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Therapeutic landscape and future direction of metastatic colorectal cancer

Nature Reviews Gastroenterology & Hepatology volume 20, pages 306–322 (2023)Cite this article

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Abstract

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, BRAFV600E mutations, ERBB2, and microsatellite instability and/or mismatch repair (MMR) status is recommended. In patients with deficient MMR and BRAFV600E 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 KRASG12C 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.

Key points

  • For the best practice of metastatic colorectal cancer, the determination of tumour genomic status for KRAS and NRAS, BRAFV600E mutations, ERBB2, and microsatellite instability and/or mismatch repair (MMR) status is strongly recommended.

  • Immune-checkpoint inhibitors for patients with microsatellite instability-high and/or MMR-deficient tumours is the established standard therapy; combining immune-checkpoint inhibitors and stimulating agents is an emerging strategy investigated in patients with microsatellite stability and/or proficient MMR tumours.

  • In Japan, trastuzumab plus pertuzumab was approved considering real-world data from the SCRUM-Japan Registry; combining an anti-KRAS-G12C inhibitor and an anti-EGFR antibody is promising in KRASG12C-mutated tumours.

  • Rechallenge of anti-EGFR therapy in former responders with wild-type RAS in circulating tumour DNA assay after an interval of >4 months is also a promising treatment option.

  • Based on longitudinal genomic alteration data from the SCRUM-Japan platform, National Cancer Center Hospital East aims to establish a gene alteration database and identify artificial intelligence-based predictors for a pre-emptive treatment strategy.

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Fig. 1: Frequency of targetable alterations.
Fig. 2: Correlation with SCRUM-Japan-related studies and SCRUM-Japan Registry.
Fig. 3: Proposed treatment chart.
Fig. 4: Suggested strategy for rare molecular fractions.
Fig. 5: Present and next-generation clinical trials for resistant genomic alterations.

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  1. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Hideaki Bando, Atsushi Ohtsu & Takayuki Yoshino

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H.B. reports research funding from Ono Pharmaceutical and honoraria from Taiho Pharmaceutical and Eli Lilly, Japan. A.O. reports research funding from BMS and honoraria from Chugai and Ono Pharmaceutical. T.Y. reports research funding from Taiho Pharmaceutical, Sumitomo Dainippon Pharma, Ono Pharmaceutical, Chugai Pharmaceutical, Amgen, Parexel International, MSD, Daiichi Sankyo and Sanofi.

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Bando, H., Ohtsu, A. & Yoshino, T. Therapeutic landscape and future direction of metastatic colorectal cancer. Nat Rev Gastroenterol Hepatol 20, 306–322 (2023). https://doi.org/10.1038/s41575-022-00736-1

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