Late-line Systemic Therapy in Metastatic Colorectal Cancer: A Narrative Review and Australian Expert Perspective.

Metastatic colorectal cancer (mCRC) remains a major clinical challenge, particularly for patients with disease progression after multiple lines of therapy. Advances in molecular profiling have transformed the therapeutic landscape, enabling personalized treatment selection and expanding third- and later-line options. Targeted therapies such as BRAF inhibitors, anti-HER2 agents, and KRASG12C inhibitors are utilized in patients whose tumors harbor specific molecular alterations, with their use increasingly being explored across various lines of therapy. Agents such as trifluridine/tipiracil, regorafenib, and fruquintinib offer additional benefit in heavily pretreated mCRC. The integration of broad molecular testing, including emerging rare biomarkers, further supports individualized management. Despite these developments, prognosis in late-line mCRC remains poor, underscoring the need for ongoing research and clinical trial participation. This review summarizes contemporary evidence supporting third- and later-line therapies, highlights key clinical trial data, and discusses practical considerations in treatment sequencing. Potential treatment algorithms designed to aid clinicians in the selection and sequencing of therapies for refractory mCRC are also proposed. Anticipated paradigm shifts with novel agents may further refine management strategies and improve outcomes for these patients. As the landscape evolves, ongoing multidisciplinary collaboration will be essential in optimizing both patient selection and therapy sequencing as new options become available.