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.

在过去的几年里，针对难治性转移性结直肠癌患者出现了几种新的全身治疗方法，因此选择最有效的后线疗法对肿瘤内科医生来说是一个挑战。在过去十年中，瑞戈非尼和曲氟尿苷-替吡嘧啶是唯一可用的药物，与最佳支持性治疗相比，其临床益处通常有限。随后改变实践的试验结果为未经选择的患者（如曲氟尿苷-替吡嘧啶加贝伐珠单抗或呋喹替尼）和肿瘤存在可操作改变（如 HER2 靶向治疗或 KRAS^G12C 抑制剂）或对循环肿瘤 DNA 中既往接受的靶向药物没有获得性耐药机制（如抗 EGFR 再次治疗）的亚组开辟了几种新的治疗途径。抗体）。在本综述中，我们全面概述了过去几年该领域的进展，并提供了使用循证算法将最相关结果转化为转移性结直肠癌患者日常管理的实用观点。最后，我们讨论了一些最具吸引力的持续研究领域，并重点介绍了有可能进一步扩展治疗武器的方法。