Few clinical studies have evaluated the role of anti-EGFR therapy rechallenge in metastatic colorectal cancer patients and there is no prospective clinical trial assessing the activity of treatment rechallenge with panitumumab-based therapy after initial progression. This study aims at exploring the concept of evolution and expansion of RAS wild type clones in order to restore sensitivity of the tumor to prior anti-EGFR therapy after a time interval in which a different, non-anti-EGFR second-line therapy is administered. Based on aforementioned data, it is hypothesized that rescue through rechallenge with panitumumab-based third-line therapy combined with chemotherapy could be associated with further response and clinical benefit. A significant component of the proposed prospective trial is exploratory translational: cell free plasma and platelet-based genotyping for genetic mutations in different time points will be undertaken in order to study the genetic composition of the metastatic tumour at initiation of and at progression through, anti-EGFR rechallenge therapy.