Clinical, molecular, and immune correlates of Immunotherapy Response Score in advanced urothelial carcinoma patients under atezolizumab monotherapy: Analysis of the phase 2 IMvigor210 trial

Background In the advanced urothelial carcinoma (aUC) scenario there are no consistent biomarkers to predict the benefit patients derived from immune checkpoint blockade. Recently a novel pan-tumor molecular tissue-based biomarker, the Immunotherapy Response Score (IRS), has been proposed. Herein we conducted a retrospective study to validate the prognostic and predictive utility of the IRS in aUC patients under atezolizumab monotherapy and to characterize its underline molecular and immune features in the context of the IMvigor210 phase 2 clinical trial. Methods This is a retrospective study of 261 patients with available clinical, molecular, and immune tumor data treated with atezolizumab monotherapy in the IMvigor210 phase 2 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-squared or Fisher exact tests. All p values were 2-sided, and those less than 0.05 were considered statistically significant. Results High IRS was significantly associated with a better OS in univariable [hazard ratio (HR)=0.49, 95% CI 0.33–0.74, p<0.001] and multivariable (HR=0.57, 95% CI 0.37–0.86, p=0.007) analyses. DCR and ORR were significantly higher among high IRS patients (DCR for high IRS vs low IRS patients: 57% vs 32%, p<0.001; ORR for high IRS vs low IRS patients: 42% vs 10%, p<0.001). High IRS patients presented a higher probability of DC and response in univariable [DC: odds ratio (OR)=2.72, 95% CI 1.54–4.81, p<0.001; Response: OR=3.92, 95% CI 2.11–7.31; p<0.001] and multivariable (DC: OR=2.38, 95% CI 1.28–4.44, p=0.006; Response: OR=3.36, 95% CI 1.68–6.69, p<0.001) analyses. Conclusions This study validates IRS as a strong independent prognostic and predictive biomarker for OS and DC/response in aUC patients treated with atezolizumab monotherapy in the IMvigor210 phase 2 clinical trial. Clinical Trial Registration NCT02108652, [NCT02951767][1]. ### Competing Interest Statement Urbano Anido-Herranz - Travel, accommodations, expenses: Ipsen, Bayer, Merck, and Pfizer; honoraria for educational activities: Advanced Accelerator Applications - Novartis, Bayer, Ipsen, MSD, AstraZeneca, Merck, Eisai, Bristol-Myers Squibb, Kyowa Kirin, Rovi, GlaxoSmithKline, and LEO Pharma; honoraria for consultancies: Advanced Accelerator Applications - Novartis, Ipsen, AstraZeneca, Merck, Pfizer, Astellas, and Bayer. Victor Cebey-Lopez - Travel, accommodations, expenses: AstraZeneca, Bristol-Myers Squibb, Eisai, Ipsen, Kyowa Kirin, Merck, Novartis, Pfizer, Pharmamar, Pierre-Fabre, Roche, and Sanofi; honoraria for educational activities: AstraZeneca and Pharmamar. Luis Leon-Mateos - Travel, accommodations, expenses: Bristol-Myers Squibb, Lilly, MSD, and Roche; honoraria for educational activities: AstraZeneca, Boehringer Ingelheim, Novartis, Jansen, Astellas, and Sanofi; honoraria for consultancies: AstraZeneca, Boehringer Ingelheim, Novartis, Jansen, Astellas, and Sanofi. Jorge Garcia-Gonzalez - Travel, accommodations, expenses: AstraZeneca, Bristol-Myers Squibb, MSD, Roche, Sanofi, and Takeda; honoraria for educational activities: AstraZeneca, Bristol-Myers Squibb, MSD, Novartis, Pierre-Fabre, Roche, Sanofi, and Takeda; honoraria for consultancies: AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, MSD, Novartis, Roche, Sanofi, and Takeda. Natalia Fernandez-Diaz - Travel, accommodations, expenses: GlaxoSmithKline, and Sanofi. Rafael Loopez-Loopez - Travel, accommodations, expenses: Lilly, Novartis, Pfizer, Merck, Roche, and Bristol-Myers Squibb; honoraria for educational activities: Lilly, Novartis, Pfizer, Merck, Roche, and Bristol-Myers Squibb; honoraria for consultancies: Pharmamar, Bayer, and Pierre Fabre. Juan Ruiz-Bañobre - Honoraria for educational activities: Ipsen; institutional research funding: Pfizer and Roche. The other authors have no conflicts of interest to declare. ### Funding Statement The authors received no specific funding for this work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: All data used for the analyses presented here have been previously deposited to the European Genome-Phenome Archive under accession number EGAS00001002556 and is available in IMvigor210CoreBiologies, a fully documented software and data package for the R statistical computing environment. This package is freely available under the Creative Commons 3.0 license and can be downloaded from . I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data used for the analyses presented here have been previously deposited to the European Genome-Phenome Archive under accession number EGAS00001002556 and is available in IMvigor210CoreBiologies, a fully documented software and data package for the R statistical computing environment. This package is freely available under the Creative Commons 3.0 license and can be downloaded from . [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT02951767&atom=%2Fmedrxiv%2Fearly%2F2023%2F04%2F17%2F2023.04.11.23288423.atom