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COLORECTAL CANCER IN 2018

New therapies and insights into the changing landscape of colorectal cancer

Nature Reviews Gastroenterology & Hepatology volume 16, pages 79–80 (2019)Cite this article

Subjects

In 2018, advances were made in immunotherapy for colorectal cancers with microsatellite instability but, by contrast, immunotherapy studies in microsatellite-stable colorectal cancer had disappointing results. However, novel insights into the tumour microenvironment barriers that might limit therapeutic efficacy were identified, thereby offering new strategies.

Key advances

  • The incidence of colorectal cancer in young patients continues to rise leading to changes in a key guideline for age of first screening1.

  • Nivolumab and ipiliumumab in combination were approved for treatment of metastatic colorectal cancer with microsatellite instability3.

  • TGFβ was identified as a key modulator of the immunosuppressive tumour microenvironment in microsatellite stable colorectal cancer5.

Colorectal cancer (CRC) is one of the most common cancers worldwide, with 1.8 million new cases in 2018 and approximately one-third of patients presenting with metastatic disease. Challenges in this disease include determining optimal screening strategies to enable early detection and the treatment of advanced disease once detected. A family history of CRC has long prompted screening in individuals <50 years of age, with most recommendations suggesting that screening begin 10 years before the age of diagnosis of the family member1. Universal testing of all CRCs for microsatellite status is now recommended, with a goal of detecting previously unappreciated families with hereditary non-polyposis colorectal cancer (HNPCC) in which early screening is recommended1. This testing, which is usually accomplished through immunohistochemistry tests to look for loss of one of the four mismatch repair proteins, or PCR assays to identify microsatellite regions in the DNA with genomic instability, can identify a subset of tumours classified as deficient in mismatch repair and microsatellite-instability-high (MSI-H). Although not all MSI-H tumours are associated with a hereditary syndrome, they do define a subgroup of tumours with a high mutation load that results in the generation of many neoantigens with high potential for immune recognition. Programmed cell death 1 (PD1) checkpoint inhibition with pembrolizumab or nivolumab has been shown to result in a high response rate and durable disease control in patients with MSI-H CRC2. Cytotoxic T lymphocyte antigen 4 (CTLA4) inhibition has also been shown to provide additional benefit in other settings such as melanoma, and so in 2018 the combination of nivolumab with the CTLA4 inhibitor ipilimumab was reported in a cohort of patients with metastatic MSI-H CRC3. This nonrandomized study enrolled 119 patients who had received more than two prior regimens for their disease3. The treatment regimen consisted of a low 1 mg/kg dose of ipilimumab in combination with four doses of nivolumab (3 mg/kg), followed by continued administration of nivolumab. The primary end point was investigator-assessed objective response rate, with 55% of patients obtaining at least a partial response. Impressively, the progression-free survival rate at 12 months was 71%, whereas historic comparisons suggest a rate of <10% with standard-of-care chemotherapy. This benefit was seen regardless of PD1 ligand 1 (PDL1) expression level, BRAF mutation status or a diagnosis of HNPCC. On the basis of this study, the FDA approved the combination of nivolumab and ipilimumab for use in patients with MSI-H CRC who have been previously treated with chemotherapy. Further follow-up with this new combination is needed to establish whether patients could be free of active disease or potentially cured.

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Fig. 1: Colorectal cancer immunotherapy advances in 2018.

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  1. University of Texas, MD Anderson Cancer Center, Houston, TX, USA

    Scott Kopetz

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Correspondence to Scott Kopetz.

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Kopetz, S. New therapies and insights into the changing landscape of colorectal cancer. Nat Rev Gastroenterol Hepatol 16, 79–80 (2019). https://doi.org/10.1038/s41575-018-0100-z

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