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:
Clinical Significance of the IRS
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.
Biological Significance of the IRS. To fully characterize the IRS from a biological viewpoint, we carried out a differential gene expression analysis followed by a GSEA. As expected, this analysis revealed an enrichment of important biological processes associated with immune system activation such as natural killer cell-mediated immunity (adjusted P value <0.001), lymphocyte-mediated immunity (adjusted P value <0.001), lymphocyte migration (adjusted P value <0.001), and response to interferon-g (adjusted P value <0.001) in IRS high cases. By contrast, processes associated with stroma such as extracellular matrix organization (adjusted P value <0.001) and extracellular structure organization (adjusted P value <0.001) were upregulated in IRS low cases.
Today, either in daily clinical practice or in a clinical trial scenario, there are available different treatment options for the management of patients with aUC. In this context, the development of tools to help in the decision-making process is mandatory. In this study, in addition to demonstrating the prognostic and predictive utility of the IRS in patients with aUC under atezolizumab monotherapy, we characterized its underline molecular and immune features. If the results of this study are definitively validated, the IRS will represent a valuable tool for therapy selection in this setting: immuno- therapy yes or not, alone or in combination.
Written by: M. Ferreiro-Pantín,1 U. Anido-Herranz,2 Y. Z. Betancor,1 V. Cebey-López,2 L. León-Mateos,3 J. García-González,3 S. M. García-Acuña,4 N. Fernández-Díaz,2 J. M. C. Tubio,5 R. López-López,3 J. Ruiz-Bañobre6
- Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), Santiago de Compostela; Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), Santiago de Compostela.
- Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), Santiago de Compostela; Department of Medical Oncology, University Clinical Hospital of Santiago de Compostela (SERGAS), University of Santiago de Compostela (USC), Santiago de Compostela.
- Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), Santiago de Compostela; Department of Medical Oncology, University Clinical Hospital of Santiago de Compostela (SERGAS), University of Santiago de Compostela (USC), Santiago de Compostela; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid.
- Department of Pathology, University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), Santiago de Compostela, Spain.
- Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), Santiago de Compostela.
- Translational Medical Oncology Group (ONCOMET), Health Research Institute of Santiago de Compostela (IDIS), University Clinical Hospital of Santiago de Compostela, University of Santiago de Compostela (USC), Santiago de Compostela; Genomes and Disease, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), Santiago de Compostela; Department of Medical Oncology, University Clinical Hospital of Santiago de Compostela (SERGAS), University of Santiago de Compostela (USC), Santiago de Compostela; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto de Salud Carlos III, Madrid.
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