Association of Tumor Mutational Burden (TMB) and Microsatellite Instability (MSI) with Response and Outcomes in Patients with Urothelial Carcinoma (UC) Treated with Immune Checkpoint Inhibitor (ICI)

Background Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. Methods Patients from 15 institutions were treated with ICI monotherapy (in any setting). Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs <10 mut/Mb) and continuous variable. Results We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2+L. For the 1L/upfront: median [m]OS was numerically longer in patients with TMB≥10 vs TMB <10: mOS 35 vs 26 months (HR= 0.6) and with MSI-H and MSI-S (mOS NR vs 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR= 0.96, p=0.01). For 2+L: mOS was numerically longer in patients with TMB≥10 vs TMB<10: (20 vs 12 months; HR=0.9) and in patients with MSI-H and MSI-S was 12 vs 17 months, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB≥10 vs TMB <10: 61 vs 17 months; (HR = 0.2, p=0.02) and with MSI-H and MSI-S (NR vs 24 months). Conclusions Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Findings may have been inconclusive due to limited power and further validation is needed.Micro-Abstract: Based on published data, Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with response and survival in patients with advanced urothelial carcinoma treated with ICI in a “real-world” setting. High TMB and MSI were associated with better outcomes consistent with prior data.