Clinical and Molecular Differences Suggest Different Responses to Immune Checkpoint Inhibitors in Microsatellite-Stable Solid Tumors with High Tumor Mutational Burden

<b>Background/Objectives</b>: We aim to identify predictors of response to ICIs in patients with advanced solid tumors that exhibiting a TMB ≥ 10 mut/Mb. <b>Methods</b>: Patients treated with ICIs alone at Northwestern University between 1 January 2015 and 31 December 2020 were identified. Progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method, and groups were compared using the log-rank test. Wilcoxon rank sum tests, chi-squared tests, and Fisher's exact tests were used for univariable analyses evaluating the impact of clinical and genetic variables on response, with significance defined as <i>p</i> < 0.05. <b>Results</b>: A total of 117 patients were classified as ICI-sensitive (n = 88) or non-ICI-sensitive (n = 29). Among evaluable patients (n = 105), the overall response rate was 34% with 14% achieving a complete response. Median PFS and OS were 8.05 months and 26.8 months, respectively. Higher PFS rates were significantly linked to the ICI-sensitive tumor group (<i>p</i> = 0.009), absence of liver metastasis (<i>p</i> = 0.015), and no prior systemic treatment (<i>p</i> = 0.001) in both cohorts. In non-ICI-sensitive patients, a TMB of ≥15 mut/Mb correlated with improved outcomes (<i>p</i> = 0.012). Mutations in the <i>MYC</i> pathway (<i>p</i> = 0.03) and the <i>MLL2</i> gene (<i>p</i> = 0.014) were associated with poorer responses, while mutations in the <i>TERT</i> gene were linked to better responses (<i>p</i> = 0.031). <b>Conclusions</b>: Patients without liver metastasis, mutations in <i>TERT</i>, and TMB ≥ 15 mut/Mb are associated with superior response, while mutations in the <i>MYC</i> pathway and <i>MLL2</i> are associated with worse responses.