Background: The prognostic advantage of early stage deficient-MMR/MSI-High CRC is lost after relapse, so there is a pressing clinical need to maximize the chance of cure in the early stages where prevalence of dMMR is higher comprising approximately 12% of Stage 3 and 20% of Stage 2 CRC. The efficacy of adjuvant checkpoint inhibition in this patient group has yet to be demonstrated in the context of micrometastatic disease without a supporting immune-competent microenvironment. Longitudinal studies especially in the neoadjuvant setting would optimally interrogate post-immunotherapy changes both in time and space. The NEOPRISM-CRC (NEOadjuvant PembRolizumab In Stratified Medicine – ColoReCtal) study is a Phase II Trial to determine whether neoadjuvant Pembrolizumab stratified to tumour mutation burden (TMB) is efficacious and safe. It will also be a platform to explore the relationships between possible predictive novel biomarkers and response to Pembrolizumab in blood, tumour tissue and microbiome. Methods: The study population consists of subjects with newly diagnosed operable dMMR/MSI-H CRC. Patients must be fit and eligible for planned curative surgery based on a) radiological node positive T1-4 CRC or b) high risk T3 defined as EITHER ≥ 5mm of extramural depth of invasion or unequivocal EMVI on imaging (regardless of depth), or T4 disease. They will receive one of two pre-operative regimens depending upon their TMB based on the FoundationOne®CDx test (FM1CDx). All patients will have one 21 day cycle of Pembrolizumab 200 mg IV. Prior to cycle 2 and with the result of the FM1CDx test, patients will continue their treatment as follows: A) TMB-high (defined as ≥20 mutations per Mb) or TMB-medium (defined as 6-19 mutations per Mb), or MSI-H on PCR if FM1CDx test is not evaluable: A further 2 cycles of Pembrolizumab 200 mg IV every 21 days. B) TMB-low (defined as ≤5 mutations per Mb), or if FM1CDx and PCR tests are not evaluable: No further Pembrolizumab given. Surgery to remove the CRC will be performed 4-6 weeks after the last dose of Pembrolizumab in both arms. Following resection patients may receive adjuvant chemotherapy in accordance with local institutional guidelines. The primary end point is pathological complete response rate (pCR). Secondary endpoints include 3 year RFS, OS, safety and health-related quality of life. Up to 32 patients will be registered over a 18-24 month period assuming that the pCR with 3 cycles of Pembrolizumab will be ≥ 33% for patients with high or medium TMB based on the FM1CDx profile, and intend to rule out a percentage ≤10%. To reach 80% power with 5% statistical significance, 19 patients are required in the high/medium TMB arm. The trial will be considered a success if at least 5/19 patients have a pCR after 3 cycles of Pembrolizumab. Enrolment will commence in March 2022. Clinical trial information: NCT05197322.