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Immune checkpoint therapy is being tested in the neoadjuvant setting for patients with localized urothelial carcinoma.sup.1,2, with one study reporting data in cisplatin-ineligible patients who received anti-PD-L1 monotherapy.sup.2. The study reported that patients with bulky tumors, a known high-risk feature defined as greater than clinical T2 disease, had fewer responses, with pathological complete response rate of 17%.sup.2. Here we report on the first pilot combination neoadjuvant trial (NCT02812420) with anti-PD-L1 (durvalumab) plus anti-CTLA-4 (tremelimumab) in cisplatin-ineligible patients, with all tumors identified as having high-risk features (n = 28). High-risk features were defined by bulky tumors, variant histology, lymphovascular invasion, hydronephrosis and/or high-grade upper tract disease.sup.3-5. The primary endpoint was safety and we observed 6 of 28 patients (21%) with grade [greater than or equal to]3 immune-related adverse events, consisting of asymptomatic laboratory abnormalities (n = 4), hepatitis and colitis (n = 2). We also observed pathological complete response of 37.5% and downstaging to pT1 or less in 58% of patients who completed surgery (n = 24). In summary, we provide initial safety, efficacy and biomarker data with neoadjuvant combination anti-PD-L1 plus anti-CTLA-4, which warrants further development for patients with localized urothelial carcinoma, especially cisplatin-ineligible patients with high-risk features who do not currently have an established standard-of-care neoadjuvant treatment. Neoadjuvant combination of immune checkpoint therapy in patients with cisplatin-ineligible bladder cancer achieves clinical efficacy and uncovers immune features as potential predictive biomarkers of treatment response., Author(s): Jianjun Gao [sup.1] , Neema Navai [sup.2] , Omar Alhalabi [sup.3] , Arlene Siefker-Radtke [sup.1] , Matthew T. Campbell [sup.1] , Rebecca Slack Tidwell [sup.4] , Charles C. Guo [...]