Clinical impact of chemotherapy and immune checkpoint inhibitor treatment in high-risk stage II and III colorectal cancer patients with dMMR/MSI-H and/or TMB-H status.

177 Background: The phase 3 ATOMIC trial (NCT02912559) demonstrated the addition of an immune checkpoint inhibitor (ICI) to adjuvant chemotherapy (CT) significantly improved disease-free survival in stage 3 resected deficient mismatch repair/microsatellite instability-high (dMMR/MSI-H) colon cancer. The clinical impact of CT on ICI efficacy in dMMR/MSI-H colorectal cancer (CRC) adjuvant therapy is not well characterized. Methods: This IRB-approved retrospective study included patients diagnosed between 2009-2025 with dMMR/MSI-H and/or TMB-H stage II (T4 only) or stage III CRC pts identified from multi-institutional electronic health records. Microsatellite status and genomic testing were performed in CLIA-certified, CAP-accredited labs. Pt characteristics, genomics and in-depth clinical treatment history were analyzed. Disease-free survival (DFS) and overall survival (OS) were determined by Kaplan-Meier method. Survival curves were compared using the log-rank test. Results: The 90 CRC pts included T4N0 (n = 15) and TxN + (n = 75), and 77 were MSI-H and 13 MSS/TMB-H. These pts received surgery alone (n = 33), or surgery with CT (n = 42), or ICI ± CT (n = 15). Pts who received surgery alone (median 83yo 44 – 92) were much older than those had received additional CT (median 69yo 32 - 88) or ICI ± CT (median 67yo 35 - 86). The median DFS (3.3yr and 4.5yr; p = 0.36) and 5yrs OS rate (74.1% vs 62.2% p = 0.34) were not significantly improved in pts who received adjuvant CT compared to surgery alone, and only 16% of these pts received ICI subsequently. Pts who received ICI after prior CT had significantly decreased median DFS compared to those who received treatment-naive immunotherapy (median DFS of 8.9 mo vs NR; p = 0.043), although both 5y OS rate were ≥ 90% and not significantly different. Of the 16 pts who received ICI, only 1 had tumor progression and 11 developed no evidence of disease. Pts who had received ICI compared to CT alone showed trend toward higher rate of 5yr OS (0.93 vs 0.70; p = 0.27). Conclusions: This study supports the use of adjuvant immunotherapy alone in dMMR/MSI-H and TMB-H colorectal cancer (CRC) ), with possible detriment including shorter DFS when ICI is administered following upfront CT. Clinical trial investigation comparing adjuvant ICI alone to CT + ICI is warranted in T4 stage 2 and stage 3 MSI-H CRC.