Inclusion Criteria:
* Newly diagnosed confirmed or probable leptomeningeal metastases according to European Association of Neuro-Oncology (EANO) - European Society for Medical oncology (ESMO) criteria (Le Rhun et al., 2017).
* Histologically confirmed (from primary tumor or from a metastatic lesion, including in the brain) non-small cell lung cancer without actionable oncogenic driver mutation or melanoma. Programmed death-ligand 1 (PD-L1) expression status (from primary tumor or from a metastatic lesion, including brain) is optional, but should be documented if available
* Requirements for patients with non-small cell lung cancer: non-small cell lung cancer without a specified targetable oncogenic driver alteration: sensitising Epidermal Growth Factor Receptor (EGFR) mutation (exon 19-del and 21-L858R), anaplastic lymphoma kinase (ALK) or ROS proto-oncogene-1 (ROS1) rearrangement.
* Clinically eligible for systemic immunotherapy with nivolumab and ipilimumab at the time of enrolment as judged by the investigator. If already initiated, the systemic treatment must be well tolerated, without common terminology criteria for adverse events (CTCAE) grade 3 or more toxicity, and there must be no evidence of systemic progression and no indication for whole brain radiotherapy. Intrathecal immunotherapy alone may be acceptable for exceptional patients after discussion with the coordinators of the study. Systemic immunotherapy can be started later in these patients based on investigator decision.
* Patients previously treated with systemic chemotherapy must have received the last dose at least 21 days prior to treatment initiation, patients who have received another investigational agent must have received the last treatment at least 14 days prior to treatment initiation.
* Age of 18 years or older on day of signing informed consent, female or male.
* Karnofsky performance status of 60 or more.
* Life expectancy \>8 weeks. Patients with rapidly progressive systemic disease are not eligible.
* Patients may receive steroids to control symptoms related to central nervous system involvement, but the dose must be stable or decreasing and \< 4 mg per 24 hours of dexamethasone (or equivalent) in the last 7 days. Patients should experience stability of neurological symptoms for at least 7 days. Physiologic replacement doses of steroids are permitted.
* Cerebrospinal MRI criteria (on the baseline MRI, performed within 14 days prior to study treatment initiation)
* MRI can be normal or can show leptomeningeal metastases, including nodules \<0.5 cm diameter largest diameter (or more if stereotactic radiosurgery is planned)
* No evidence of cerebrospinal fluid flow obstruction at the discretion of the investigator
* Co-existing asymptomatic brain metastases \<2 cm diameter are permitted. Larger asymptomatic or oligosymptomatic brain metastases are permitted if they are planned to be treated by stereotactic radiosurgery
* Central nervous system radiotherapy criteria:
* Focal brain radiotherapy by stereotactic radiotherapy is allowed for meningeal nodules \> 5 mm diameter or concomitant brain metastases. The treated lesions cannot be used as a target for the evaluation of the study treatment
* Prior brain focal radiotherapy for central nervous system metastases is permitted if completed at least 14 days prior to enrolment, but the treated lesions cannot be used as a target for the evaluation of the study treatment
* Planned whole brain radiotherapy is not allowed
* Prior whole brain radiotherapy for brain metastases is permitted if terminated at least 3 months prior enrolment.
* Planned or prior craniospinal irradiation is not allowed
* Women of childbearing potential, including women who had their last menstruation in the last 2 years, must have a negative urinary or serum pregnancy test within 24 hours before the first dose of study treatment.
* Ability to understand the requirements of the study, provide written informed consent and authorization of use and disclosure of protected health information, and agree to abide by the study restrictions and return for the required assessments.
* Written informed consent for study participation must be signed and dated by the patient and the investigator prior to any study-related intervention.
Exclusion Criteria:
* Leptomeningeal metastases related to primary tumors other than non-small cell lung cancer without driver mutation or melanoma.
* Inability to undergo craniospinal MRI evaluation.
* Progressive parenchymal brain metastases thought to require whole brain radiotherapy.
* Contra-indication to lumbar puncture or to implantation of a ventricular device.
* Prior intrathecal chemotherapy, intrathecal immunotherapy or intrathecal targeted therapy.
* Ventriculo-peritoneal shunt (except if intrathecal therapy is administered via a ventricular device with an ON/OFF option).
* Condition requiring systemic treatment with either corticosteroids (\> 4 mg daily dexamethasone equivalents) or other immunosuppressive medications within 7 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \< 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
* Patients with a history of pneumonitis or previous non-hematological grade \>2 toxicity under previous immunotherapy treatment.
* Active infection (systemic or central nervous system) within 7 days prior to initiation of the study drug.
* Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
* Known positive test for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody) indicating acute or active chronic infection.
* Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS) even if fully immunocompetent on antiretroviral therapy due to the unknown effects of HIV on the immune response to combined nivolumab plus ipilimumab or the unique toxicity spectrum of these drugs in patients with HIV infection.
* Use of vaccines containing live virus for prevention of infectious disease within 12 weeks prior to study drug.
* History of allergy to study drug components and history of severe hypersensitivity reaction to any monoclonal antibody.
* Concurrent treatment with other systemic cancer-derived pharmacotherapies is not allowed. No other concomitant intrathecal therapy is allowed.
* Any investigational anticancer therapy other than those under investigation in this study.
* Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements.
* Intention to become pregnant during the course of the study. Women who are pregnant.
* Women who are breast feeding and who do not agree to discontinue nursing prior to the first study treatment and for the period defined in the protocol.
* Sexually active men and women of childbearing potential who are not willing to use an effective contraceptive method during the study.
