFR mutation-positive NSCLC at the time of diagnosis or during treatment, and treatments include systemic therapy, intrathecal methotrexate, whole brain radiotherapy, and supportive care. Among these treatments, third-generation EGFR-TKIs have demonstrated increased survival. 
The BLOOM study is a phase I, prospective study confirming the efficacy of osimertinib in EGFR mutation-positive patients with confirmed leptomeningeal metastases. It reported a CSF response rate of 30.0% and overall survival of 16.1 months, regardless of T790M status. However, leptomeningeal metastases often occur in the late stages of treatment, especially in patients who have failed 1-2 EGFR-TKIs and are detected at a single point in time, or who have been previously treated with a third-generation EGFR-TKI, progressed, and are on cytotoxic chemotherapy. However, cytotoxic chemotherapy is poorly effective due to poor blood-brain barrier (BBB) penetration, difficult to maintain for long periods of time due to toxicity, and patients progress rapidly. Therefore, there are limited systemic treatment options for late-stage leptomeningeal metastases in patients with EGFR-mutant positive NSCLC, and there is a significant clinical unmet need to treat these patients. Based on this hypothesis, we aim to demonstrate that lazertinib provides a post-LMS OS benefit in patients with leptomeningeal metastases from non-small cell lung cancer (NSCLC) with a history of failure after prior EGFR-TKI therapy.

Treatment

Lazertinib 240 mg PO QD. Until confirmed disease progression, unless unacceptable toxicity, withdrawal of consent, or other criteria for discontinuation occur. However, lazertinib may be continued if the investigator determines that it is clinically beneficial to the patient. Also, at this time, a cytotoxic chemotherapy that has not been used before may be added while continuing lazertinib. The cytotoxic chemotherapy you add at this time may be covered by insurance. In these cases (where lazertinib is maintained despite disease progression, in the opinion of the investigator, and a previously unused cytotoxic chemotherapy is added, in addition to lazertinib, in the opinion of the investigator that maintaining lazertinib is beneficial), the efficacy evaluation will be analyzed separately. 

Arm Label

Target Number of Participant

Arm Type

Arm Description

Lazertinib 240 mg PO QD. Until confirmed disease progression, unless unacceptable toxicity, withdrawal of consent, or other criteria for discontinuation occur. However, lazertinib may be continued if the investigator determines that it is clinically beneficial to the patient. Also, at this time, a cytotoxic chemotherapy that has not been used before may be added while continuing lazertinib. The cytotoxic chemotherapy you add at this time may be covered by insurance. In these cases (where lazertinib is maintained despite disease progression, in the opinion of the investigator, and a previously unused cytotoxic chemotherapy is added, in addition to lazertinib, in the opinion of the investigator that maintaining lazertinib is beneficial), the efficacy evaluation will be analyzed separately. 

Gender

Age

Description

(1) Patients with pathologically diagnosed non-small cell lung cancer (adenocarcinoma) with confirmed exon 19 deletion or Leu858Arg +/-Thr790Met. 
(2) Patients with leptomeningeal seeding diagnosed by brain MRI and CSF (CSF cytology positive or atypical cells).  
(3) Can be enrolled even if they have received prior therapy, including EGFR-TKIs (gefitinib, erlotinib, osimertinib, or lazertinib or other EGFR-TKIs). Prior cytotoxic or immunologic therapy is eligible for enrollment regardless of treatment sequence. However, patients who have used a third-generation EGFR-TKI may be enrolled if they have used a third-generation EGFR-TKI, without LMS, within 3 months prior to enrollment in this study, and subsequently received other systemic therapy (cytotoxic or immuno-oncology) and developed LMS. However, LMS must not have occurred during or within 3 months after use of a third-generation EGFR-TKI. 
(4) Age 20 years or older 
(5) ECOG 0-2
(6) Minimum life expectancy of 8 weeks
(7) Adequate organ function 
  - Absolute neutrophil count (ANC) ≥1500 cells/mm3
  - Platelets ≥100,000 cells/mm3
  - Total bilirubin ≤1.5 x upper limit of normal (ULN)
  - Asparagine aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 5.0 x ULN (
  - Serum creatinine ≤1.5 x upper limit of normal (ULN) or CCr ≥ 50 mL/min (calculated using the weight-based Cockcroft- Gault formula).
(8) Female patients must be of childbearing potential or agree to use adequate contraception for the duration of the study.
Female patients must agree to use adequate contraception and must not be lactating, and for women of childbearing potential, must have a negative pregnancy test prior to initiation of treatment or evidence of non-childbearing status at screening by meeting one of the following criteria: 1.
   - "Postmenopausal" women who are >50 years of age and have been amenorrheic for at least 12 months after discontinuation of all exogenous hormonal therapy.
   - Documented irreversible surgical sterilization by hysterectomy, bilateral oophorectomy, or bilateral salpingo-oophorectomy; tubal ligation is not permitted.
   - Women 50 years of age or younger will be considered postmenopausal only if they have been amenorrheic for at least 12 months after discontinuing all exogenous hormonal therapy and their luteinizing hormone (LH) levels and follicle-stimulating hormone (FSH) levels are within the site's postmenopausal range.
   - Use reliable contraception during sexual intercourse with all partners from the screening period through 12 weeks after discontinuation of study therapy.
For male patients who have not had a vasectomy, must agree to all of the following
   - Use reliable contraception during sexual intercourse with all partners from the screening period until 12 weeks after stopping study therapy. 
   - Not donate sperm from the date of initiation of study therapy until 12 weeks after discontinuation of study therapy. 
   - If male patients wish to have children during the aforementioned period, they should be advised to arrange for freezing of their sperm samples prior to initiation of study therapy.
(9) Patients who are willing and able to comply with the protocol. 
(10) Who have made a voluntary decision to participate in this study and have signed a written informed consent.
(11) Patients who can take medication orally or through L-tube, PEG, etc.

(1) Patients with serious, symptomatic brain metastases, requiring emergency radiation therapy, or using high-dose steroids (high-dose steroid definition: dexamethasone > 10 mg/day) are excluded. Patients with previously diagnosed brain metastases treated with radiotherapy or stereotactic radiosurgery may be enrolled 2 weeks after such treatment if symptoms are stable.
(2) Patients who have received 2 or more first or second generation EGFR-TKIs. 
(3) Uncontrolled systemic disease, including uncontrolled hypertension, active bleeding, or active infection.
(4) Patients with documented interstitial lung disease, drug induced interstitial lung disease, or radiation pneumonitis at a level requiring steroid treatment. 
(5) Unresolved toxicity from prior therapy, > CTCAE grade 1.
(6) Pregnant and lactating women.
(7) Excluded if they have a prior or coexisting malignancy (but may be enrolled if they have been cured with no recurrence within 5 years).
(8) Participants with a history of clinically significant cardiovascular disease, including but not limited to the following 
- Diagnosis of deep vein thrombosis or pulmonary embolism within 1 month prior to the first dose of study therapy or any of the following within 6 months prior to the first dose of study therapy: myocardial infarction, unstable angina, stroke, transient ischemic attack, coronary artery/peripheral artery bypass grafting, or any wet coronary syndrome. Clinically insignificant thrombosis, such as non-obstructive catheter-related thrombi, is not excluded. 9.
- Prolonged QTcF interval >480 msec or clinically significant cardiac arrhythmia or electrophysiologic disease (e.g., implantable cardioverter-defibrillator or uncontrolled atrial fibrillation).
- Pericarditis/clinically significant pericardial effusion.
- Myocarditis
(9) Mental illness or dementia that would interfere with the ability to cooperate with the requirements of this study.

Post-LMS overall survival

12 month after completion of enrollment

CSF-WBC, CEA improvement (50% decrease of baseline)

up to 30 month

Neurologic symptom improvement by RANO-LM criteria

up to 30 month

Progression free survival

up to 30 month

CSF response rate: CSF response rate is defined as the percentage of LM patients who have at least 1 CSF response (100% clearance of tumor cells from CSF)

up to 30 month

Safety (adverse events, lab tests)

From the start to the end of the subject's study.