Immune Checkpoint Inhibitors for the Treatment of Central Nervous System (CNS) Metastatic Disease

While the CNS has long been viewed as an immune-privileged environment, a paradigm shift in neuro-immunology has elevated the role of systemic immunotherapy for the treatment of metastatic disease. Increasing knowledge regarding the presence of a CNS lymphatic system and the physical and biochemical alteration of the blood brain barrier (BBB) by the tumor microenvironment suggests immune cell trafficking in and out of the CNS is possible. Emerging clinical data suggest immune checkpoint inhibitors (ICIs) can stimulate T cells peripherally to in turn have anti-tumor effects in the CNS. For example, anti-programmed cell death-1 (PD-1) monotherapy with pembrolizumab has shown intracranial response rates of 20–30% in patients with melanoma or non-small cell lung cancer (NSCLC) brain metastases. The combination of nivolumab and ipilimumab [anti-PD-1 and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4)] showed an intracranial response rate of 55% in patients with melanoma brain metastases. More data are needed to confirm these response rates and to determine mechanisms of efficacy and resistance. While local therapies such as stereotactic radiosurgery (SRS), whole-brain radiation therapy (WBRT), and surgery remain current mainstays, ICIS offer potential decreased neurotoxicity. This review summarizes the biological rationale for systemic immunotherapy to treat CNS metastatic disease, existing clinical data on ICIs in this setting and ongoing clinical trials exploring areas of unmet need

Phase I/randomized phase II trial of TRC105 plus bevacizumab versus bevacizumab in recurrent glioblastoma: North Central Cancer Treatment Group N1174 (Alliance)

Background Patients with glioblastoma (GBM) have a poor prognosis and limited effective treatment options. Bevacizumab has been approved for treatment of recurrent GBM, but there is questionable survival benefit. Based on preclinical and early clinical data indicating that CD105 upregulation may represent a mechanism of resistance to bevacizumab, we hypothesized that combining bevacizumab with the anti-CD105 antibody TRC105 may improve efficacy in recurrent GBM.Methods Phase I dose-escalation/comparative randomized phase II trial in patients with GBM. During phase I, the maximum tolerated dose (MTD) of TRC105 in combination with bevacizumab was determined. In phase II, patients were randomized 1:1 to TRC105 and bevacizumab or bevacizumab monotherapy. Patients receivedTRC105 (10 mg/kg) weekly and bevacizumab (10 mg/kg) every 2 weeks. Efficacy, as assessed by progression-free survival (PFS), was the primary endpoint; safety, quality of life, and correlative outcomes were also evaluated.Results In total, 15 patients were enrolled in phase I and 101 in phase II; 52 patients were randomized to TRC105 with bevacizumab and 49 to bevacizumab monotherapy. The MTD was determined to be 10 mg/kg TRC105 weekly plus bevacizumab 10 mg/kg every 2 weeks. An increased occurrence of grade >= 3 adverse events was seen in the combination arm, including higher incidences of anemia. Median PFS was similar in both treatment arms: 2.9 months for combination versus 3.2 months for bevacizumab monotherapy (HR = 1.16, 95% CI = 0.75-1.78, P = .51). Quality of life scores were similar for both treatment arms.Conclusions TRC105 in combination with bevacizumab was well tolerated in patients with recurrent GBM, but no difference in efficacy was observed compared to bevacizumab monotherapy

Updates on Molecular Targeted Therapies for Intraparenchymal CNS Metastases

Central nervous system (CNS) metastases can occur in a high percentage of systemic cancer patients and is a major cause of morbidity and mortality in these patients. Almost any histology can find its way to the brain, but lung, breast, and melanoma are the most common pathologies seen in the CNS from metastatic disease. Identification of many key targets in the tumorigenesis pathway has been crucial to the development of a number of drugs that have demonstrated successful penetration of the blood–brain, blood–cerebrospinal fluid, and blood–tumor barriers. Targeted therapy and immunotherapy have dramatically revolutionized the field with treatment options that can provide successful and durable control of even CNS disease. In this review, we discuss major targets with successful treatment options as demonstrated in clinical trials. These include tyrosine kinase inhibitors, monoclonal antibodies, and antibody–drug conjugates. We also provide an update on the state of the field and highlight key upcoming trials. Patient-specific molecular information combined with novel therapeutic approaches and new agents has demonstrated and continues to promise significant progress in the management of patients with CNS metastases

Updates on Molecular Targeted Therapies for Intraparenchymal CNS Metastases.

Central nervous system (CNS) metastases can occur in a high percentage of systemic cancer patients and is a major cause of morbidity and mortality in these patients. Almost any histology can find its way to the brain, but lung, breast, and melanoma are the most common pathologies seen in the CNS from metastatic disease. Identification of many key targets in the tumorigenesis pathway has been crucial to the development of a number of drugs that have demonstrated successful penetration of the blood-brain, blood-cerebrospinal fluid, and blood-tumor barriers. Targeted therapy and immunotherapy have dramatically revolutionized the field with treatment options that can provide successful and durable control of even CNS disease. In this review, we discuss major targets with successful treatment options as demonstrated in clinical trials. These include tyrosine kinase inhibitors, monoclonal antibodies, and antibody-drug conjugates. We also provide an update on the state of the field and highlight key upcoming trials. Patient-specific molecular information combined with novel therapeutic approaches and new agents has demonstrated and continues to promise significant progress in the management of patients with CNS metastases

CSF-Administered Therapies for Leptomeningeal Metastases from Solid Tumors - supplementary material

Supplementary File A: Table Compiling Key Data from Intrathecal trials for treatment of Leptomeningeal Metastasis (LM)</p