Overall survival with circulating tumor DNA –guided therapy in advanced non-small-cell lung cancer

Circulating tumor DNA (ctDNA) sequencing guides therapy decisions but has been studied mostly in small cohorts without sufficient follow-up to determine its influence on overall survival. A prospective trial in a binational cohort of advanced NSCLC patients found that detection of ctDNA (64% of patients) was associated with shorter OS (HR 2.05; p<0.001). Among the patients with detectable ctDNA, 23% received targeted therapy matched to the detected ctDNA alteration. This matched therapy was associated with longer OS compared to patients not receiving matched therapy (HR 0.63; p<0.001). Genomic alterations in ctDNA not detected by time-matched tissue sequencing were found in 25% of patients. These ctDNA-only alterations disproportionally featured subclonal drivers of resistance, and were associated with short survival. The authors conclude that minimally invasive ctDNA profiling can identify heterogeneous drivers not captured in tissue sequencing and expand community access to life-prolonging therapy.