crizotinib and Meningeal-Neoplasms

Topics: Adenocarcinoma of Lung; Antineoplastic Combined Chemotherapy Protocols; Circulating Tumor DNA; Crizotinib; Drug Resistance, Neoplasm; Female; Gefitinib; Gene Amplification; Humans; Lung Neoplasms; Meningeal Neoplasms; Middle Aged; Mutation; Neoplasm Staging; Proto-Oncogene Proteins c-met; Remission Induction

Anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (3 to 5% of all non-small cell lung cancers) carries a particularly high risk of central nervous system dissemination (60% to 90%). As the use of ALK inhibitors improves treatment outcomes over chemotherapy, the determent of central nervous system metastases has become an increasingly relevant therapeutic dilemma considering young age and possible extended overall survival. The goal of brain metastases management is to optimize both overall survival and quality of life, with the high priority of neurocognitive function preservation. Unfortunately in the first year on crizotinib, the pioneering ALK inhibitors, approximately one third of these patients fail in the central nervous system, which is explained by an inadequate central nervous system drug penetration through the blood-brain barrier. Central nervous system-directed radiotherapy represents the most important strategy to control intracranial disease burden and extend the survival benefit with crizotinib. The role of whole brain irradiation in the treatment of brain metastases diminishes, as this technique is associated with the risk of neurocognitive decline. Stereotactic radiotherapy represents an alternative technique that delivers ablative doses of ionizing radiation to the limited volume of oligometastatic brain disease, offering sparing of the adjacent brain parenchyma and reduced neurotoxicity. The next generation ALK inhibitors were designed to cross the blood-brain barrier more efficiently than crizotinib and achieve higher concentration in the cerebrospinal fluid, offering prominent ability to control central nervous system spread. In the phase III ALEX trial the intracranial control was significantly better with alectinib as compared to crizotinib and it translated into survival benefit. Other next generation ALK inhibitors (i.e. ceritinib, brigatinib, lorlatinib) also demonstrated promising activity in the central nervous system.

Topics: Anaplastic Lymphoma Kinase; Animals; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Carbazoles; Carcinoma, Non-Small-Cell Lung; Cisplatin; Clinical Trials as Topic; Combined Modality Therapy; Cranial Irradiation; Crizotinib; Disease Management; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Meningeal Neoplasms; Mice; Molecular Targeted Therapy; Neoplasm Proteins; Neurocognitive Disorders; Observational Studies as Topic; Oncogene Proteins, Fusion; Pemetrexed; Piperidines; Protein Kinase Inhibitors; Radiosurgery

Topics: Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Carcinoma, Non-Small-Cell Lung; Crizotinib; Female; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Spinal Cord Neoplasms; Sulfones; Treatment Outcome

Meningiomas are rare in children. They are highly complex, harboring unique clinical and pathological characteristics, and many occur in patients with neurofibromatosis type 2. Hereby, we present a case of a two-year-old boy presented with a diagnostically challenging intraventricular tumor. It was incompletely resected 6 times over 14 months but kept progressing and was ultimately deemed unresectable. Histologically, the tumor was initially classified as schwannoma, but extensive international review concluded it was most likely an atypical meningioma, WHO grade II. Comprehensive genomic profiling revealed a TFG-ROS1 fusion, suggesting that ROS1-signaling pathway alterations were driving the tumor growth. In light of this new information, the possibility of a diagnosis of inflammatory myofibroblastic tumor was considered; however the histopathological results were not conclusive. This specific molecular finding allowed the potential use of precision medicine and the patient was enrolled in the AcSé phase 2 trial with crizotinib (NCT02034981), leading to a prolonged partial tumor response which is persisting since 14 months. This case highlights the value of precision cancer medicine in children.

Topics: Child, Preschool; Crizotinib; Diagnosis, Differential; Gene Fusion; Humans; Male; Meningeal Neoplasms; Meningioma; Protein-Tyrosine Kinases; Proto-Oncogene Proteins; Pyrazoles; Pyridines; Transforming Growth Factors

BACKGROUND ALK gene rearrangements as oncogenic drivers have been described in many cancers, including inflammatory myofibroblastic sarcoma (IMS). The first-generation ALK inhibitor was limited in its ability to cross the blood-brain-barrier to treat brain metastasis. Drug-resistance invariably develops over time in ALK-rearranged tumors, which leads to disease progression. The newer generations of ALK inhibitors are designed to have higher potency in ALK inhibition and improved CNS penetration. CASE REPORT We report a rare case of pulmonary IMS with ALK-1 gene rearrangement and multiple brain metastases as initial presentation. After the primary lung tumor and the larger brain metastases were resected, control of residual CNS disease and subsequent progression and CNS spread was achieved with favorable clinical response by all three generations of ALK inhibitors. CONCLUSIONS ALK inhibitors may be an effective therapy for this rare and unusual form of ALK-1-rearranged cancer, even in the presence of multifocal CNS metastases with leptomeningeal involvement.

Topics: Adolescent; Aminopyridines; Anaplastic Lymphoma Kinase; Brain Neoplasms; Crizotinib; Female; Gene Rearrangement; Humans; Lactams; Lactams, Macrocyclic; Lung Neoplasms; Meningeal Neoplasms; Myofibroblasts; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Receptor Protein-Tyrosine Kinases; Sarcoma; Sulfones