Case Report: Complete response and prolonged survival to alectinib in a NSCLC patient with metastases harboring a...

Anaplastic lymphoma kinase (ALK) rearrangements define a distinct molecular subset of non-small cell lung cancer (NSCLC) that is highly sensitive to ALK tyrosine kinase inhibitors (TKIs). While canonical EML4::ALK fusions are well characterized, the clinical significance of rare noncanonical ALK rearrangements and structural alterations remains incompletely understood and may present interpretive challenges across sequencing platforms. Here, we present the case of a 61-year-old never-smoker with metastatic lung adenocarcinoma harboring a rare ALK structural deletion identified through complementary genomic profiling. Initial comprehensive genomic profiling identified an EML4::ALK rearrangement, while subsequent orthogonal DNA/RNA genomic based profiling identified a rare WDR43::ALK structural deletion resulting in a fusion transcript. ALK immunohistochemistry demonstrated ALK protein expression, supporting oncogenic ALK pathway activation despite the atypical genomic architecture. The patient was treated with frontline alectinib and achieved a rapid, deep, and durable response with sustained systemic and intracranial disease control for more than six years. This case highlights the importance of integrative genomic interpretation in precision oncology and supports that rare ALK structural alterations may retain clinically meaningful sensitivity to modern ALK inhibition. As comprehensive sequencing becomes increasingly incorporated into routine oncologic practice, correlation of genomic findings with protein expression, clinicopathologic features, and treatment response may help determine the therapeutic relevance of unconventional ALK alterations.