BACKGROUND
Despite high response rates to first-Line (1L) standard of care (SoC) for locally advanced or metastatic urothelial cancer (UC) chemotherapy (gemcitabine + cisplatin or gemcitabine + carboplatin for patients who are cisplatin-ineligible [poor performance status, impaired renal function, comorbidities]), most patients experience disease progression. Novel strategies such as combining chemotherapy and immunotherapy offer hope for improving clinical outcomes. Durvalumab is a selective, high affinity, engineered human IgG1 mAb that blocks PD-L1 binding to PD-1 and CD80. Tremelimumab is a human IgG2 mAb directed against CTLA-4. The mechanisms of action of PD-1 and CTLA-4 are nonredundant, so targeting both checkpoint pathways may have additive or synergistic efficacy compared with monotherapy. Studies of platinum-based chemotherapy combined with checkpoint blockade in other tumor types have yielded improved efficacy with acceptable safety and support exploration of this approach for 1L locally advanced or metastatic UC.
METHODS
NILE (NCT03682068) is a randomized, open-label, multicenter, global trial that will enroll approximately 1265 patients with histologically or cytologically documented, unresectable, locally advanced, or metastatic transitional cell carcinoma of the urothelium. Patients will be randomized (1:1:1) to durvalumab + SoC chemotherapy, durvalumab + tremelimumab + SoC chemotherapy, or SoC chemotherapy as 1L therapy. Primary endpoints are progression-free survival using blinded independent central review assessments per RECIST 1.1 and overall survival (OS). Secondary endpoints include objective response rate, OS at 24 months, proportion of patients alive and progression free at 12 months, duration of response, disease control rate, time from randomization to second progression, and health-related quality of life. Safety, pharmacokinetics, immunogenicity, and biomarkers will also be assessed. The study opened for enrollment in September 2018.

A Phase 3, Randomized, Open-Label, Multicenter, Global Study of First-Line Durvalumab + SoC Chemotherapy and Durvalumab + Tremelimumab and SoC Chemotherapy vs SoC Chemotherapy Alone in Unresectable Locally Advanced or Metastatic Urothelial Cancer