Clinical, molecular, and immune correlates of the Immunotherapy Response Score in patients with advanced urothelial carcinoma under atezolizumab monotherapy: analysis of the phase II IMvigor210 trial.

BACKGROUND: In the advanced urothelial carcinoma (aUC) scenario there are no consistent immune checkpoint blockade predictive biomarkers. Recently a novel pan-tumor molecular tissue-based biomarker, the Immunotherapy Response Score (IRS), has been proposed. We conducted a retrospective study to validate the prognostic/predictive utility of the IRS in patients with aUC under atezolizumab monotherapy and to characterize its underlying molecular/immune features in the context of the IMvigor210 phase II trial. PATIENTS AND METHODS: This is a post hoc pooled analysis of 261 patients with available clinical, molecular, and immune tumor data treated with atezolizumab monotherapy in the IMvigor210 phase II clinical trial. Efficacy endpoints were overall survival (OS), disease control rate (DCR), and overall response rate (ORR). Survival estimates were calculated by the Kaplan-Meier method, and groups were compared with the log-rank test. The Cox proportional hazards regression model was used to evaluate factors independently associated with OS. Factors associated with disease control (DC) and response were tested with logistic regression in univariable and multivariable analyses. Comparisons between patient and disease characteristics were carried out using chi-square or Fisher's exact tests. All P values were two-sided, and those <0.05 were considered statistically significant. RESULTS: High IRS was significantly associated with a better OS in univariable [hazard ratio (HR) = 0.49, P < 0.001] and multivariable (HR = 0.60, P = 0.018) analyses. DCR and ORR were significantly higher among high IRS patients (DCR for high IRS versus low IRS patients: 57% versus 32%, P < 0.001; ORR: 42% versus 10%, P < 0.001). High IRS patients presented a higher probability of DC and response in univariable [DC: odds ratio (OR) = 2.72, P < 0.001; response: OR = 3.92, P < 0.001] and multivariable (DC: OR = 2.72, P < 0.001; response: OR = 3.92, P < 0.001) analyses. CONCLUSIONS: This study validates IRS as a strong independent prognostic and predictive biomarker for OS and DC/response in patients with aUC treated with atezolizumab monotherapy in the IMvigor210 phase II clinical trial.

Rethinking prognostic factors in locally advanced or metastatic urothelial carcinoma in the immune checkpoint blockade era: a multicenter retrospective study.

BACKGROUND: Few studies have investigated the safety and efficacy of anti-PD-(L)1 antibodies in metastatic urothelial carcinoma (mUC) in daily clinical practice. Knowledge about the influence of baseline clinical and analytical factors on therapy outcomes is scarce. PATIENTS AND METHODS: We conducted a multicenter retrospective study involving 119 previously treated or untreated mUC patients under anti-PD-(L)1 therapy in a real-world scenario. The objectives of this study were to confirm the safety and efficacy of anti-PD-(L)1 monotherapy and to identify pretreatment factors influencing therapy outcomes. In addition, an independent prognostic model for overall survival (OS) was developed and internally validated. RESULTS: Median OS was 7.8 months [95% confidence interval (CI), 5.4-10.4], median progression-free survival (PFS) was 2.80 months (95% CI, 2.4-3.4), disease control rate (DCR) was 40% (95% CI, 31-49), and overall response rate (ORR) was 24% (95% CI, 15-31). Presence of peritoneal metastases was associated with poor OS [hazard ratio (HR) = 2.40, 95% CI, 1.08-5.33; P = 0.03]. Use of proton-pump inhibitors (PPI) was associated with poor OS (HR = 1.83, 95% CI, 1.11-3.02; P = 0.02) and PFS (HR = 1.94, 95% CI, 1.22-3.09; P = 0.005), and lower DCR (OR = 0.38, 95% CI, 0.17-0.89; P = 0.03) and ORR (OR = 0.18, 95% CI, 0.02-1.60; P = 0.002). The three risk category prognostic model developed included Eastern Cooperative Oncology Group performance status, PPI use, albumin level, presence of liver metastases, and presence of peritoneal metastases variables and was associated with higher risk of death (HR = 3.00, 95% CI, 1.97-4.56; P = 0.0001). CONCLUSIONS: This study confirms anti-PD-(L)1 monotherapy as a safe and effective treatment option in daily clinical practice for mUC patients. It also describes the presence of peritoneal metastases as an independent prognostic factor for OS and underlines the association between PPI use and worse therapeutic outcomes. Finally, it proposes a new easy-to-use risk-assessment model for OS prediction.