Panelists discuss how third-line metastatic colorectal cancer treatment has evolved from limited options like FOLFOX and FOLFIRI to multiple available agents including regorafenib, trifluridine/tipiracil, trifluridine/tipiracil plus bevacizumab, and fruquintinib, emphasizing the importance of comprehensive biomarker testing to identify rare fusions and actionable targets before selecting among these therapies, each with distinct mechanisms of action and tolerability profiles that require careful sequencing and adherence management to optimize clinical outcomes.