Spatial Tumor Immune Microenvironment as a Prognostic and Predictive Biomarker in Anti-EGFR-Based Maintenance for RAS wt Metastatic CRC-The PanaMa (AIO KRK0212) Trial

Abstract

Purpose: Tumor immune cell infiltration patterns in the tumor microenvironment serve as prognostic biomarkers in metastatic colorectal cancer. This study analyzed the spatially resolved tumor immune microenvironment for prognostic and predictive impact in patients with RAS wild-type metastatic colorectal cancer receiving 5-fluoruracil/folinic acid ± panitumumab (Pmab) maintenance after Pmab + fluorouracil, folinic acid, and oxaliplatin induction (PanaMa AIO KRK0212; NCT01991873).

Patients and methods: Twelve immune parameters (lymphocyte markers: CD3, CD8, CD45RO, FOXP3, CD20, granzyme B, and perforin; immune checkpoints: PD-1, PD-L1, IDO1, and LAG3; and monocyte marker CD163) were quantified in spatially resolved tumor and stroma regions [invasive-margin (Inv) and center (Cen)] on tissue microarrays from available surgical resections using digital pathology. Prognostic and predictive associations were assessed using percentile cutoffs, immunoscore (IS), PD-L1 combined positive score, and an immunoactivation score (IAS). The median progression-free (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method, log rank test, and Cox regression.

Results: In 194 patients, low CD163 and high PD-1 in the tumor center were independent prognostic factors for prolonged PFS, whereas high central LAG3 was associated with improved OS. Pmab maintenance conferred PFS benefit in patients with low CD3InvStr, CD8Inv, LAG3CenTum, CD163CenTum, and IS and high CD45ROCen. CD45ROCen high and LAG3Cen low also predicted OS benefit. A positive IAS (≥2 predictive markers) identified patients deriving significant PFS (HR = 0.50; 95% confidence interval, 0.32-0.76; P < 0.001) and OS (HR = 0.54; 95% confidence interval, 0.33-0.86; P = 0.009) benefit from Pmab.

Conclusions: Immune microenvironment factors, including CD3, CD8, CD163, LAG3, CD45RO, IS, and IAS, predict benefit from Pmab maintenance, suggesting immune activation as a key component of anti-EGFR efficacy.