Detection of non-reciprocal/reciprocal ALK translocation as poor predictive marker in first-line crizotinib-treated ALK-rearranged non-small cell lung cancer patients.

Abstract Background During non-reciprocal/reciprocal translocation process, 5'-ALK sometimes get retained in the genome and are detectable by next-generation sequencing (NGS); however, no report have investigated its clinical significance. Our study aimed to assess the impact of harboring 5'-ALK on the efficacy of crizotinib. Patients and methods A total of 150 patients with NGS-identified ALK-rearranged NSCLC from March 2014 to July 2018 at the Hunan Cancer Hospital were enrolled in this study. The efficacy of crizotinib as first-line therapy was evaluated in 112 patients according to the retention of 5'-ALK. Results Among 150 NSCLC patients, non-reciprocal/reciprocal translocation was detected in 18.7% (28/150) and 3'-ALK fusion alone was detected in 81.3% (122/150). Among the 112 patients who received first-line crizotinib, 89 patients had 3'-ALK fusion alone (79 EML4-ALK and 10 non-EML4 ALK) and 23 patients had non-reciprocal/reciprocal ALK translocation. Among the patients with non-reciprocal/reciprocal ALK translocation, 3 patients harbored dual concurrent 3'-ALK fusions. Patients with non-reciprocal/reciprocal ALK translocation had higher incidence of brain metastasis at baseline than those with 3'-ALK fusion alone (39.1% vs. 13.4%, p=0.028). Crizotinib-treated patients with non-reciprocal/reciprocal ALK translocation had significantly shorter mPFS compared with patients carrying 3'-ALK fusion alone (6.1m vs. 12.0m, p=0.001) or with EML4-ALK fusion alone (6.1m vs. 12.6m, p=0.001). Multivariate analysis revealed that harboring non-reciprocal/reciprocal ALK translocation was an independent predictor of worse PFS for crizotinib-treated ALK-rearranged NSCLC (p=0.0046). Conclusions Presence of non-reciprocal/reciprocal ALK translocation was predictive for worse PFS and greater likelihood of baseline brain metastases in patients with ALK-rearranged NSCLC who received first-line crizotinib.