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

Nature Reviews Clinical Oncology volume 22, pages 28–45 (2025)Cite this article

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Abstract

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.

Key points

  • 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.

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Fig. 1: Timeline of available targeted and untargeted options for patients with treatment-refractory metastatic CRC.
Fig. 2: Suggested algorithm for selection of late-line treatment in patients with metastatic CRC.

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  1. Unit of Medical Oncology 2, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy

    Paolo Ciracì, Vittorio Studiale, Ada Taravella, Carlotta Antoniotti & Chiara Cremolini

  2. Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy

    Paolo Ciracì, Vittorio Studiale, Ada Taravella, Carlotta Antoniotti & Chiara Cremolini

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Ciracì, P., Studiale, V., Taravella, A. et al. Late-line options for patients with metastatic colorectal cancer: a review and evidence-based algorithm. Nat Rev Clin Oncol 22, 28–45 (2025). https://doi.org/10.1038/s41571-024-00965-0

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