Successful intracranial response of lorlatinib after resistance with alectinib and brigatinib in patients with ALK-positive lung adenocarcinoma: Implications of CNS penetration rate of brigatinib.
Yuki SatoYoshiharu SatoKei IrieShigeki NanjoShigeo HaraSatoru FujiwaraKeisuke TomiiPublished in: Thoracic cancer (2024)
We present the case of a 34-year-old Japanese man with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer and brain metastases. After central nervous system (CNS) disease progression with alecintib and brigatinib, treatment with lorlatinib resulted in a good intracranial response. In this case, we investigated brain penetration ratio of brigatinib using cerebrospinal fluid and paired serum samples, and the ratio was 0.012. Further, we investigated resistance mechanisms via next-generation sequencing (NGS) using lung biopsy at lung cancer diagnosis and brain biopsy sample at progressive disease of brigatinib. No apparent resistance mechanism of known ALK resistance, such as ALK mutations, amplifications, epithelial-mesenchymal transition (EMT) and bypass pathway activation were detected. Taken together, we speculate that the low CNS penetration rate of brigatinib confers CNS progression. Further studies are warranted to reveal the resistance mechanism and propose a treatment strategy for CNS progression in ALK-positive patients.
Keyphrases
- epithelial mesenchymal transition
- blood brain barrier
- advanced non small cell lung cancer
- cerebrospinal fluid
- small cell lung cancer
- end stage renal disease
- resting state
- chronic kidney disease
- magnetic resonance imaging
- newly diagnosed
- gene expression
- ultrasound guided
- dna methylation
- computed tomography
- genome wide
- single cell
- copy number
- high resolution
- optic nerve
- brain injury
- transforming growth factor