Unique molecular features and clinical outcomes in young patients with non-small cell lung cancer harboring ALK fusion genes

This study aimed to determine the molecular features and clinical outcomes of young patients with non-small cell lung cancer (NSCLC) harboring ALK fusion genes. We interrogated the genomic profile of 1652 patients with lung cancer who underwent targeted next-generation sequencing to screen for candidate oncogenic drivers using histological specimens acquired from January 2016 to December 2018. ALK fusions were identified in 101 NSCLC patients, and 52 of them were diagnosed before the age of 50 years (52/367, 14.2%). Of the 52 patients with early-onset disease, 22 (42.3%) were male and 43 (82.7%) never smoked; the median patient age was 44 years (range 28–50 years). The most frequently occurring ALK fusion partner was EML4, which was identified in 80.8% (42/52) of young patients. Compared to the older patients, patients with early-onset disease were more likely to harbor EML4-ALK variant 1 (38.5% vs. 14.3%; P = 0.007). We also identified rare ALK fusions, including CHRNA7-ALK, TACR1-ALK, HIP1-ALK, DYSF-ALK and ITGAV-ALK, in patients with early-onset disease, and patients with these fusions responded well to crizotinib treatment. A statistically significant difference was observed in progression-free survival (PFS) between the young patients and older patients who received crizotinib as the first-line therapy (17.5 months vs 9.0 months, P = 0.048). However, the median PFS of young patients harboring concurrent TP53 mutations was only 6.2 months. Unique genetic characteristics were found in ALK-rearranged NSCLC patients with early disease onset, and these patients responded better to crizotinib and had longer PFS compared to patients with later disease onset. However, patients with concomitant TP53 mutations may not have a significant response to treatment.