Short Pembrolizumab Course Before Surgery Keeps

How Does Neoadjuvant Pembrolizumab Work in dMMR Colorectal Cancer?

Mismatch repair deficient (dMMR) and microsatellite instability-high (MSI-H) colorectal cancers accumulate large numbers of mutations because they cannot reliably correct DNA replication errors. This high mutational burden produces abundant neoantigens on the tumour surface, making dMMR tumours uniquely visible to the immune system. Pembrolizumab is a monoclonal antibody that blocks the PD-1 receptor on T cells, releasing a brake that tumours exploit to evade immune attack.

By administering pembrolizumab before surgery — known as neoadjuvant therapy — clinicians expose an intact tumour and draining lymph nodes to immune activation. Preclinical and translational work, including studies published in Nature Medicine by Chalabi and colleagues at the Netherlands Cancer Institute, has shown that this pre-surgical window can generate broader and more durable T cell responses than checkpoint blockade given after surgery, when much of the antigenic material has already been removed.

What Did the UK Trial Show About Long-Term Outcomes?

The UK-led trial enrolled patients with localised dMMR or MSI-H colorectal cancer and treated them with a brief course of pembrolizumab before planned surgery. Investigators reported that a substantial proportion of patients showed pathological complete responses, meaning no viable tumour was identified in the resected specimen. Crucially, with extended follow-up, the great majority of patients remained free of cancer recurrence, suggesting that the deep responses seen at surgery translate into durable clinical benefit.

These findings build on earlier landmark work, including the NICHE studies from the Netherlands and a small but striking trial of dostarlimab in rectal cancer led by Andrea Cercek and Luis Diaz at Memorial Sloan Kettering, in which all evaluable patients with dMMR rectal tumours achieved a clinical complete response. Together, the evidence supports a paradigm shift in which selected patients with dMMR colorectal cancer may receive shorter, less toxic, organ-sparing treatment than the conventional combination of surgery and chemotherapy.

What Are the Implications for Standard Colorectal Cancer Care?

Major guideline bodies, including the National Comprehensive Cancer Network and the European Society for Medical Oncology, already recommend universal mismatch repair or microsatellite instability testing for colorectal cancer at diagnosis, both to identify Lynch syndrome and to guide immunotherapy decisions. As neoadjuvant data mature, oncology services will need to ensure that molecular results are available early enough to inform pre-surgical treatment planning, and that multidisciplinary teams are prepared to discuss watch-and-wait or organ-preserving strategies with eligible patients.

Important questions remain. Researchers are still defining the optimal duration of neoadjuvant immunotherapy, the role of surgery in patients with apparent complete clinical responses, and how to manage the minority of patients whose tumours do not respond. Immune-related adverse events — including colitis, hepatitis, endocrinopathies and pneumonitis — also require careful monitoring. Even so, the consistency of the signal across multiple independent trials marks one of the most significant advances in localised colorectal cancer treatment in decades.