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Background We evaluated whether next generation sequencing (NGS) of cfDNA could be used for patient selection and as a tumor clone response biomarker in patients with advanced cancers participating in early phase clinical trials of targeted drugs. Methods Plasma samples from patients with known tumor mutations who completed at least 2 courses of investigational targeted therapy were collected monthly, until disease progression. NGS was performed sequentially on the Ion Torrent PGM platform. Results cfDNA was extracted from 39 patients with various tumor types. Treatments administered targeted mailnly the PI3K-AKT-mTOR pathway (n=28) or MEK (n=7). Overall 159 plasma samples were sequenced with a mean sequencing coverage achieved of 1,685X across experiments. At trial initiation (C1D1), 23 of 39 (59%) patients had at least one mutation identified in cfDNA (mean 2, range 1-5). TP53, PIK3CA and KRAS were the top 3 mutated genes identified, with 16 (39%), 9 (22%) and 8 (17%) different mutations, respectively. Out of these 23 patients, 13 received a targeted drug matching their tumor profile. For the 23 patients with cfDNA mutation at C1D1, the monitoring of mutation allele frequency (AF) in consecutive plasma samples during treatment with targeted drugs demonstrated potential treatment associated clonal responses. Longitudinal monitoring of cfDNA samples with multiple mutations indicated the presence of separate clones behaving discordantly. Molecular changes at cfDNA mutation level were associated with time to disease progression by RECIST criteria. Conclusion Targeted NGS of cfDNA has potential clinical utility to monitor the delivery of targeted therapies.