Beyond ALK fusion positivity: structural complexity as a prognostic indicator in first-line ALK-TKI therapy

Although tyrosine kinase inhibitors (TKIs) have significantly improved survival outcomes in patients with anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC), the efficacy of current TKIs for emerging ALK rearrangement subtypes warrants further investigation, particularly with the advancements in genomic sequencing technologies.

We retrospectively analyzed 118 NSCLC patients with ALK rearrangements identified by next-generation sequencing (NGS) from January 2015 to April 2024. Among these, 89 patients who received first-line ALK-TKIs were assessed to determine therapeutic outcomes based on ALK rearrangement subtypes.

Among 118 NSCLC patients, 36 (30.5%) harbored nonreciprocal/reciprocal translocations, 73 (61.9%) carried solitary EML4-ALK fusion, and 9 (7.6%) had solitary non-EML4-ALK fusions. Of the 89 patients treated with first-line TKIs, 60 (67.4%) had solitary 3'-ALK fusions, whereas 29 (32.6%) exhibited nonreciprocal/reciprocal ALK translocations. Compared with patients harboring solitary 3'-ALK fusions, those with nonreciprocal/reciprocal translocations experienced significantly shorter median progression-free survival (mPFS) (15.6 vs. 31.1 months; HR = 1.805; P = 0.048), although no significant difference in median overall survival (mOS) was observed (66.6 vs. 75.7 months; HR = 1.162; P = 0.714). Additionally, TP53 mutations were the most common co-occurring alterations in both groups, with no significant difference in frequency (P = 0.650).

Nonreciprocal/reciprocal ALK translocations represent an independent adverse prognostic factor for ALK-positive NSCLC patients compared with solitary 3'-ALK fusions. However, their poorer prognosis does not appear to be directly associated with TP53 co-mutations.