Refining Tumor Mutational Burden as a Predictive Biomarker for Pembrolizumab: A Real‐World Analysis in Japanese Patients

ABSTRACT Tumor mutational burden (TMB) is a key biomarker for predicting the response to immune checkpoint inhibitors (ICIs). However, its predictive accuracy in real‐world clinical practice, particularly in Asian populations, remains inadequately evaluated. We addressed this issue by analyzing real‐world data from 63,952 patients registered in the Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) database, which integrates genomic and clinical information from Japanese patients with various advanced solid tumors. We assessed the therapeutic efficacy of pembrolizumab in 1899 patients who underwent one of three comprehensive genomic profiling tests: FoundationOne CDx, the OncoGuide NCC Oncopanel System, or the GenMine TOP Cancer Genome Profiling System. Based on the reported TMB values, patients were classified as TMB‐high (≥ 10 mutations per megabase) or TMB‐low (< 10 mutations per megabase). The objective response rate (ORR) among 946 TMB‐high patients exceeded 30% and was significantly higher than that observed in 953 TMB‐low patients (16.8%, p < 0.001). Notably, patients with borderline TMB values (10 to less than 13 mutations per megabase) exhibited relatively modest responses (20.8%). The ORR improved when hotspot mutations were excluded from the TMB calculation, suggesting that this adjustment enhances the predictive accuracy of TMB. These findings support the clinical utility of TMB as a biomarker for predicting ICI response in routine oncology practice. In particular, excluding hotspot mutations from TMB calculations may improve response prediction in patients whose TMB values are near the threshold.