Third and Later Line Therapy in Metastatic Colorectal Cancer – Current Landscape and Future Perspectives

Background: Colorectal cancer (CRC) is the third most common malignancy globally, with metastatic disease (mCRC) carrying a poor prognosis. Despite advances in first- and second-line therapies, long-term survival in later-line (?3L) mCRC remains limited. Molecular profiling has enabled personalized treatment strategies, yet optimal sequencing and therapy selection in refractory disease are still evolving. Aim: This review aims to summarize current treatment options for ?3L mCRC, highlighting recent advances in targeted therapies, biomarker-driven rechallenge strategies, and the unmet clinical needs in this setting. Main Findings: Regorafenib, an oral multikinase inhibitor, was the first agent approved for ?3L mCRC, providing modest survival benefits primarily through disease stabilization. Trifluridine/tipiracil (FTD/TPI), alone or combined with bevacizumab, improves overall survival (OS) and disease control with manageable hematologic toxicity. Fruquintinib, a selective VEGFR inhibitor, has shown similar efficacy with a favorable safety profile. Molecularly guided therapies, including anti-EGFR rechallenge based on circulating tumor DNA (ctDNA), demonstrate promising clinical acti