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

: We aim to identify predictors of response to ICIs in patients with advanced solid tumors that exhibiting a TMB ≥ 10 mut/Mb. : 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 < 0.05. : 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 ( = 0.009), absence of liver metastasis ( = 0.015), and no prior systemic treatment ( = 0.001) in both cohorts. In non-ICI-sensitive patients, a TMB of ≥15 mut/Mb correlated with improved outcomes ( = 0.012). Mutations in the pathway ( = 0.03) and the gene ( = 0.014) were associated with poorer responses, while mutations in the gene were linked to better responses ( = 0.031). : Patients without liver metastasis, mutations in , and TMB ≥ 15 mut/Mb are associated with superior response, while mutations in the pathway and are associated with worse responses.