Complete Response to Lorlatinib in Lung Adenocarcinoma With EML4-ALK Fusion Variant (E6;A18): Case Report and Literature Review

ALK gene rearrangements represent a targetable driver in non–small cell lung cancer (NSCLC), but rare fusion variants remain poorly characterized and their sensitivity to ALK inhibitors is uncertain. This report describes a 67-year-old woman with stage IV lung adenocarcinoma in whom comprehensive genomic profiling (CGP) identified a rare EML4-ALK (E6;A18) fusion, subsequently confirmed by immunohistochemistry (IHC). Following first-line therapy with lorlatinib, the patient demonstrated rapid clinical improvement, radiologic tumor regression, and a complete metabolic response, including resolution of central nervous system metastases. No significant adverse effects were observed during treatment. This case provides the first evidence of complete and durable response with lorlatinib in a patient with NSCLC harboring the rare EML4-ALK (E6;A18) fusion. This report underscores the importance of integrating CGP with IHC for accurate molecular diagnosis and therapeutic decision-making in the context of atypical ALK fusions. It also highlights the clinical activity of next-generation ALK inhibitors against uncommon fusion variants, suggesting that even structurally distinct fusions may be sensitive to targeted therapy. Further research is warranted to validate treatment strategies in these rare genomic contexts.