crizotinib and Meningeal-Carcinomatosis

The central nervous system is a common site of relapse in patients receiving crizotinib, which is presumed to be associated with the low concentration of crizotinib in the cerebrospinal fluid (CSF). Our patient received surgical treatment for anaplastic lymphoma kinase-positive stage IIA lung adenocarcinoma. His cancer recurred with brain metastases and carcinomatous meningitis. We started whole-brain radiation therapy (WBRT) and subsequently administered crizotinib. The concentration of crizotinib on day 15 in the plasma was 158 ng/mL, and that in the spinal fluid was 4.32 ng/mL. WBRT may elevate the CSF/plasma crizotinib concentration ratio; clinicians may therefore consider performing WBRT prior to crizotinib initiation.

Topics: Adenocarcinoma of Lung; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Disease Progression; Fatal Outcome; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Neoplasm Recurrence, Local

Lung cancer is the most common tumor and the leading cause of cancer-related death worldwide. Approximately 6.7% of non-small-cell lung cancers (NSCLCs) show anaplastic lymphoma kinase (ALK) rearrangement and could benefit from ALK-targeted treatment. Various anti-ALK drugs have been developed during the past years, but it is actually controversial which sequence and which ALK inhibitor is recommended for a single patient. Leptomeningeal carcinomatosis (LC) is associated with a poor prognosis, with an overall survival of 2-4 months for treated patients. The data about LC management derive mainly from retrospective studies, being an exclusion criterion for most trials. Intrathecal chemotherapy and whole-brain radiotherapy (WBRT), associated with a systemic treatment, are the most commonly used approach. Here we present a case of NSCLC harboring an ALK translocation treated with four lines of ALK inhibitors and receiving WBRT for LC, showing an overall survival of ∼5 years from the diagnosis of metastatic disease. This case report focuses mainly on several controversial clinical aspects, that is, the sequence of treatment in ALK-positive NSCLC, the ALK inhibitors' efficacy on brain disease and beyond progression, the management of LC, and the role of WBRT despite the risk of cognitive impairment.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Chemoradiotherapy; Cisplatin; Crizotinib; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Pemetrexed; Prognosis

Brigatinib is a second-generation ALK inhibitor which demonstrated activity over crizotinib-resistance, especially on brain metastasis by increased blood-brain penetration. However, its activity on lepto-meningeal disease is unknown and scarcely reported.. We hereby report the case of lepto-meningeal disease in crizotinib- and ceretinib- treated patient who was successfully treated by brigatinib.. The patient achieved intracranial response to brigatinib more than 14 months.. Our case provides additional data on brigatinib's intracranial activity, not only on brain metastasis but also on leptomeningeal disease, after experiencing resistance to both crizotinib and ceretinib, 1

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Brain; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Organophosphorus Compounds; Pyrimidines; Survival Analysis

The mechanisms underlying anaplastic lymphoma kinase (ALK) resistance have not been well investigated in clinical practice. We herein report the case of a lung cancer patient with carcinomatous meningitis who had an ALK I1171T resistance mutation revealed by direct DNA sequencing of the cerebrospinal fluid after treatment with cytotoxic chemotherapy, crizotinib, and alectinib. I1171T is considered to be sensitive to ceritinib. Although ceritinib was not effective initially, we chose ceritinib again after whole-brain radiotherapy and ventriculoperitoneal shunting. Although the response duration was short, spinal magnetic resonance imaging revealed a marked response. The identification of an acquired ALK resistance mutation will aid in choosing the optimum sequence therapy.

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carbazoles; Carcinoma, Non-Small-Cell Lung; Crizotinib; Drug Resistance, Neoplasm; Female; Humans; Lung Neoplasms; Meningeal Carcinomatosis; Mutation; Piperidines; Pyrimidines; Sulfones

Topics: Activin Receptors, Type II; Adult; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cerebellum; Crizotinib; Female; Humans; Meningeal Carcinomatosis; Neoplasm Staging; Piperidines; Pyrazoles; Pyridines; Radiography; Randomized Controlled Trials as Topic

Topics: Adult; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Leptomeningeal carcinomatosis (LM) is an infrequent yet morbid and often fatal complication of non-small cell lung cancer (NSCLC). Management of LM is multimodal, often involving systemic chemotherapy, radiotherapy, and a variety of symptom management maneuvers to address elevated intracranial pressure, pain, and mood changes that can accompany the disease. It is increasingly recognized that tumors with actionable mutations in NSCLC, including epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) translocations, respond well to systemic therapy with tyrosine kinase inhibitors yet often progress in the central nervous system. More information is needed regarding the natural history and optimal management of LM in specific molecular subtypes of NSCLC. This case report summarizes the management of a patient with ALK-positive NSCLC who developed LM while on targeted treatment with crizotinib within the context of current NCCN Clinical Practice Guidelines in Oncology and recently published studies.

Topics: Anaplastic Lymphoma Kinase; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Crizotinib; Disease Progression; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Middle Aged; Molecular Targeted Therapy; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases

Anaplastic lymphoma kinase (ALK) inhibitor has shown dramatic efficacy in non-small cell lung cancer (NSCLC) patients harboring ALK rearrangements in phase I trial. Herein we report two cases of NSCLC patients with leptomeningeal carcinomatosis (LM), treated with ALK inhibitor under emergent use of investigational new drug combined with intrathecal methotrexate treatment. Progression free survival was 10 months and 6 months, respectively, and little additional toxicities were observed. These results suggest that ALK inhibitor might be safely administered even in patients or those with metastases in central nervous system.

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lung Neoplasms; Male; Meningeal Carcinomatosis; Methotrexate; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases