Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors through Longitudinal Analysis of Circulating Tumor DNA.

PURPOSE

rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, responses to ALK TKIs are generally short-lived. Serial molecular analysis is an informative strategy for identifying genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer.

METHODS

Using a 566-gene hybrid-capture next-generation sequencing (NGS) assay, we performed longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue-plasma concordance, we compared plasma findings to results of repeat biopsies.

RESULTS

At progression, we detected an fusion in plasma from 19 (86%) of 22 patients, and identified resistance mutations in plasma specimens from 11 (50%) patients. There was 100% agreement between tissue- and plasma-detected fusions. Among 16 cases where contemporaneous plasma and tissue specimens were available, we observed 100% concordance between mutation calls. mutations emerged and disappeared during treatment with sequential ALK TKIs, suggesting that plasma mutation profiles were dependent on the specific TKI administered. G1202R, the most frequent plasma mutation detected after progression on a second-generation TKI, was consistently suppressed during treatment with lorlatinib.

CONCLUSIONS

Plasma genotyping by NGS is an effective method for detecting fusions and mutations in patients progressing on ALK TKIs. The correlation between plasma mutations and response to distinct ALK TKIs highlights the potential for plasma analysis to guide selection of ALK-directed therapies.