Therapeutic Advances of Rare ALK Fusions in Non-Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer cases and is the leading cause of cancer-related death. Despite advances in chemotherapy and immunotherapy, the prognosis for advanced patients remains poor. The discovery of oncogenic driver mutations, such as anaplastic lymphoma kinase (ALK) mutations, means that a subset of patients has opportunities for targeted therapy. With the improvement of genetic testing coverage, more and more ALK fusion subtypes and ALK partners have been discovered, and more than 90 rare ALK fusion subtypes have been found in NSCLC. However, unlike the common fusion, echinoderm microtubule-associated protein-like 4 (EML4)-ALK, some rare ALK fusions such as striatin (STRN)-ALK and huntingtin interacting protein 1 (HIP1)-ALK, etc., the large-scale clinical data related to its efficacy are still immature. The clinical application of ALK-tyrosine kinase inhibitors (ALK-TKIs) mainly depends on the positivity of the ALK gene, regardless of the molecular characteristics of the fusion partner. Recent clinical studies in the ALK-positive NSCLC population have demonstrated differences in progression-free survival (PFS) among patients based on different ALK fusion subtypes. This article will introduce the biological characteristics of ALK fusion kinase and common detection methods of ALK fusion and focus on summarizing the differential responses of several rare ALK fusions to ALK-TKIs, and propose corresponding treatment strategies, so as to better guide the application of ALK-TKIs in rare ALK fusion population.