Colorectal cancer is the third most commonly occurring cancer in men and the second most commonly occurring cancer in women, with over 1.8 million new cases reported worldwide in 2018.1 The prognosis depends on the stage at diagnosis. However, most cases are diagnosed at later stages, and the 5-year survival rate is only around 12% for those with distant metastases.2 Although the response rate of metastatic colorectal cancer to combined chemotherapy is around 50%, the disease inevitably progresses, highlighting the need for more selective biomarkers.3
Clinical outcomes vary considerable between patients with colorectal cancer since it is a heterogeneous disease with several molecular subtypes. Advances in the molecular classification of colorectal cancer can identify patient subgroups at different risk of recurrence and death and for who personalised approaches to therapy may beneficial. Microsatellite (MSI)-high tumours are found in around 15% of patients with colorectal cancer overall and 5% of patients with metastatic disease, and are due to a germline mutation in mismatch repair genes that usually correct for single base nucleotide mismatches, insertions, or deletions that arise during DNA replication.4–6 MSIs are short DNA motifs of 1–6 bases that are repeated and distributed throughout the genome, both in coding and noncoding regions. Owing to their repeated structures, MSIs are particularly prone to replication errors that are normally repaired by the mismatch repair system. Loss of function of only one of the mismatch repair proteins may lead to the accumulation of errors in MSIs, resulting in genetic instability.6,7 Patients with MSI-high tumours have shorter survival (14–19 months) than those with non-MSI-high tumours (17–25 months), when treated with chemotherapy in the first-line setting.5,8
Until recently, immunotherapy has not provided the spectacular advances in colorectal cancer that has been seen in other malignancies. However, metastatic MSI-high colorectal cancer tumours have been found to contain high levels of tumour neoantigens, tumour-infiltrating lymphocytes, and checkpoint regulators, all of which are associated with response to programmed cell death-1 (PD-1) blockade. The phase II CheckMate-142 study (NCT02060188) is the largest trial to date investigating the investigating the efficacy and safety of immune checkpoint inhibitors in patients with metastatic colorectal cancer.9 Initial data focussed on single-agent nivolumab (Opdivo®; Bristol-Myers Squibb, New York, NY, US) in patients with MSI-high metastatic colorectal cancer who had progressed on, or were intolerant to, at least one previous line of treatment. Findings at 12 months showed durable responses and impressive disease control in responders (overall response rate 31.1%), with manageable side effects.9 Earlier this year, results were presented from 119 previously treated patients who received nivolumab plus low-dose ipilimumab (Yervoy®; Bristol-Myers Squibb, New York, NY, US) every 3 weeks for four doses, followed by nivolumab every 2 weeks. The objective response rate was 55%, and the disease control rate was 80%. In addition, this presentation showed that the complete response rate in the monotherapy arm deepened with longer follow-up.10
Results from a cohort of 45 previously untreated patients who received nivolumab plus low-dose ipilimumab in CheckMate-142 were presented at the European Society for Medical Oncology (ESMO) 2018 Congress, 19–23 October 2018, in Munich, Germany. The objective response rate was 60% including complete responses in 7%. Tumour shrinkage was seen in 84% of patients. Median time to treatment response was 2.6 months. The median duration of response, median progression-free survival, and median overall survival have not yet been reached. The 12-month progression-free survival and overall survival rates were 77% and 83%, respectively. The combination of low-dose ipilimumab with nivolumab resulted in reduced toxicity. Treatment-related grade 3 and 4 toxicities were reported in 16% of patients and 7% discontinued therapy due to treatment-related adverse events.11
Professor Thierry André, Head of Medical Oncology, Hôpital Saint-Antoine, Assistance Publique – Hôpitaux de Paris, France, commented for ESMO: 'Nivolumab plus low-dose ipilimumab is effective in most patients with MSI-high metastatic colorectal cancer. Patients improve dramatically and some return to work. It means healthcare systems can be confident that resources are being targeted effectively. This is in contrast to other metastatic cancers (melanoma, lung or kidney) where it is more difficult to select patients who benefit from immunotherapy.' 12
It is hoped that the combination of nivolumab and low-dose ipilimumab will receive US Food and Drug Administration (FDA) approval on the basis of these findings, but European approval will probably require phase III trial data. Pembrolizumab (Keytruda®; Merck, Kenilworth, NJ, US) has received FDA approval in patients with previously treated, MSI-high tumours following promising clinical trial data in metastatic colorectal cancer and other cancers.13,14 This is the first time that approval has been based on the presence of a biomarker rather than tumour type. The phase III KEYNOTE-177 study (NCT02563002 ) is currently is comparing first-line treatment with pembrolizumab versus chemotherapy with or without targeted therapy, with results expected in 2019. In addition, the anti-PD-L1 agent durvalumab (Imfinzi®; AstraZeneca, Cambridge, UK) is currently being tested in patients with MSI-high colorectal cancer (NCT02227667). Atezolizumab (Tecentriq®; Genentech, South San Francisco, CA, US), another anti-PD-L1 agent is also being evaluated in combination with standard chemotherapy in this cohort (NCT01633970 ).
Unfortunately, only a minority of patients have MSI-high metastatic colorectal cancer. However, in these patients, immunotherapy is providing a much-needed change to the standard of care. Understanding why MSI-high tumours are responsive to immune checkpoint inhibitors will help develop better treatment options for all patients with colorectal cancer. Combination regimes involving immunotherapies may improve outcomes, but this will depend on identifying crucial molecular pathways and combining treatment modalities in the right sequence.