An early on-treatment "coordinated inflammatory niche" plasma signature as a predictor of response in the SYLT026 trial: Cadonilimab combined with FOLFIRINOX and bevacizumab as first-line treatment for microsatellite-stable/proficient mismatch repair (MSS/pMMR) metastatic colorectal cancer (mCRC).

3600 Background: The SYLT026 trial is a phase II study investigating the efficacy and safety of cadonilimab (an anti-CTLA-4/PD-1 bispecific agent) combined with FOLFIRINOX and bevacizumab as first-line treatment for microsatellite-stable/proficient mismatch repair (MSS/pMMR) metastatic colorectal cancer (mCRC). We previously reported the promising outcomes at ASCO GI 2026. Updated survival data are reported here. The determinants of effective immune responses in MSS/pMMR mCRC remain elusive; the "Coordinated Inflammatory Niche" plasma signature was analyzed to predict the immune checkpoint inhibitor (ICI) response. Methods: Plasma samples from eligible patients were collected before ICI treatment and profiled using three non-overlapping protein arrays comprising 120 human cytokines (QAH-CAA-2000). These cytokines were integrated into an Inflammatory Niche Index (INI) using machine learning (random forest algorithm). Its predictive value for durable PFS ( > 12 months) was evaluated and compared with single markers. Results: Between November 16, 2023, and July 26, 2024, 20 patients were enrolled. The ORR was 100% (all partial responses). As of the data cutoff (December 31, 2025), the median follow-up was 24.4 months (IQR 22.4–26.4), the median PFS (mPFS) was 17.2 months (IQR 13.6–20.7), and the OS maturity rate was 20%. Seventeen patients underwent cytokine array analysis. Cytokine profiling identified a 9-protein panel (IP-10, eotaxin, MCP-1, IGFBP-3, MCP-4, TARC, IL-17, CCL28, I-TAC) that was significantly upregulated in responders. Further random forest modeling revealed the importance ranking of each protein, with TARC and IP-10 as the two most significant predictors, consistent with their most pronounced differential expression in the heatmap. The INI demonstrated superior predictive accuracy (AUC = 0.944) compared with IP-10 alone (AUC = 0.71, p = 0.03). Patients with a high INI (n = 9) had promising outcomes: mPFS was not reached (12-month PFS rate 90%), compared with 6.5 months in the low INI group (n = 8) (HR = 0.16, p = 0.001). Gene set enrichment analysis linked a high INI to a baseline tumor microenvironment enriched for NK T cell-related signatures, suggesting a biological basis for the niche. Conclusions: CTLA-4/PD-1 immunochemotherapy induced deep and durable responses in MSS/pMMR mCRC. An early on-treatment plasma proteomic signature (INI) powerfully identifies patients destined for durable benefit, offering a transformative tool for ultra-early, biology-guided patient selection in MSS/pMMR mCRC. Clinical trial information: NCT05839470 .