Background: SCC of anus (SCCA) are considered rare tumours, but the incidence is increasing. Only 65% patients with later stage T3/T4 +/-N1 SCCA remain disease free at 3 years (Gunderson 2013, James 2013). The cytotoxicity of IMCRT enhances tumour antigen presentation and promotes cytokine release as well as enhancing the MHC (Demaria 2004, Reits 2006). Immune therapy, against PD-1, have been approved for patients with SCC arising from other primary sites eg. head and neck, lung cancer. The addition of such checkpoint inhibitors might also result in improved PFS and OS for higher risk SCCA patients. Methods: A multicentre, single arm, open-label, non-randomised study to evaluate the safety and tolerability of different schedules of exposure to pembrolizumab (P) with standard IMCRT in 50 patients with locally advanced T3/4 anal cancer. The first cohort of 6 patients commenced standard IMCRT and received P 200mg every 21d beginning at Week 5 day 1 of the IMCRT schedule. If this is considered safe and tolerable with not more than 3/6 SAEs within first 6 weeks after completion IMCRT, a second cohort of 6 patients will be recruited where P is introduced on Week 1 Day 1 with standard IMCRT. Pembrolizumab monotherapy will be continued for a total of 6 months. Primary endpoint is safety and tolerability by assessing AEs and protocol adherence. Secondary endpoints include feasibility, clinical response assessment by RECIST (MRI) for ORR at 3, 6 and 12 months, imaging response assessments by TRG MRI using changes in Apparent Diffusion Coefficient (ADC) on diffusion weighted sequences and patient reported outcomes, using EORTC quality of life questionnaires. Patients are being asked to contribute to translational endpoints with the donation of tissue and blood samples. Eligible patients will have Stage IIIA/B (T3/4, any N, M0) SCCA, performance status 0 or 1 and be suitable for IMCRT. Patents with anal tumours of non-epithelial origin, metastatic disease or a diagnosis of immunodeficiency are excluded. Single phase IMRT with a simultaneous integrated boost to achieve 53.2Gy in 28 fractions over 5.5 weeks to PTV_A, according to the UK consensus is mandated. Concomitant chemotherapy can either be cisplatin 60mg/m2/ or mitomycin 12mg/m2 with either 5FU 1000mg/m2 or capecitabine 825mg/m2 at investigator discretion. The first cohort has completed recruitment with Safety Review Committee / IDMC review planned for April 2022. Patients will then be sought to start P on Week 1 Day 1 with IMCRT. Further safety review will be undertaken following the first 6 patients entered into the second cohort but recruitment will continue in an expansion phase to a maximum of 44 patients. Clinical trial information: NCT04046133.