Immunotherapy for downstaging of locally advanced mismatch repair deficient colorectal cancer: A prospective institutional case series.

[INTRODUCTION] Mismatch repair deficiency (MMRd) is a tumour-agnostic biomarker predicting response to immune checkpoint inhibition (ICI). Microsatellite unstable (MSI-H) colorectal cancers (CRC) display poor response to 5-Fluorouracil-based chemotherapy. ICIs demonstrate benefit in stage IV disease, but data on neoadjuvant ICI remain limited.

[METHODS] Prospective case series evaluating early outcomes of downstaging PD-1 inhibition for locally unresectable ± oligometastatic MMRd colorectal adenocarcinomas. Primary endpoints are complete clinical response, conversion to curative resection or disease progression. Ethical approval was granted by the institution's ethical review board.

[RESULTS] From October 2022-September 2024, ten patients started downstaging ICI, including six right-sided, one left-sided and three rectal tumours. Median age was 59 (IQR 54-68). One patient had stage II, six stage III and three stage IV disease. All had threatened surgical margin necessitating downstaging. Three patients with rectal cancer also received radiotherapy, and two commenced systemic chemotherapy before switching to ICI. Five patients required a defunctioning stoma. Median follow-up was 21.5 months (IQR 16-26). Objective response rate (RECIST 1.1) was 9/10. Six of ten tumours were resected, with complete pathological response (pCR) in four. Three others underwent non-operative management, following a complete or near-complete clinical response (cCR/ncCR). Nine of ten patients are alive. Four patients had grade 2/3 toxicity, while four developed a clinically significant treatment-related stricture, with one perforation.

[CONCLUSION] We report promising downstaging and pCR/cCR rate of ICI for initially-unresectable MMRd CRC. ICI-first can permit curative resection, with risk of local complication from significant treatment response. Larger, multi-centre studies are needed to validate these findings.