Repotrectinib's Clinical Benefit and Its Brain Penetration in a Patient with Meningeal Carcinomatosis from G2032R-Mutated ROS-1 Positive Non-Small Cell Lung Cancer.

In this work, we report on a clinically significant response of meningeal carcinomatosis to repotrectinib in a woman with a heavily pretreated ROS1-rearranged non-small cell lung cancer (NSCLC) that harbored the concomitant solvent front G2032R mutation. Meningeal carcinomatosis has a higher incidence in oncogene addicted NSCLC due to increased life expectancy, yet no report has ever documented the activity of repotrectinib in this context. In line with its activity, we documented the presence of the drug at potentially active concentrations in the cerebrospinal fluid. Nevertheless, the short-lived response reported by our patient highlights the importance for novel ROS1-tyrosine kinase inhibitors (TKIs) to be specifically developed to be able to penetrate the blood-brain barrier.

An Updated Overview of the Magnetic Resonance Imaging of Brain Iron in Movement Disorders.

Brain iron load is one of the most important neuropathological hallmarks in movement disorders. Specifically, the iron provides most of the paramagnetic metal signals in the brain and its accumulation seems to play a key role, although not completely explained, in the degeneration of the basal ganglia, as well as other brain structures. Moreover, iron distribution patterns have been implicated in depicting different movement disorders. This work reviewed current literature on Magnetic Resonance Imaging for Brain Iron Detection and Quantification (MRI-BIDQ) in neurodegenerative processes underlying movement disorders.

Fractionated Stereotactic Sequential Boost in a Selected Cohort of Glioblastoma Patients: A Mono-institutional Analysis.

AIM: To retrospectively assess toxicity and survival in 15 selected Glioblastoma patients treated with a sequential fractionated stereotactic radiotherapy (FSRT) boost after chemo-radiotherapy (CHT-RT) and compare their survival outcomes with a control group. PATIENTS AND METHODS: Toxicity was assessed with the CTCAE 3.0 scale. The Kaplan-Meier method was used to design survival curves, log-rank test for bivariate analysis and Cox proportional hazard regression model for multivariate analysis. RESULTS: The median follow-up was 16 months (range=5-60). One case of headache and one of radionecrosis (RN) occurred. Median overall survival (OS) was 25 months in the boost group vs. 14 in the no-boost group (p=0.004). Median progression-free survival (PFS) was 15 months in the boost group versus 8 in the no-boost group (p=0.046). At multivariate analysis FSRT boost resulted significantly associated with OS and PFS. CONCLUSION: In our series a sequential FSRT boost resulted in safe outcomes and significantly associated with survival.

Alectinib's activity against CNS metastases from ALK-positive non-small cell lung cancer: a single institution case series.

In the present study we assessed the activity of the next-generation anaplastic lymphoma kinase (ALK)-tyrosine kinase inhibitor (-TKI) alectinib, in patients with ALK-postive, advanced non-small cell lung cancer (NSCLC) and central nervous system (CNS) metastases. NSCLCs with ALK-positive disease, as assessed by fluorescence in situ hybridization, and CNS metastases were treated with alectinib 600 mg BID. Included patients were followed prospectively in order to evaluate the efficacy of the drug, with particular emphasis on activity in the CNS. Eleven consecutive patients were enrolled. The majority of them were pretreated with crizotinib (n = 10, 90.9 %), and cranial radiotherapy (n = 8, 72.7 %). Six of the seven patients with measurable CNS disease experienced a CNS response, including three patients who were naïve for cranial radiation. Median duration of response was 8 months. For the whole population, median CNS-progression-free survival (-PFS), systemic-PFS, overall-PFS, overall survival, and 1-year survival were 8, 11, 8, 13 months, and 31.1 %, respectively. Two patients experiencing a CNS response were assessed for alectinib's concentrations in serum and cerebro-spinal fluid (CSF), and showed a CSF-to-serum ratio ranging from 0.001 to 0.003 ng/mL. Alectinib is highly active against CNS metastases from ALK-positive NSCLCs, irrespective of prior treatment(s) with ALK-TKI(s) and/or cranial radiotherapy. The low CSF-to-serum ratio of alectinib suggests that measuring the concentrations of the drug in the CSF may not be a reliable surrogate of its distribution into the CNS.

Osimertinib (AZD9291) and CNS Response in Two Radiotherapy-Naïve Patients with EGFR-Mutant and T790M-Positive Advanced Non-Small Cell Lung Cancer.

The discovery of sensitizing epidermal growth factor receptor (EGFR) mutations as a predictive marker of sensitivity to first-generation EGFR tyrosine kinase inhibitors (TKIs) has dramatically changed the paradigm of care for advanced non-small cell lung cancer (NSCLC) patients. Unfortunately, the majority of patients with EGFR-mutant NSCLC treated with EGFR-TKIs develop acquired resistance within 14-16 months. T790M mutation recently emerged as a major determinant of acquired resistance to gefitinib and erlotinib. Osimertinib (AZD9291) is a novel mono-anilino-pyrimidine third-generation EGFR TKI targeting both sensitizing and T790M EGFR-mutation which showed promising results in T790M-positive NSCLC. Here we report two cases of gefitinib- or erlotinib-pretreated NSCLCs with a T790M mutation-positive (as assessed on plasma through the therascreen EGFR test) disease and untreated, asymptomatic central nervous system metastases that responded to treatment with osimertinib.

Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer.

INTRODUCTION: Central nervous system (CNS) metastases represent an important cause of morbidity and mortality in non-small cell lung cancer (NSCLC) patients. Local approaches of neurosurgery (usually for single brain lesions), whole brain radiotherapy, and stereotactic radiosurgery are often withheld for the treatment of NSCLC-derived brain metastases (BMs). However, systemic treatment is consistently emerging as an option for patients with asymptomatic BMs, which could allow for delaying cranial radiotherapy at symptomatic/radiological progression. AREAS COVERED: Chemotherapy, monoclonal antibodies, tyrosine-kinase inhibitors (TKIs) for molecularly selected NSCLCs, such as epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged diseases, and immune checkpoint inhibitors are all systemic treatments that have shown activity against NSCLC-derived CNS metastases. Among these, EGFR- and ALK-TKIs will be discussed more in detail owing to their superior efficacy in this context. EXPERT OPINION: Up-front systemic treatment should be considered for patients with asymptomatic, multiple BMs, as recently acknowledged by the European Society of Medical Oncology guidelines. Nevertheless, it must be emphasized that the best treatment strategy for NSCLC-derived BMs has to be defined within a multidisciplinary team.