Tumor Mutational Burden in Real-World Patients With Pancreatic Cancer: Genomic Alterations and Predictive Value for Immune Checkpoint Inhibitor Effectiveness.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is largely considered a nonimmunogenic malignancy; however, approximately 1%, of patients may have tumors with deficient mismatch repair, high microsatellite instability, or high tumor mutational burden (TMB ≥10 mutations/Mb), which may be predictive of response to immune checkpoint inhibitor (ICI) therapy. We sought to analyze outcomes of patients with high-TMB and pathogenic genomic alterations observed in this population.

Methods: This study included patients with PDAC who underwent comprehensive genomic profiling (CGP) at Foundation Medicine (Cambridge, MA). Clinical data were obtained from a US-wide real-world clinicogenomic pancreatic database. We report genomic alterations in those with high and low TMB, and compare outcomes on the basis of receipt of single-agent ICI or therapy regimens not containing ICI.

Results: We evaluated 21,932 patients with PDAC who had tissue CGP data available, including 21,639 (98.7%) with low-TMB and 293 (1.3%) with high-TMB. Among patients with high-TMB, a greater number of alterations were observed in , , , and genes of the mismatch repair pathway, whereas fewer alterations were observed in . Among patients who received an ICI (n = 51), those with high-TMB had more favorable median overall survival when compared with the low-TMB subset (25.7 5.2 months; hazard ratio, 0.32; 95% CI, 0.11 to 0.91; = .034).

Conclusion: Longer survival was observed in patients with high-TMB receiving ICI compared with those with low-TMB. This supports the role of high-TMB as a predictive biomarker for efficacy of ICI therapy in PDAC. Additionally, we report higher rates of and mutations and lower rates of mutation among patients with PDAC and high-TMB, which to our knowledge, is a novel finding.