A phase III, randomized, open-label, multicenter, global study of first-line durvalumab plus standard of care (SoC) chemotherapy and durvalumab plus tremelimumab, and SoC chemotherapy versus SoC chemotherapy alone in unresectable locally advanced or metastatic urothelial cancer (NILE).
Authors: Galsky Matt D. , Necchi Andrea , Sridhar Srikala S. , Ogawa Osamu , Angra Natasha , Hois Stephan , Xiao Feng , Goluboff Erik , Bellmunt Joaquim 
Published: March 2021

TPS504 Background: Despite high response rates with first-Line (1L), standard, platinum-based chemotherapy (CT) (gemcitabine + cisplatin or gemcitabine + carboplatin) for patients (pts) with locally advanced or metastatic urothelial cancer (mUC), prognosis remains poor. Studies of immune checkpoint inhibitors + CT in 1L mUC have demonstrated mixed results. In IMvigor130, an improvement in progression-free survival (PFS) with atezolizumab + CT vs placebo + CT reached statistical significance, although overall survival (OS) had not reached statistical significance at the interim analysis. A subgroup analysis suggested a possible larger effect size for PFS and OS for pts with high PD-L1 expression. In KEYNOTE-361, no improvement in either PFS or OS was observed with pembrolizumab + CT vs CT alone. The combination of durvalumab (anti–PD-L1 antibody) and tremelimumab (anti–CTLA-4 antibody) has shown activity in previously treated mUC. In the DANUBE trial of 1L mUC, the co-primary endpoints were OS compared between durvalumab and CT in pts whose tumor cells and/or tumor-infiltrating immune cells express high levels of PD-L1 (≥25%) and between durvalumab + tremelimumab and CT regardless of PD-L1 expression. While neither co-primary endpoint was met, durvalumab + tremelimumab showed evidence of activity, particularly in the PD-L1–high population (hazard ratio: 0.74 [95% CI 0.59–0.93]). Collectively, these results led to an update to the NILE protocol, focusing on pts with PD-L1–high expression. Methods: NILE (NCT03682068) is a randomized, open-label, multicenter, phase III global trial that will randomize ~1215 previously untreated pts with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Eligible pts aged ≥18 years will be randomized 1:1:1 to durvalumab + CT (Arm 1), durvalumab + tremelimumab + CT (Arm 2), or CT (Arm 3). A tumor tissue sample for biomarker analysis is mandatory as PD-L1 status is a stratification factor. The original co-primary endpoints were PFS and OS for durvalumab + CT vs CT in the intention-to-treat population. However, based on the DANUBE trial results, the primary endpoint was revised to a co-primary endpoint OS in pts with high PD-L1 expression for Arm 1 vs Arm 3 and Arm 2 vs Arm 3. Secondary endpoints will include OS, OS rate at 24 months, PFS, objective response rate, proportion of pts alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, health-related quality of life, and safety. Pharmacokinetics, immunogenicity, and biomarkers are exploratory endpoints. The study opened for enrollment in September 2018. Clinical trial information: NCT03682068.