Real-world outcomes for pembrolizumab in MSI-high (MSI-H) advanced colorectal cancer (CRC).

223 Background: 5-year follow-up data from the KEYNOTE-177 trial have demonstrated an overall survival (OS) benefit for pembrolizumab compared to chemotherapy for patients with MSI-H/mismatch repair deficient (MMRd) advanced stage CRC. We evaluated the efficacy and safety of pembrolizumab in this patient population in a UK Cancer Network. Methods: Retrospective analysis of patients with advanced MSI-H CRC who received first-line pembrolizumab in Northern Ireland (1.9M population) from 2021 - 2024. Descriptive and Kaplan-Meier analyses of patient demographics and clinical outcomes were performed. Results: Of 38 identified patients, 34 (89%) had metastatic disease, 2 (5%) had inoperable locally advanced disease, and 2 (5%) had residual disease after R2 resection. Median age was 64 (range 36-83), with 12 patients (31.5%) over 70. 16 (42%) and 11 (28.9%) patients had BRAF and RAS mutations, respectively; 4 (10%) had Lynch syndrome, and 1 (2.5%) had Familial Adenomatous Polyposis. Nodal metastasis was seen in 5.8(22), peritoneal in 31.5 %( 12), liver in 26% (10), lungs in 5%(2), and local recurrence in 5%(2). The median treatment duration was 7.0 months (range 0.7 – 25.9); 3 patients (7.5%) received only one cycle and are included in the analysis. The response rate was 50%, with 4 (10%) achieving complete response and 3 (7.5%) undergoing complete resection. 10 of 16 BRAF mutant patients had a demonstrable response, including 2 with a complete response. Disease progression occurred in 13 patients (34%) and the death rate was also 13 patients (34%). At a median follow up of 26 months, the median OS and progression-free survival have not yet been reached. Grade 3 or higher toxicities were observed in 13 patients (34%) and led to treatment discontinuation in 7 (18%). These included colitis/enteritis in 6 (15.5%), nephritis in 3 (9%), endocrinopathy in 2 (5%), neutropenia in 1 (2.5%), and arthritis in 1 (2.5%). Conclusions: Pembrolizumab showed a favourable response in about 50% of patients, more than comparable with the 43.8% response rate observed in KEYNOTE-177. However, grade 3 or higher adverse events were more frequent (34% vs. 22%) but were overall manageable for nearly half of patients.