Multicenter prospective study of ctDNA-based MRD detection in stage III NSCLC treated with chemoradiotherapy and durvalumab

Benefit from durvalumab after chemoradiotherapy (CRT) varies widely in unresectable stage III NSCLC. Circulating tumor DNA (ctDNA)-based minimal residual disease (MRD) detection may help identify patients at high risk of early treatment failure during and after durvalumab. In a multicenter prospective study in Norway, patients with unresectable stage III NSCLC received CRT followed by durvalumab. Plasma samples were collected at screening, after CRT, at predefined timepoint during durvalumab, and during post-treatment follow-up. A tumor-agnostice, hybrid-capture ctDNA MRD assay personalized to each patients classified samples as ctDNA detected (MRD-positive) or not detected (MRD-negative). A total of 659 plasma samples from 84 patients were analyzed. Detectable ctDNA before the seventh durvalumab cycle (HR 2.45; p=0.013) and three months after treatment completion (5.37; p<0.001) was strongly associated with inferior progression-free survival, whereas ctDNA detection after CRT but before durvalumab initiation was not prognostic (1.38; p=0.269). In a multivariable model incorporating all post-CRT samples, detectable ctDNA was associated with a nearly threefold higher risk of progression (HR 2.95; p<0.001). The authors conclude that serial ctDNA-based MRD assessment may help identify patients at high risk of relapse who could benefit from alternative treatment strategies (graphical abstract).