Neoadjuvant Pembrolizumab stratified to tumour mutation burden for High Risk Stage 2 or Stage 3 MMR-deficient Colorectal Cancer

The NEOPRISM-CRC study is a phase II clinical trial. The purpose of the trial is to evaluate the efficacy and safety of pembrolizumab (Study IMP) in patients with high risk Stage 2 or Stage 3 MMR-deficient colorectal cancer stratified with tumour mutation burden status. Pembrolizumab is a type of immunotherapy that has demonstrated excellent results in clinical trials for patients with advanced colorectal cancer who have certain genetic characteristics (mismatch repair deficiency (MMR-d) / high microsatellite instability (MSI-H)). There are previous studies providing evidence that checkpoint inhibitors when given before surgery have shown better local and systemic anti-tumour responses in melanoma and glioblastoma than surgery alone. The main question the researcher wants to investigate is whether pembrolizumab given prior to having surgery improves pathological complete response rate in advanced colorectal cancer patients with MSI-H or MMR-d. The trial will investigate whether the treatment is safe,and whether it improves the chances of the tumour being removed completely,and whether this delays or prevents the cancer from coming back. The trial will also investigate whether pembrolizumab causes any delay to surgery due to side effects. The trial will also measure post-surgery complications and impact of the treatment on patient's quality of life. Once patients have consented to the NEOPRISM-CRC trial,a trial colonoscopy will be performed and tissue samples taken during the procedure will be shipped to the FoundationOne Medicine testing Laboratory and analysed to determine the TMB (tumour mutation burden) status assessed by the FOUNDATIONONE®CDx (FM1) test. In addition,a PCR (Polymerase Chain reaction) test or Microsatellite testing will be done to confirm the Microsatellite Instability (MSI) status. Patients will receive one of two pre-operative regimens depending upon their TMB status/MSI status. All patients will have one cycle of pembrolizumab 200 mg IV (a cycle is 21 days). Prior to cycle 2 the FM1 result should be available and patients will continue their treatment as follows: If results is TMB-high or medium (or MSI-h if FM1 test is not evaluable): A further two cycles of pembrolizumab 200 mg IV every 21 days and then will proceed to surgery 4 - 6 weeks after last dose of pembrolizumab.