Clinical and molecular characterization of AXL in colorectal cancer, CALGB (Alliance)/SWOG 80405 and real-world data

Background AXL dysregulation is associated with both intrinsic resistance in tumor cells and reprogramming of the immune microenvironment. However, it is still unclear which patients would benefit from AXL-targeting therapies. We conducted a clinical and molecular characterization of AXL in colorectal cancer (CRC). Methods This study integrated real-world molecular profiling (Caris cohort; n=24,257) and randomized clinical trial data (phase III Cancer and Leukemia Group B/Southwest Oncology Group (CALGB/SWOG) 80405; n=433) to assess AXL messenger RNA expression in patients with CRC. Tumor samples underwent RNA sequencing and analysis of the immune microenvironment. AXL expression was categorized into tertiles. We assessed associations between molecular features, immune biomarkers, and clinical outcomes, including overall survival (OS) and progression-free survival (PFS), using Kaplan-Meier and Cox proportional hazards models while adjusting for relevant covariates. Results Elevated AXL expression correlated with increased programmed death-ligand 1 immunohistochemistry positivity (6.2% vs 2.5%, q<0.0001), immune checkpoint-related gene expression, and infiltration of immunosuppressive cell populations (T-regulatory cells, M2 macrophages, monocytes, and B cells). Pathway analyses demonstrated links between high AXL expression and epithelial–mesenchymal transition, inflammatory signaling, interferon-gamma response, and tumor necrosis factor alpha signaling. In the Caris cohort, high AXL predicted worse OS in patients treated with fluorouracil, leucovorin, and oxaliplatin/fluorouracil, leucovorin, and irinotecan (38.0 vs 34.7months, p=0.027; HR 1.07), bevacizumab (36.8 vs 32.6months, p=0.013; HR 1.21), and anti-epidermal growth factor receptor therapy (28.4 vs 22.2months, p=0.005; HR 1.21), but profoundly improved OS in KRAS mutant patients treated with immunotherapy (11.6 vs 23.4months, p=0.012; HR 0.65). CALGB/SWOG 80405 findings confirmed shorter PFS (9.2 vs 12.9months, p=0.001; HR 1.56) and OS (24.2 vs 34.7months, p<0.001; HR 1.68) with high AXL expression across treatment arms. Conclusions Elevated AXL expression in CRC correlated with an immunosuppressive microenvironment and worse outcomes across standard treatments. However, it identifies a distinct subgroup of KRASmutant patients who significantly benefit from immunotherapy, supporting AXL as a context-specific biomarker and therapeutic target.