Stage IV colorectal cancer treatment includes targeted therapy depending on RAS status. During disease progression, loss or gain of RAS mutations could happen, supporting the hypothesis of the evolutionary pressure of therapy. Circulating tumor DNA (ctDNA) are nucleic acids released to the bloodstream by the tumor during its development and may be detected by liquid biopsy. The Idylla© Biocartis, a fully automated real-time-PCR-based molecular diagnostic system, was used in a patient with metastatic colorectal cancer with a NRAS mutation in progression after several therapeutic lines. The ctDNA mutational analysis was performed and revealed the absence of mutations in the KRAS, NRAS, and BRAF genes. The patient started the third line of palliative chemotherapy with irinotecan + cetuximab and achieved a partial response for the first time. The authors describe a case in which liquid biopsy determined the higher progression-free survival achieved.