Interplay between Tumor Mutational Burden and Mutational Profile and its effect on overall survival: A Post Hoc Analysis of Metastatic Patients Treated with Immune Checkpoint Inhibitors

ABSTRACT Purpose Solid tumors harboring tumor mutational burden (TMB) ≥ 10 mutations per megabase (mut/Mb) received agnostic approval for pembrolizumab. However, TMB cut-off alone is not a predictor of overall survival (OS). This work aims to analyze the somatic mutational profile’s influence in the outcomes of patients with TMB-high tumors treated with immune checkpoint inhibitors (ICIs). Methods This post-hoc analysis evaluated clinical and molecular features of 1,661 patients with solid tumors treated with ICIs. We performed OS analysis for TMB thresholds of ≥ 10, ≥ 20, and < 10 mut/Mb. For a TMB ≥ 10mut/Mb cutoff, we assessed OS according to mutational profile. For genes exhibiting a correlation with OS (P < 0.05) at the univariate assessment, we conducted a Cox multivariate analysis adjusted by median TMB, sex, age, microsatellite instability (MSI), and histology. Results 1,661 patients were investigated, and 488 harbored a TMB ≥ 10 mut/Mb (29.4%). The median OS was 42 months for TMB ≥ 10 or 20 mut/Mb, and 15 months for TMB < 10 mut/Mb (P < 0.005). In patients harboring TMB ≥ 10mut/Mb, mutations in E2F3 or STK11 were correlated with worse OS, and mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1 or ZFHX3 with better OS. These associations were confirmed by univariate and multivariate analyses (P < 0.05). Melanoma histology and TMB above the median endowed patients with better OS (P < 0.05). MSI status, age, and gender did not have a consistent statistically significant effect on OS Conclusion Combining TMB information and mutation profiles in key cancer genes can be used to better qualify patients for ICI treatment and predict their OS. CONTEXT SUMMARY Key objective Tumor mutational burden (TMB) of ≥ 10 mutations per megabase (mut/Mb) grant agnostic indication of pembrolizumab for advanced solid tumors’ treatment, however a substantial number of patients do not respond to therapy. This work aims to analyze the somatic mutational profile’s influence in the outcomes of patients with TMB ≥ 10mut/Mb tumors treated with ICIs. Knowledge generated Mutation profile can modify survival outcomes to ICIs in patients with TMB ≥ 10 mut/Mb. Mutations in E2F3 or STK11 correlate with worse OS, while mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1 or ZFHX3 correlate with better OS in TMB-high patients receiving ICIs. Relevance We found that the combination of a high TMB and the somatic mutational profile in key cancer genes can be decisive in better qualify patients for ICI treatment.