A novel HEAT repeat protein 5B anaplastic lymphoma kinase fusion in lung adenocarcinoma confers sensitivity to ensartinib.

Anaplastic lymphoma kinase (ALK) rearrangements are rare but highly actionable drivers in non-small cell lung cancer; however, uncommon fusion variants lack standard management. We report the clinical outcome of a novel HEAT repeat protein 5B (HEATR5B)-ALK fusion treated with ensartinib. A 52-year-old Chinese woman with stage IVA lung adenocarcinoma and left adrenal metastasis underwent tumor biopsy. Targeted DNA-based next-generation sequencing (NGS) identified HEATR5B(END..EX7)-ALK(IVS19..END) fusion; ALK protein expression was confirmed by immunohistochemistry (IHC). Ensartinib 225 mg orally once daily was initiated. Serial CT scans were evaluated according to RECIST 1.1; progression-free survival (PFS) and adverse events were recorded. The patient achieved a confirmed partial response at first restaging and maintained treatment for greater than 24 months without radiologic progression. No grade greater than or equal to 3 adverse events were observed; preexisting weight loss ceased. PFS is ongoing at the last follow-up (24+ months). The HEATR5B-ALK fusion is targetable by ensartinib, producing durable disease control and excellent tolerability. Comprehensive NGS and ALK IHC are essential for detecting rare actionable ALK variants.