Detection of Resistance Mechanisms in Cerebrospinal Fluid for EGFR-mutant, ALK- and ROS1-rearranged

Inclusion Criteria:

1. Provision to sign and date the consent form
2. Stated willingness to comply with all study procedures and be available for the duration of the study.
3. Be aged 18 or older.
4. Pathologically confirmed NSCLC with EGFR-mutation, or ALK- or ROS1-rearrangement and currently on an EGFR, or ALK or ROS1 tyrosine-kinase inhibitor (TKI) as applicable
5. Stage IV NSCLC disease according to AJCC 8th edition
6. Known CNS metastasis prior to current line of therapy with CR/PR/SD for at least 6 months (not purely attributable to prior local therapy such as radiation) on current EGFR, or ALK or ROS1 TKI, confirmed by at least one of the following modalities:

   * CT/MRI for brain metastases
   * characteristic signs and/or symptoms indicating progression,
   * cytology,
   * imaging findings for leptomeningeal disease
7. Confirmed current CNS progression, with or without eCNS progression, on the same TKI based on at least one of the following modalities:

   * CT/MRI for brain metastases
   * characteristic signs and/or symptoms indicating progression,
   * cytology,
   * imaging findings for leptomeningeal disease
8. Prior CNS radiation therapy is allowed

Exclusion Criteria:

1. Has contraindications to receive a lumbar puncture which may include, but are not limited to the following, at the discretion of the patient's oncologist or physician performing the LP:

   * Clinical and/or radiographic evidence of mass effect of raised intracranial pressure (ICP) with risk for cerebral herniation
   * Thrombocytopenia (defined as platelet count ≤ 50 or per local guidelines) or other bleeding diathesis
   * Currently on antiplatelet or anticoagulant therapy at time of consent, for which the thrombosis risk of holding for LP is deemed unacceptable
   * Suspected spinal epidural abscess
   * Any other condition determined by the clinician to be a contraindication
2. History of a second primary malignancy (including a second primary lung cancer) with the exceptions for:

   * Malignancy treated with curative intent and with no known active disease ≥5 years, and of low potential risk for recurrence
   * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
   * Adequately treated carcinoma in situ without evidence of disease
3. Women who are documented as pregnant or breastfeeding