Abstract

INTRODUCTION: Despite initial effectiveness of ALK tyrosine kinase inhibitors (TKIs) in patients with ALK+ non-small cell lung cancer (NSCLC), therapeutic resistance will ultimately develop. Serial tracking of genetic alterations detected in circulating tumor DNA (ctDNA) can be an informative strategy to identify response and resistance. This study evaluated the utility of analyzing ctDNA as a function of response to ensartinib, a potent second-generation ALK TKI.METHODS: Pre-treatment plasma was collected from 76 patients with ALK+ NSCLC who were ALK TKI naive or had received prior ALK TKI, and analyzed for specific genetic alterations. Longitudinal plasma samples were analyzed from a subset (N=11) of patients. Analysis of pre-treatment tumor biopsies from 22 patients was compared with plasma.RESULTS: Disease-associated genetic alterations were detected in 74% (56/76) of patients, the most common being EML4-ALK. Concordance of ALK fusion between plasma and tissue was 91% (20/22). Twenty-four ALK kinase domain mutations were detected in 15 patients, all had previously received an ALK TKI; G1269A was the most prevalent (4/24). Patients with a detectable EML4-ALK variant 1 (V1) fusion had improved response (9/17, 53%) to ensartinib compared to patients with EML4-ALK V3 fusion (1/7, 14%). Serial changes in ALK alterations were observed during therapy.CONCLUSIONS: Clinical utility of ctDNA was demonstrated, both at pre-treatment by identifying a potential subgroup of ALK+ NSCLC patients that may derive more benefit from ensartinib and longitudinally by tracking resistance. Prospective application of this technology may translate to improved outcomes for NSCLC patients treated with ALK TKIs.

View details for DOI 10.1016/j.jtho.2019.08.003

View details for PubMedID 31446141