Current and emerging concepts for systemic treatment of metastatic colorectal cancer
Christoph Steup et al.
Abstract
Colorectal cancer (CRC) is one of the most common malignant cancers and its incidence is steadily rising particularly in young patients. While screening measures and the widespread availability of surgical treatment have led to an impressive improvement of prognosis within the overall CRC population, patients with metastatic CRC still face 5-year survival rates of around 10–25%. Despite continuous development of new systemic treatment strategies that include cytotoxic chemotherapy and targeted therapy, most patients with metastatic CRC eventually progress. However, a small proportion of patients with mismatch repair-deficient or microsatellite unstable CRC responds exceptionally well to treatment with immune checkpoint inhibitors, thereby proving that CRC is in principle amenable to immunotherapy and showing that long-term disease stabilisation can be achieved even in metastasised stages. However, the reasons for the lack of response to immunotherapy in the vast majority of CRC cases remain to be elucidated. Yet, recent evidence suggests that the tumour stroma, which includes non-immune cells in the colorectal tumour microenvironment, mediates immunosuppressive mechanisms that prevent effective immunotherapy. These findings open new avenues for the development of advanced immunotherapies for CRC. In this review, we summarise major developments in the systemic therapy of CRC within the last couple of decades, provide an overview of emerging and soon-to-be implemented therapeutic strategies and present concepts from clinical and preclinical research to manipulate tumour cells and the tumour stroma to sensitise microsatellite stable colorectal tumours to immunotherapy.
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WHAT IS ALREADY KNOWN ON THIS TOPIC
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Despite major advances in multimodal treatment for metastatic colorectal cancer (mCRC) – including radical surgical resection of local and distant disease, radiotherapy, ablation and various combinatorial and targeted systemic treatments – patient prognosis has only modestly improved over the past decades.
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For the small subset of patients with mismatch repair-deficient (dMMR)/microsatellite instability high CRC, immune checkpoint blockade (ICB) has tremendously improved prognosis.
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The majority of mismatch repair-proficient (pMMR)/microsatellite stable (MSS) mCRCs does not respond to ICB.
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Novel biomarker-driven treatment approaches for pMMR/MSS mCRC, targeting factors such as VEGF(R) (vascular endothelial growth factor (receptor)), EGFR (epidermal growth factor receptor), ERBB2 (erb-b2 receptor tyrosine kinase 2) and KRAS (Kirsten rat sarcoma) p.G12C, continue to expand treatment options but do not replicate the striking therapeutic effect of ICB in dMMR/MSS mCRC.
WHAT THIS STUDY ADDS
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The tumour microenvironment (TME), which includes tumour-infiltrating immune cells and stromal cells such as cancer-associated fibroblasts, can serve as a pool of predictive and prognostic biomarkers in CRC, with the immunoscore being an important example.
HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY
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Together with approaches that aim to augment the immunogenicity of pMMR/MSS tumours, TME-targeted and stroma-targeted therapies represent a promising strategy to overcome ICB resistance.
Figure 1
Metastatic colorectal cancer therapy evolution. Median overall survival for systemic treatment and in regard to surgical resection is based on Zeineddine, FA, Zeineddine, MA, Yousef, A et al. Survival improvement for patients with metastatic colorectal cancer over twenty years. npj Precis. Onc. 7, 16 (2023). The median response and survival times reported for the sequential treatment options are based on prototypical patients who are willing to undergo intensive treatment and who are fit and healthy enough. If patients are unable or unwilling to receive the proposed intensive treatment, further treatment should be determined through a process of shared decision-making with the patient. Whenever treatment is ended, further therapy should be symptom-driven in the form of best supportive care. Treatment durations are estimated based on progression-free survival in the relevant trials indicated or discussed in the text. There is a large interindividual variation in progression-free survival, and therefore the actual duration of treatment may be shorter for patients with progressive disease and longer for those with stable disease based on tumour biology. Some patients may even undergo treatment breaks, which are not shown for graphical illustration purposes. Further, for the MSI-high/dMMR subgroup, the overall survival data are not available yet and therefore the response times for further treatment lines can only be estimated, and some patients will not need further treatment due to a complete response. In addition, experimental therapies in clinical trials should be considered at any new treatment point. The figure is not intended to be used as a treatment algorithm and local guidelines should always be used for clinical decision-making and local drug approval status must be considered. BRAF, v-Raf murine sarcoma viral oncogene homolog B; CLMR, colorectal cancer liver metastasis resection; CRC, colorectal cancer; dMMR, mismatch repair deficiency; EGFR, epidermal growth factor receptor; ERBB2, erb-b2 receptor tyrosine kinase 2; FDA, Food and Drug Administration; FOLFOX, doublet chemotherapy regimen with intravenous fluorouracil/leucovorin and oxaliplatin; FOLFIRI, doublet chemotherapy regimen with intravenous fluorouracil/leucovorin and irinotecan; HER2, human epidermal growth factor receptor 2; KRAS, Kirsten rat sarcoma; mCRC, metastatic CRC; mOS, median OS; MSI, microsatellite instability; MSS, microsatellite stable; OS, overall survival; pMMR, mismatch repair proficient; RAS, rat sarcoma; TS-1/S-1, tegafur/gimeracil/oteracil; VEGF, vascular endothelial growth factor; VEGFR, VEGF receptor; WT, wild type.
