Abstract 719: Clinical and molecular differences suggest different responses to immune checkpoint inhibitors in microsatellite-stable solid tumors with high tumor mutational burden

Introduction: High tumor mutational burden (TMB) has shown promise in specific tumor types; however, its broad applicability across all solid tumors remains unclear. We aim to evaluate the outcomes of patients with advanced solid tumors exhibiting TMB ≥10 mutations per megabase (mut/Mb) who were treated with immune checkpoint inhibitors (ICIs) and to identify resistance mechanisms. Methods: Patients who received treatment at the Northwestern University between January 2015 and December 2020 with ICIs and a TMB of ≥10 mut/Mb were identified through an Enterprise Data Warehouse grant and determined by next-generation sequencing. Tumors with microsatellite instability were excluded. Survival curves were calculated using the Kaplan-Meier method, and multivariate analyses were conducted to evaluate the impact of clinical variables on response, with significance defined as p≤0.05. Results: 117 patients were enrolled, median age of 68 years, and 61% of the participants were male. The patient cohort was categorized into two distinct groups based on their sensitivity to ICI treatments: Group 1: ICI-sensitive (75%, 88/117 patients). Group 2: Non-ICI-sensitive (25%, 29 /117 patients). Upon evaluation of treatment efficacy (n=105), the overall response rate was recorded at 34%, with 14% of patients achieving a complete response (CR). The median progression-free survival and overall survival were 10.9 months and 29.9 months, respectively. Positive treatment responses were associated with a lack of prior exposure to systemic therapy (p=0.046), specific tumor types (p=0.009), absence of liver metastasis (p=0.015) across all group. Additionally, the presence of POLE mutations was associated with better outcomes (p=0.037), as well as a TMB of ≥15 mut/Mb in non-ICI-sensitive cancer group (p=0.012). However, PD-L1 status, specific ICI regimen, age, and sex did not demonstrate prognostic significance. Regarding genetic pathways, mutations in the TP53 pathway were significantly correlated with poorer treatment response (p=0.018). No significant differences were observed in the RTK/RAS, NRF2, PI3K, TGFβ, WNT, MYC, cell cycle, and Notch pathways. Furthermore, specific mutations in the TP53 (p = 0.029) and PIK3CA (p = 0.033) genes were linked to diminished responses. A trend was also noted suggesting ROS1 mutations may be associated with a poorer response (p=0.057). Conclusion: Immunotherapy utilizing ICIs effectively treats TMB-H tumors, which typically demonstrate low CR rates. Enhanced therapeutic responses have been observed in patients who have not previously undergone systemic therapy, do not present with liver metastasis, and possess a TMB level of ≥15 mut/Mb. Mutations in the TP53 pathway are linked to a diminished response, while other pathways analyzed did not exhibit statistically significant differences in response rates. Citation Format: Tarik Demir, Imran Nizamuddin, Katrina Dobinda, Ruohui Chen, Masha Kocherginsky, Peter Doukas, Neelima Katam, Carolyn Moloney, Devalingam Mahalingam. Clinical and molecular differences suggest different responses to immune checkpoint inhibitors in microsatellite-stable solid tumors with high tumor mutational burden [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 719.