Analysis of clinical features and outcomes in a Chinese cohort with ALK fusion across pan-cancer: a retrospective study

Abstract

Background ALK fusions are validated oncogenic drivers, yet their molecular heterogeneity and therapeutic implications remain poorly characterized. This study defined the landscape of ALK fusion partners, EML4-ALK variants, and co-mutations and their impact on treatment responses in a large Chinese pan-cancer cohort. Methods We retrospectively analyzed 16,335 consecutive pan-cancer patients via next-generation sequencing to identify ALK fusions. Clinical characteristics, fusion partners, co-mutations, and treatment responses were evaluated. Progression-free survival (PFS) was assessed in advanced non-small cell lung cancer (NSCLC) patients receiving first-line ALK tyrosine kinase inhibitors (TKIs), stratified by EML4-ALK variants and TP53 status. Results ALK fusions were detected in 321 patients. NSCLC accounted for 93.1% (299/321), predominantly adenocarcinomas (292/299, 97.7%). EML4 was the predominant fusion partner, accounting for 92.1% of ALK fusion in lung adenocarcinoma but only 27.3% in extrapulmonary tumors. Conversely, non-EML4 fusions were more frequent in extrapulmonary tumors (72.7%). Among 13 evaluable advanced-stage patients with rare ALK fusions, 10 achieved objective response (76.9%). In 161 advanced or recurrent NSCLC patients treated with ALK-TKIs, the median PFS was 28.2 months. Patients with long EML4-ALK variants had superior PFS than those with short variants when treated with second-generation TKIs (55.7 vs. 27.1 months; p = 0.019). TP53 co-mutations were associated with shorter PFS in the first-generation TKI subgroup (5.6 vs. 21.4 months; p = 0.009). Conclusions While ALK fusion partners exhibit tumor-type specificity, ALK-TKIs demonstrate potential efficacy in rare fusions though these findings are exploratory and need validation. Short EML4-ALK variants and TP53 co-mutation are associated with poorer TKI efficacy.