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Analysis of circulating tumor DNA (ctDNA) is a potential minimally invasive molecular tool to guide treatment decision-making and disease monitoring. A suitable diagnostic-grade platform is required for the detection of tumor-specific mutations with high sensitivity in the circulating cell-free DNA (ccfDNA) of cancer patients. In this multicenter study, the ccfDNA of 72 patients treated for advanced-stage non-small cell lung cancer (NSCLC) was evaluated using the UltraSEEK^® Lung Panel on the MassARRAY^® System, covering 73 hotspot mutations in <i>EGFR</i>, <i>KRAS</i>, <i>BRAF</i>, <i>ERBB2</i>, and <i>PIK3CA</i> against mutation-specific droplet digital PCR (ddPCR) and routine tumor tissue NGS. Variant detection accuracy at primary diagnosis and during disease progression, and ctDNA dynamics as a marker of treatment efficacy, were analyzed. A multicenter evaluation using reference material demonstrated an overall detection rate of over 90% for variant allele frequencies (VAFs) > 0.5%, irrespective of ccfDNA input. A comparison of UltraSEEK^® and ddPCR analyses revealed a 90% concordance. An 80% concordance between therapeutically targetable mutations detected in tumor tissue NGS and ccfDNA UltraSEEK^® analysis at baseline was observed. Nine of 84 (11%) tumor tissue mutations were not covered by UltraSEEK^®. A decrease in ctDNA levels at 4–6 weeks after treatment initiation detected with UltraSEEK^® correlated with prolonged median PFS (46 vs. 6 weeks; <i>p</i> < 0.05) and OS (145 vs. 30 weeks; <i>p</i> < 0.01). Using plasma-derived ccfDNA, the UltraSEEK^® Lung Panel with a mid-density set of the most common predictive markers for NSCLC is an alternative tool to detect mutations both at diagnosis and during disease progression and to monitor treatment response.