Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm

Over the past few years, several novel systemic treatments have emerged for patients with treatment-refractory metastatic colorectal cancer, thus making selection of the most effective later-line therapy a challenge for medical oncologists. Over the past decade, regorafenib and trifluridine-tipiracil were the only available drugs and often provided limited clinical benefit compared to best supportive care. Results from subsequent practice-changing trials opened several novel therapeutic avenues, both for unselected patients (such as trifluridine-tipiracil plus bevacizumab or fruquintinib) and for subgroups defined by the presence of actionable alterations in their tumours (such as HER2-targeted therapies or KRAS^G12C inhibitors) or with no acquired mechanisms of resistance to the previously received targeted agents in circulating tumour DNA (such as retreatment with anti-EGFR antibodies). In this Review, we provide a comprehensive overview of advances in the field over the past few years and offer a practical perspective on translation of the most relevant results into the daily management of patients with metastatic colorectal cancer using an evidence-based algorithm. Finally, we discuss some of the most appealing ongoing areas of research and highlight approaches with the potential to further expand the therapeutic armamentarium.