Cerebrospinal Fluid Concentration of the RET Inhibitor Pralsetinib: A Case Report

Abstract

<b><i>Introduction:</i></b> Pralsetinib is used to treat metastatic RET fusion-positive non-small cell lung cancer. Preclinical studies of pralsetinib have shown blood-brain barrier (BBB) penetration and intracranial activity. The intracranial efficacy of pralsetinib in patients with brain metastasis is considered to be greater compared to older multikinase tyrosine kinase inhibitors. However, CSF concentrations of pralsetinib in patients are not well described in the literature. <b><i>Case Presentation:</i></b> We report a case of a patient with RET fusion-positive NSCLC treated with pralsetinib. Despite extracranial clinical and radiological remission, the patient developed progressive brain metastasis during treatment with pralsetinib. We measured the pralsetinib concentration in plasma and in CSF to determine the CSF-to-unbound plasma ratio. The measured pralsetinib concentrations in plasma and CSF were 1,951 ng/mL (∼57 unbound) and 14 ng/mL, respectively, reflecting a CSF-to-unbound plasma concentration ratio of 0.25. Our findings were compared with data from the literature. <b><i>Conclusion:</i></b> We showed that pralsetinib penetrates the CSF well and is expected to be an effective treatment for brain metastasis of RET fusion-positive NSCLC. Lack of intracranial efficacy is more likely to be caused by intrinsic or acquired tumor resistance instead of suboptimal exposure of pralsetinib in the brain.