<i>KMT2C</i> mutation to identify an immunotherapy-sensitive subset of gastrointestinal cancers: A large real-world analysis.

3565 Background: KMT2C (MLL3) encodes a histone methyltransferase involved in enhancer regulation and DNA damage repair. Loss-of-function KMT2C mutations occur in approximately 4–7% of gastrointestinal cancers and represent one of the most recurrent chromatin regulator alterations across GI malignancies. Preclinical studies demonstrate that KMT2C deficiency impairs homologous recombination–mediated DNA repair and increases tumor immunogenicity. We hypothesized that KMT2C mutations define a biologically distinct subset of GI cancers associated with enhanced responsiveness to immune checkpoint inhibitors (ICI). Methods: Using the Tempus Lens Platform, we identified patients with colorectal cancer (CRC), pancreatic ductal adenocarcinoma (PDAC), or gastroesophageal adenocarcinoma (GEA) who underwent Tempus xT DNA and RNA sequencing within a de-identified multimodal real-world dataset. Clinical and molecular features were compared between KMT2C -mutant (MUT) and wild-type (WT) tumors. Real-world progression-free survival (rwPFS) and overall survival (rwOS) following ICI initiation were estimated by Kaplan–Meier methods and compared using log-rank tests. Risk-set adjustment was applied to address left truncation and mitigate immortal time bias. Results: Among 14,413 patients, 83% had stage IV disease; CRC comprised 58.1%, PDAC 23.7%, and GEA 18.2%. KMT2C mutations were identified in 4.1% of CRC, 3.4% of PDAC, and 4.3% of GEA. Across all tumor types, KMT2C MUT tumors had significantly higher tumor mutational burden (TMB) compared with WT (CRC: 39.2 vs 4.7 mut/Mb; PDAC: 3.68 vs 3.16; GEA: 7.9 vs 4.6; all p≤0.02). TMB-High status (≥10 mut/Mb) and MSI-High status were markedly enriched in KMT2C MUT tumors (CRC MSI-H: 57% vs 2.6%; PDAC: 6.9% vs 0.1%; GEA: 38% vs 2%; all p &lt; 0.001). High Immune Profile Score (IPS) was more frequent in KMT2C MUT versus WT tumors in CRC (35% vs 8.3%, p &lt; 0.001) and GEA (36% vs 19%, p &lt; 0.001). Following ICI, rwPFS was not reached in both KMT2C MUT CRC and KMT2C MUT GEA compared with 6.2 and 6.0 months in WT tumors (CRC p = 1.1×10⁻¹⁷; GEA p = 0.004). rwOS was significantly improved in CRC KMT2C MUT versus WT (not reached vs 20.2 months; p = 0.0001). Conclusions: KMT2C mutations identify a molecularly and immunologically distinct subset of GI cancers enriched for MSI-High and TMB-High status and associated with superior outcomes following immune checkpoint inhibition. These findings support KMT2C as a potential predictive biomarker for immunotherapy responsiveness in gastrointestinal malignancies.