Background: Immune checkpoint inhibitors (ICI) have demonstrated their efficacy in advanced dMMR/MSI (deficient mismatch repair/microsatellite instability) tumors and increasing data are also accumulating in localized resectable stages with about 60% of pathological complete response rate. The goal of the IMHOTEP trial is to assess the safety and efficacy of peri-operative pembrolizumab in localized dMMR/MSI tumors independently of their anatomical origin. Methods: IMHOTEP is a prospective, multicenter, phase II study aimed to include 120 patients (pts) with localized resectable dMMR/MSI tumors, eligible for curative surgery. Pembrolizumab 400 mg flat dose is administered as a perioperative treatment with 1 or 2 doses every 6 weeks before surgery and thereafter every 6 weeks for one year. Primary objective is to evaluate the pathological complete response (pCR) rate defined as ypT0N0 stage. Secondary objectives are to assess major pathological response, centralized pathological review, safety, clinical response rate, recurrence-free survival and overall survival. Here, we present the interim analysis of safety and pathologic response data for the first 70 treated pts. Results: Median age was 67.5 years (26-89), 54.3% were males, and 42.0% were ECOG-PS 0. Surgery was performed in 54/70 pts including 27/35 colorectal (CRC), 16/21 oesogastric (OGC), 4/5 endometrial (EC) and 7/9 other (6 small intestine, 1 bile duct) (OC) cancers. 16 pts (22.9%) were not operated, mainly due to patient’s decision following complete clinical response (n=7). Only one patient was not submitted to surgery because of disease progression. Focusing on the 54 operated pts, 31 and 23 pts received 1 and 2 neoadjuvant pembrolizumab doses respectively. The pCR rate was 38.9% (40.7%, 25.0%, 0.0% and 85.7% in CRC, OGC, EC and OC respectively). Grade 3-4 immune-related adverse events were observed in 4 (5.7%) patients including transaminases increase (n=1), arthritis (n=1), acute kidney injury (n=1) and pneumonitis (n=1). Conclusions: In this IMHOTEP interim analysis, we observed a limited complete pathologic response rate to short-course neoadjuvant pembrolizumab. If we add patients in clinical complete response who chose not to be operated to those with pCR, our results compare with those previously reported. But we can also hypothesize that preoperative treatment duration should be prolonged to obtain more pCR. Overall, tolerance of pembrolizumab was acceptable without new safety signal. Centralized pathological review, major pathological response evaluation and clinical response rate analysis are ongoing. IMHOTEP trial has been registered (first post: March 12^th, 2021). Clinical trial information: NCT04795661.