Biological features and clinical outcomes in atezolizumab (atezo)-treated patients (pts) with metastatic urothelial cancer (mUC) of the upper vs lower urinary tract (UTUC vs LTUC)

Background: mUC arising from UTUC vs LTUC may involve distinct biology resulting in different treatment responses & outcomes. However, this hypothesis has not been comprehensively explored. Here, data from 2 prospective trials of atezo (anti–PD-L1) in platinum-treated mUC (IMvigor210 Cohort 2; IMvigor211) were used to explore relationships between UTUC/LTUC primary tumor site, objective response rate (ORR)/overall survival (OS) & biomarker status. Methods: PD-L1 (VENTANA SP142 IHC assay), targeted DNA sequencing (FoundationOne) and RNA sequencing (Expression Analysis) were evaluated in archival samples. Microsatellite status (MSI) was determined at 114 loci, & tumor mutational burden (TMB) on 1.1 Mb sequenced DNA. Biomarker-evaluable pts had tumors with known baseline PD-L1 status & RNAseq profiles. Results: 220 IMvigor210 & 339 IMvigor211 pts were efficacy evaluable (Table), of whom 24% & 28%, respectively, had UTUC. Numerically higher ORR was seen in LTUC vs UTUC (IMvigor210, 23% vs 14%; IMvigor211, 18% vs 10%); these differences were not statistically significant. In both cohorts LTUC pts had significantly higher TMB (IMvigor210 P = 0.05; IMvigor211 P = 0.02) & a trend toward higher PD-L1 expression. Lund molecular subtype distribution also differed between UTUC vs LTUC (IMvigor210 P = 0.005; IMvigor211 P = 0.098) with increased frequency of genomically unstable tumors in LTUC pts. FGFR3 alterations did not associate with UTUC vs LTUC or with response in these groups. In the combined IMvigor210 and IMvigor211 cohorts, MSI-high tumors occurred in 1/146 (< 1%) of UTUC and 5/413 (1%) of LTUC subgroups. Conclusions: Our data suggest pts with LTUC may have improved outcomes with atezo vs pts with UTUC, although benefit was observed in both groups. Numerically higher ORR/OS in pts with platinum-treated LTUC may be partly related to non-overlapping underlying biology & warrants further study in different settings.Table: 902PUTUCLTUCIMvigor210 (n = 220)aBiomarker-evaluable pts from overall cohorts of 310 pts (IMvigor210 cohort 2) & 467 pts (IMvigor211). P values in the abstract are shown for descriptive purposes only based on this post hoc analysis.n52168ORR (%)1323Median OS (mo)10.311.7IMvigor211 (n = 339)aBiomarker-evaluable pts from overall cohorts of 310 pts (IMvigor210 cohort 2) & 467 pts (IMvigor211). P values in the abstract are shown for descriptive purposes only based on this post hoc analysis.n94245ORR (%)1118Median OS (mo)9.710.9a Biomarker-evaluable pts from overall cohorts of 310 pts (IMvigor210 cohort 2) & 467 pts (IMvigor211). P values in the abstract are shown for descriptive purposes only based on this post hoc analysis. Open table in a new tab Clinical trial identification: NCT02108652, NCT02302807. Editorial acknowledgement: Medical writing support provided by Paige S. Davies, PhD, of Health Interactions. Legal entity responsible for the study: F. Hoffmann-La Roche AG. Funding: F. Hoffmann-La Roche AG. Disclosure: M.D. Galsky: Advisory boards and research funding: Merck, Genentech, AstraZeneca, BMS; Advisory boards: Pfizer. R. Banchereau: Employee of Genentech. E.E. Kadel, III: Employee of Genentech/Roche; Stock: Roche, Compugen, Clinuvel, Epizyme, Mannkind, Merck; Immediate family member who owns stock in Gilead Sciences; Travel, accommodations, expenses: Genentech/Roche. T. Ramirez-Montagut, S. Mariathasan, A. Thåström: Employee and stock owner: Genentech. J. Rosenberg: Consultant: Merck, Roche/Genentech, AstraZeneca, BMS, Inovio, EMD-Serono, Bayer, Seattle Genetics, Astellas; Speaking fees: Chugai, AstraZeneca. Research sponsorship: Novartis, Roche/Genentech, Astellas, Seattle Genetics, Bayer, Mirati, Oncogenex, Incyte. T. Powles: Funding: AstraZeneca, Roche; Honoraria: AstraZeneca, Roche, Pfizer, Merck, BMS. M.S. van der Heijden: Consultancy fees and research funding: BMS, Astellas; Consultancy fees: Roche/Genentech, MSD, AstraZeneca/Medimmune, Seattle Genetics. A. Necchi: Research grants: AstraZeneca and Merck; Advisor: Merck, Incyte, Roche, AstraZeneca, Janssen, Clovis Oncology, BioClin Therapeutics, BMS.