Abstract 1314: Circulating tumor DNA (ctDNA) clearance dynamics in microsatellite instability-high metastatic (MSI-H) colorectal cancer (CRC) treated with immune checkpoint inhibitors (ICI).

Abstract Background: ICI offers durable responses in MSI-H CRC. However, factors for long-term disease control and the optimal ICI duration are unclear, and radiographic assessments can be challenging. ctDNA provides an opportunity to monitor molecular changes during treatment. This retrospective analysis evaluated ctDNA clearance patterns and their relationship to survival in a large real-world cohort of patients with MSI-H metastatic CRC treated with first-line ICI. Methods: We selected MSI-H metastatic CRC patients treated with first-line ICI (March 2021-June 2025) from Natera’s real-world cohort and analyzed Signatera™ ctDNA data linked to an insurance claims database (Forian, CHRONOS™). ctDNA status was assessed pre ICI (within 12 weeks) and longitudinally. ctDNA clearance was defined as early (within 4 months) or sustained (≥6 months of ctDNA negativity). Descriptive analyses assessed ctDNA clearance frequency, timing, and correlation with overall survival (OS). Results: A total of 465 patients with MSI-H metastatic CRC, treated with first-line IO, predominantly pembrolizumab (67%), ipilimumab + nivolumab (14%), and nivolumab (12%), were identified. Post-IO ctDNA-negativity was observed in 60.5% within 4 months and in 83.5% at any time point. Among 146 patients with pre-ICI ctDNA results, 44% had prior chemotherapy for localized disease, and 77% (106/146) were baseline ctDNA-positive. Of these, 37.7% (40/106) patients had early clearance, 65.1% (69/106 achieved anytime ctDNA clearance (median time to clearance 96 days (range: 12-777), and 19.8% (21/106) remained persistently positive. Of those who cleared, 77.4% achieved sustained ctDNA clearance with a median duration of ctDNA-negativity of 526 days (range: 105-1564). In the entire cohort (N=465), patients ctDNA-positive at their first post-IO ctDNA test had shorter OS (HR 4.75, 95%CI 2.26-9.96, p0.0001) with an estimated 3-year OS of 96% versus 75% for ctDNA-negative versus -positive, respectively. Persistent ctDNA positivity after IO initiation was associated with inferior OS compared to anytime ctDNA negativity (HR 10.04, 95% CI 4.84-20.83, p0.0001). Conclusions: These findings suggest ctDNA kinetics as a reliable tool for evaluating benefit from ICI in patients with metastatic MSI-H CRC. ctDNA monitoring tracked distinct clearance trajectories. Consistent with ICI efficacy, most patients achieved ctDNA clearance. Importantly, early ctDNA clearance was strongly prognostic for improved OS, while persistent ctDNA-positivity was associated with markedly inferior OS. This supports prospective evaluation of ctDNA to guide ICI use in MSI-H CRC. Citation Format: Hannah R. Robinson, Christopher H. Lieu, Vasily N. Aushev, Antony Tin, Darryl Nousome, J. Bryce Ortiz, Shruti Sharma, Robert Lentz, Adham Jurdi. Circulating tumor DNA (ctDNA) clearance dynamics in microsatellite instability-high metastatic (MSI-H) colorectal cancer (CRC) treated with immune checkpoint inhibitors (ICI) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1314.