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 KRASG12C 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. Over the past few years, several novel therapies, including targeted therapies for specific subgroups as well as several non-targeted therapies, have been developed and approved for patients with chemorefractory metastatic colorectal cancer (CRC). Nonetheless, selecting patients who are most likely to benefit from one specific therapy is challenging owing to a lack of direct comparisons of the efficacy of these agents in specific settings. In this Review, the authors summarize the available evidence on the efficacy and safety of later-line therapies for patients with advanced-stage CRC and suggest an evidence-based treatment-selection algorithm. Several novel systemic therapies have emerged for unselected patients with treatment-refractory metastatic colorectal cancer, thus making the choice of later-line therapy a challenging issue for medical oncologists.Furthermore, the results of practice-changing trials, some with histology-agnostic designs, have opened several novel therapeutic avenues for subgroups with tumours harbouring actionable alterations.Other options include retreatment with anti-EGFR antibodies following at least an intervening line of therapy, which can be effective in patients who previously derived benefit from these agents, in the absence of resistance mutations on circulating tumour DNA.In this rapidly evolving treatment landscape, many early trials evaluating novel compounds and treatment combinations in patients with treatment-refractory metastatic colorectal cancer are ongoing.