Research in context
Evidence before this study
We searched PubMed for articles published between Jan 1, 2012, and Jan 1, 2017, with no language restrictions, reporting on the use of a PD-1 immune checkpoint inhibitor for the treatment of patients with DNA mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) metastatic colorectal cancer using the search terms (“DNA mismatch repair” or “microsatellite instability”) and “programmed cell death receptor-1 inhibitor” and “colorectal cancer”, filtering for articles describing clinical trials.
We also searched abstracts of the annual meeting of the American Society of Clinical Oncology using the search term “DNA mismatch repair” or “microsatellite instability” and “programmed death-1 inhibitor” and “metastatic colorectal cancer”, limiting the results to clinical trials published or presented during the past 2 years. Trials in progress were excluded from the search results.
The search yielded one article and three abstracts that reported the results of a phase 2 study that evaluated the clinical activity of pembrolizumab, an anti-PD-1 immune checkpoint inhibitor, in 35 patients with progressive metastatic carcinoma with or without mismatch repair deficiency. In this study, mismatch repair status was predictive of clinical benefit with pembrolizumab in ten patients with dMMR metastatic colorectal cancer; no responses were noted in patients with proficient MMR metastatic colorectal cancer.
Added value of this study
CheckMate 142 is the largest phase 2 study to our knowledge to assess the activity and safety of PD-1 inhibitor treatment in patients with dMMR/MSI-H metastatic colorectal cancer. Our results show that nivolumab monotherapy was well tolerated, provided durable responses and disease control with all responders alive at the time of analysis, and long-term survival in a population of pre-treated patients with dMMR/MSI-H metastatic colorectal cancer. Responses and disease control were recorded in patients with dMMR/MSI-H metastatic colorectal cancer across all subgroups including patients with tumours that were positive (≥1%) or negative (<1%) for tumour PD-L1 expression, tumours harbouring BRAF or KRAS mutations, and those with and without a clinical history of Lynch syndrome. Additionally, nivolumab was associated with clinically meaningful improvements in patient-reported functioning, symptoms, and global quality of life.
Implications of all the available evidence
Patients with dMMR/MSI-H metastatic colorectal cancer are traditionally given conventional chemotherapy with or without targeted treatments and might have significantly worse outcomes than those with proficient MMR metastatic colorectal cancer. The results from this phase 2 study confirm the clinical benefit of PD-1 inhibitor treatment in dMMR/MSI-H metastatic colorectal cancer and suggest that nivolumab is a new treatment option for patients with previously treated dMMR/MSI-H metastatic colorectal cancer. Ongoing studies are exploring the combination of nivolumab with other immunotherapies in patients with dMMR/MSI-H metastatic colorectal cancer.