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

Abstract

Purpose ALK (anaplastic lymphoma kinase) 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 used to identify 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. Patients and Methods We used a 566-gene hybrid-capture next-generation sequencing assay to perform a 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 with the results of repeat biopsies. Results At disease progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients and identified ALK resistance mutations in plasma specimens from 11 patients (50%). There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 patients for which contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, which suggests that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R—the most frequent plasma mutation detected after progression on a second-generation TKI—was consistently suppressed during treatment with lorlatinib. Conclusion Plasma genotyping by next-generation sequencing is an effective method for detecting ALK fusions and ALK mutations in patients who experience disease progression on ALK TKIs. The correlation between plasma ALK mutations and the response to distinct ALK TKIs highlights the potential for plasma analysis to guide the selection of ALK-directed therapies.