Circulating Tumor DNA Monitoring Reveals Molecular Progression before Radiologic Progression in a Real-life Cohort of Patients with Advanced Non–small Cell Lung Cancer

PURPOSE: The clinical potential of liquid biopsy in patients with advanced cancer is real-time monitoring for early detection of treatment failure. Our study aimed to investigate the clinical validity of circulating tumor DNA (ctDNA) treatment monitoring in a real-life cohort of patients with advanced non–small cell lung cancer (NSCLC). EXPERIMENTAL DESIGN: Patients with advanced or noncurative locally advanced NSCLC were prospectively included in an exploratory study (NCT03512847). Selected cancer-specific mutations were measured in plasma by standard or uniquely designed droplet digital PCR assays before every treatment cycle during first-line treatment until progressive disease (PD). Correlation between an increase in ctDNA (= molecular progression) and radiologic PD was investigated, defined as lead time, and the corresponding numbers of likely futile treatment cycles were determined. Utility of ctDNA measurements in clarifying the results of nonconclusive radiologic evaluation scans was evaluated. RESULTS: Cancer-specific mutations and longitudinal plasma sampling were present in 132 of 150 patients. ctDNA was detectable in 88 (67%) of 132 patients treated by respectively chemotherapy (n = 41), immunotherapy (n = 43), or combination treatment (n = 4). In 66 (90%) of 73 patients experiencing PD, a ctDNA increase was observed with a median lead time of 1.5 months before radiologic PD. Overall, 119 (33%) of 365 treatment cycles were administered after molecular progression. In addition, ctDNA measurements could clarify the results in 38 (79%) of 48 nonconclusive radiologic evaluations. CONCLUSIONS: ctDNA monitoring leads to earlier detection of treatment failure, and clarifies the majority of nonconclusive radiologic evaluations, giving the potential of sparing patients from likely futile treatments and needless adverse events. SIGNIFICANCE: Treatment monitoring by ctDNA has the clinical potential to reveal PD before radiologic evaluation and consequently spare patients with advanced cancer from likely ineffective, costly cancer treatments and adverse events.