Purpose: Single agent checkpoint inhibition is effective in a minority of patients with platinum-refractory urothelial carcinoma (UC); therefore, the efficacy of combining low-dose paclitaxel with pembrolizumab was tested. Patients and Methods: This was a prospective, single-arm phase 2 trial with key inclusion criteria of imaging progression within 12 months of platinum therapy and ECOG ≤1. Treatment was pembrolizumab 200mg day 1 and paclitaxel 80mg/m2 days 1 and 8 of a 21-day cycle for up to 8 cycles unless progression or unacceptable adverse events (AEs). The primary endpoint was objective response rate (ORR) with overall survival (OS), 6-month progression free survival (PFS), and safety as key secondary endpoints. Change in circulating immune cell populations, plasma and urinary microRNAs (miRs) were evaluated. Results: Twenty-seven patients were treated between 4/2016-6/2020, with median follow up of 12.4 months. Baseline median age was 68 years, with 81% men and 78% non-Hispanic white. ORR was 33% by intention to treat and 36% in imaging-evaluable patients with 3 complete responses. Six-month PFS rate was 48.1% (95%CI: 28.7%, 65.2%) and median OS 12.4 months (95%CI: 8.7 mo, NR). Common ≥ grade 2 possibly-related AEs were anemia, lymphopenia, hyperglycemia, and fatigue; grade 3/4 AEs occurred in 56%, including 2 immune-mediated AEs (pneumonitis and nephritis). Responding patients had a higher percentage of circulating CD4+IFNγ+ T cells. Levels of some miRs, including plasma miR 181 and miR 223, varied in responders compared to non-responders. Conclusions: The addition of low-dose paclitaxel to pembrolizumab is active and safe in platinum-refractory UC.

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