Neoadjuvant immunotherapy for locally advanced/metastatic mismatch repair deficient colorectal cancer: A two-year institutional experience.

Abstract

179 Background: MMRd is a tumour agnostic biomarker predictive of response to immune checkpoint inhibitors (ICIs). Given the poor response to 5-FU based chemotherapy, ICIs are now being explored in early MSI-H CRC. The outcomes on this strategy are limited. Methods: We retrospectively evaluated early outcomes for patients receiving neoadjuvant ICIs for unresectable locally advanced/oligometastatic MMRd colorectal cancer (CRC), where intention of treatment was downstaging to permit curative resection. Following discussion at regional MDT, suitable patients were administered a PD-1 inhibitor 6-weekly until disease progression or improvement rendering suitability for surgical resection (to max of 2 years). Results: From October 2022-September 2024, ten patients with MMRd CRC were commenced on neoadjuvant ICIs. These comprised six right, one left sided colonic and three rectal tumours. Median age at diagnosis was 59 (IQR54–68). Four patients had family history of CRC. One patient had clinical stage II, seven stage III and two patients oligometastatic stage IV disease. All were patients with initially unresectable disease, with potential for curative resection pending response to ICI. Histologically, two tumours were poorly differentiated, two mucinous phenotype and six moderately differentiated adenocarcinomas. BRAF mutation was identified in three patients. None had KRAS mutation. Three rectal cancers received radiotherapy in addition to immunotherapy. Five required a defunctioning stoma either prior to or on ICI. Median follow-up was 12.5 months (IQR7-17). Objective response rate by RECIST 1.1 was 100%, with significant downstaging in 9 of 10 patients. The remaining patient is early in treatment course with no reimaging. To date, complete clinical response (cCR) has been observed in three patients (33%). All 10 patients are alive. Grade 3-4 treatment-related adverse events occurred in two patients (20%) who developed treatment-related strictures (one also had tumour perforation). This was successfully managed with defunctioning ileostomy and antibiotics, with subsequent cCR. Conclusions: We report impressive early outcomes of immunotherapy for locally advanced/metastatic MMRd CRC, with excellent downstaging and high predicted cCR. This highlights the importance of screening all CRC for MSI-H/MMRd. In the setting of initially unresectable CRC, an ICI-first approach can render patients eligible for surgery, however deep responses can result in local effects including strictures and/or perforation.