Therapeutic landscape and future direction of metastatic colorectal cancer

In the era of targeted therapy based on genomic alterations, the treatment strategy for metastatic colorectal cancer (mCRC) has been changing. Before systemic treatment initiation, determination of tumour genomic status for KRAS and NRAS, BRAF(V600E) mutations, ERBB2, and microsatellite instability and/or mismatch repair (MMR) status is recommended. In patients with deficient MMR and BRAF(V600E) mCRC, randomized phase III trials have established the efficacy of pembrolizumab as first-line therapy and the combination of encorafenib and cetuximab as second-line or third-line therapy. In addition, new agents have been actively developed in other rare molecular fractions such as ERBB2 alterations and KRAS(G12C) mutations. In March 2022, the combination of pertuzumab and trastuzumab for ERBB2-positive mCRC was approved in Japan, thereby combining real-world evidence from the SCRUM-Japan Registry. As the populations are highly fragmented owing to rare genomic alterations, various strategies in clinical development are expected. Clinical development of a tumour-agnostic approach, such as NTRK fusion and tumour mutational burden, has successfully introduced corresponding drugs to clinical practice. Considering the difficulty of randomized trials owing to cost-benefit and rarity, a promising solution could be real-world evidence utilized as an external control from the molecular-based disease registry. The therapeutic landscape of metastatic colorectal cancer (mCRC) is changing. This Review provides a comprehensive overview discussing the current mCRC advances in precision oncology and suggests a treatment strategy for mCRC with rare genomic alterations.

Automated summary

In the era of targeted therapy based on genomic alterations, the treatment strategy for metastatic colorectal cancer (mCRC) is undergoing changes. Determining the genomic status of specific alterations such as KRAS and NRAS, BRAF(V600E) mutations, ERBB2, and microsatellite instability and/or mismatch repair (MMR) status is recommended before starting systemic treatment. Trials have shown the efficacy of pembrolizumab as first-line therapy and the combination of encorafenib and cetuximab as second-line or third-line therapy in patients with deficient MMR and BRAF(V600E) mCRC. New agents are also being developed for rare molecular fractions such as ERBB2 alterations and KRAS(G12C) mutations.