Abstract LB091: A multigene signature for immunotherapy in patients with high risk non-muscle-invasive bladder cancer

Abstract Introduction: Approximately 80% of bladder cancer patients are initially diagnosed with non-muscle invasive bladder cancer (NMIBC). However, most NMIBC patients have a high recurrence rates, and up to 45% progress to muscle-invasive bladder cancer (MIBC) and metastatic disease. Treatment for NMIBC includes transurethral resection and, depending on the risk of recurrence or progression, intravesical chemotherapy or immunotherapy, such as Bacillus Calmette-Guérin (BCG). Our aim is to use a multigene signature in patients with high-risk NMIBC to determine whether patients may benefit from improved ICIs compared to conventional PD-L1 expression and to evaluate the clinical utility. Methods: A multi-gene signature obtained from the various NMIBC data was applied to stratify the UROMOL2021 cohort (n=535) using consensus clustering. Each subtype was distinguished by biological pathway analysis. Validation analysis was performed in three independent cohorts including the IMvigor210 (n=298), IMvigor010 (n=377) and ABACUS (n=148) clinical trials treated with PD-L1 inhibitors. The log-rank test, chi-square test, Fisher’s exact test, and cox regression analysis were used to evaluate clinical utility. Results: Based on consensus cluster analysis, NMIBC patients in the UROMOL2021 cohort were classified into five subgroups exhibiting unique characteristics, including DNA damage repair (DDR). Cross-validation was performed using two independent NMIBC cohorts and one MIBC cohort. Survival analysis showed that the subgroup associated with DDR (DDR and DDR+Tcell) had the highest rates of relapse and disease progression (progression-free survival, p0. 001) and benefited from Immune checkpoint inhibitors (ICIs) (response, p=0. 01; overall survival, p=0. 004). Conclusions: This study suggests that the multi-gene signature may play a role to enhance the responsiveness of ICIs for high-risk NMIBC. Additionally, it is important to help improve ICI treatment approaches that currently focus on PD-L1 expression on cancer cells, allowing more patients to receive priority consideration for ICI therapy. Citation Format: Seung-Woo Baek, Seon-Kyu Kim, Sun-Hee Leem, In-Sun Chu. A multigene signature for immunotherapy in patients with high risk non-muscle-invasive bladder cancer abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (7Suppl): Abstract nr LB091.