Distribution of ALK Fusion Variants and Correlation with Clinical Outcomes in Chinese Patients with Non-Small Cell Lung Cancer Treated with Crizotinib.

Abstract

ALK-rearranged non-small cell lung cancer (NSCLC) represents a molecular subgroup with high sensitivity to ALK inhibitors. Crizotinib, a US Food and Drug Administration (FDA)-approved tyrosine kinase inhibitor for treating ALK-rearranged NSCLC, has shown remarkable response in ALK-positive NSCLC. However, heterogeneity of clinical responses exists among different ALK fusion partners. Several small studies have investigated the correlation between fusion partners and efficacy, but not yielded consistent results. We investigated the prevalence of ALK rearrangements in a Chinese NSCLC population, and correlated clinical outcomes of crizotinib with different ALK partners/variants. We retrospectively reviewed genomic profiling and clinical data of 110 ALK-rearranged NSCLC patients from five centers. The clinical response to crizotinib and survival data in ALK-positive patients was retrospectively analyzed. A total of 134 ALK rearrangements with 39 partners were identified in 110 patients (5.6%) among a cohort of 1971 NSCLC patients. The most frequently occurring ALK fusion partner was EML4, which was identified in 71.6% (96/134) of all of the rearrangements in 87.3% (96/110) patients, and with variant 3 (41/96, 42.7%) as the main variant type. No statistically significant differences in terms of progression-free survival (PFS) and overall survival (OS) were found between EML4-ALK and non-EML4-ALK NSCLC patients in our cohort (PFS, p = 0.207; OS, p = 0.678). Outcomes did not differ significantly between patients above and below 40years of age (PFS, p = 0.427; OS, p = 0.686), nor between patients treated with crizotinib in different lines of therapy (PFS, p = 0.171; OS, p = 0.922). For EML4-ALK-positive NSCLC (n = 96), patients harboring variant 3 or variant 5 displayed significantly lower PFS and OS than those with other variants (PFS, 8.6 vs. 11.3months, p = 0.046; OS, 31.0 vs. 37.6months, p = 0.026). In addition, patients with a single EML4-ALK rearrangement event displayed favorable PFS (10.0 vs. 7.2months, p = 0.040) and OS (36.0 vs. 20.0months, p = 0.029) compared to those harboring multiple ALK rearrangements. This study illustrates the patterns of ALK fusion variants present in Chinese NSCLC patients and might help explain heterogeneous clinical outcomes to crizotinib treatment according to different ALK fusion variants.