Successful Treatment With Lorlatinib Monotherapy for Secondary Central Nervous System Oligometastatic Disease in Refractory Anaplastic Lymphoma Kinase Positive Non-small Cell Lung Cancer.

The anaplastic lymphoma kinase (ALK) gene plays crucial roles in both normal brain development and oncogenesis, particularly in non-small cell lung cancer (NSCLC). Metastatic ALK-positive NSCLC is characterized by ALK tyrosine kinase domain rearrangements, prompting the use of ALK tyrosine kinase inhibitors (TKIs) to target the mutation. While first-line treatment options include alectinib, brigatinib, and lorlatinib per National Comprehensive Cancer Network (NCCN) guidelines, therapeutic challenges arise in cases of disease progression. Management strategies may involve radiation therapy, switching to alternative ALK inhibitors, or testing for resistance mutations like ALK G1202R to guide treatment selection, with lorlatinib emerging as an alternative treatment option. Here, we present the case of a 35-year-old male diagnosed with metastatic ALK-positive NSCLC. Despite initial stability on alectinib therapy, disease progression necessitated therapeutic modification, including a switch to brigatinib and subsequent treatment with lorlatinib monotherapy. Notably, the patient achieved complete remission radiologically and clinically following treatment with lorlatinib, highlighting its efficacy in refractory disease settings. While molecular research supports lorlatinib's superior central nervous system (CNS) penetrability and systemic efficacy, the absence of head-to-head clinical trials presents a significant gap in evidence. Direct comparison of second and third-generation ALK inhibitors is essential to elucidate their comparative efficacy and adverse event profiles, which could refine current management guidelines. Furthermore, if lorlatinib proves superior in terms of progression-free survival, it may offer the potential to delay or obviate the need for radiation therapy, thus mitigating the risk of neurotoxic adverse events associated with these modalities.