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

Background/Objectives: We aim to identify predictors of response to ICIs in patients with advanced solid tumors that exhibiting a TMB ≥ 10 mut/Mb. Methods: 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 p < 0.05. Results: 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 (p = 0.009), absence of liver metastasis (p = 0.015), and no prior systemic treatment (p = 0.001) in both cohorts. In non-ICI-sensitive patients, a TMB of ≥15 mut/Mb correlated with improved outcomes (p = 0.012). Mutations in the MYC pathway (p = 0.03) and the MLL2 gene (p = 0.014) were associated with poorer responses, while mutations in the TERT gene were linked to better responses (p = 0.031). Conclusions: Patients without liver metastasis, mutations in TERT, and TMB ≥ 15 mut/Mb are associated with superior response, while mutations in the MYC pathway and MLL2 are associated with worse responses.