Confirmatory study of the IO Score, a tumor immune microenvironment (TIME) classifier, demonstrates efficacy in a real-world cohort of metastatic urothelial cancer (mUC) patients treated with immune checkpoint inhibitors (ICIs)

Abstract Background: Prognosis for patients with mUC is poor with fewer than 10% surviving two years after diagnosis. As the majority of mUC patients do not survive to a second line of therapy, optimization of first line therapy is critical, especially with recently approved non-ICI therapeutics. The IO Score, a 27-gene TIME classifier, has previously demonstrated a strong association with response to ICI therapy in mUC (IMvigor210; n= 348), NSCLC, renal cancer and a randomized TNBC trial (NeoTRIPaPDL1; n= 258). In a real-world study of ICI therapy in mUC pts (UNC-108), clinical benefit was seen in less than 30% of patients (Rose, 2021). The IO Score was evaluated for efficacy to ICI in this cohort to confirm findings from IMvigor210 where the IO Score was both independent and complementary to TMB. Methods: The previously defined IO score algorithm was applied to available RNAseq data from 77 patients in the UNC-108 study. Using a six-week front censor for OS, Cox proportional hazards for OS, and PFS, the IO Score, TMB, and TMB and/or IO Score positivity were calculated. Responses (CR/PR/SD for >6 months) were used to calculate both the ORR and OR. PD-L1 staining was unavailable. Results: Conclusions: These data confirm the association of the IO Score with response to ICI treatment in a second, independent, mUC cohort using the same algorithm and threshold previously established and validated in other tumor types. The IO Score provided independent biomarker value and identified more responders than TMB alone. The IO Score provides unique information on both the inflammatory and cancer associated fibroblast biologic signatures of response to ICI’s and can be complemented by other ICI associated biomarkers. Thus, this tool can inform therapeutic decisions and has the potential to improve outcome of mUC patients. Measure IO Score Positive TMB (10mut/MB) IO Score and/or TMB Biomarker Positive 28 (36.4%) 19 (24.7%) 35 (45.5%) OS HR = 0.39 95%CI 0.21-0.75; p=0.004 HR = 0.32 95%CI 0.14-0.72; p=0.006 HR = 0.34 95%CI 0.19-0.67; p<0.001 PFS HR = 0.45 95%CI 0.26-0.77; p=0.004 HR = 0.30 95%CI 0.16-0.59; p<0.001 HR = 0.36 95%CI 0.21-0.62; p<0.001 Objective response Rate ORR = 50% (n=14) ORR = 58% (n=11) ORR = 49% (n=17) Odds Ratio 7.17 95%CI 2.3-22.2; p<0.001 7.49 95%CI 2.4-23.8; p<0.001 12.3 95%CI 3.19-47.3; p<0.001 Citation Format: Tyler Nielsen, Robert Seitz, Matthew Varga, Catherine Cronister, David Hout, Brock Schweitzer, Douglas Ross, Kim McGregor. Confirmatory study of the IO Score, a tumor immune microenvironment (TIME) classifier, demonstrates efficacy in a real-world cohort of metastatic urothelial cancer (mUC) patients treated with immune checkpoint inhibitors (ICIs) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1272.