Background: Analysis of cell-free circulating tumor DNA (ctDNA) by next-generation sequencing (NGS) is a promising method to identify druggable genomic alterations, especially when tumor specimen is inadequate for genomic sequencing or targeted sequencing. In our previous study, we have demonstrated an extremely high concordance rate between conventional sequencing and ctDNA sequencing. Based on this result, we designed a prospective trial to test the feasibility of the ctDNA genomics and to test the matched therapy rate in metastatic cancer patients focusing on lung cancer, gastric cancer and melanoma. Methods: The trial was a prospective, master protocol, trial with ctDNA genomic profiling and several matched trials were aligned to this protocol as independent trials. Guardant360 is the first comprehensive NGS-based liquid biopsy for cancer which is a 70-gene blood test interrogating all four major types of genomic alterations. Results: From Aug 2014 to Feb 2016, 210 metastatic cancer patients participated in the trial. Of 210 patients, 200 patients had analyzable ctDNA sequencing data (10 patients excluded due to follow-up loss, withdrawal of consent, etc). 73 patients were lung cancer patients, 78 patients were gastric cancer patients, 36 were melanoma patients and the remaining were rare cancer. The major alterations that were found in ctDNA were EGFR amplification, ERBB2 amplification, MET amplification, PIK3CA H1047R/E545K, TP 53 mutations, KRAS Q12, RET fusion, ALK fusion, EGFR mutation, and KIT mutation. Based on the ctDNA sequencing data, patients were directed to the matched therapy in the context of clinical trials or in clinical practice. The median turnaround time from blood draw to the sequencing report was 14 days. Conclusions: In conclusion, we have shown that the feasibility of ctDNA genomics was very high with extremely low failure rate and rapid turnaround time for sequencing report. The matched therapy rate based on ctDNA genomics will be available at the meeting for presentation. Clinical trial information: NCT02140463