Background: Immune checkpoint inhibitors (CPIs) are approved for patients (pts) with locally advanced or metastatic urothelial cancer (la/mUC) who progress on prior platinum or are ineligible for first line cisplatin. However, only a minority of pts respond to CPI monotherapy and a combination approach may be beneficial. Enfortumab vedotin (EV), an antibody-drug conjugate (ADC), delivers the microtubule-disrupting agent monomethyl auristatin E (MMAE) to tumors expressing Nectin-4, which is overexpressed in mUC. Preliminary results from an ongoing phase 1 study of EV monotherapy in pts with mUC (Petrylak ASCO 2017) showed that EV was well tolerated in pts with mUC. EV showed a 41% (29 out of 71 pts) objective response rate (ORR) across all doses (24 wks median response duration). In pts with liver metastasis the ORR was 47% (9 out 19 pts) across all doses. Preclinical data show that an MMAE ADC, but not the unconjugated antibody, increases tumor immunogenicity by inducing immunogenic cell death, antigen presentation and tumor immune infiltration (Gardai 2015). Based on encouraging phase 1 study results and potential enhanced immune response, combining EV with a CPI may result in improved response rates with longer durability. Methods: This phase 1b study (NCT03288545) evaluates the safety/activity of EV + CPI in pts with la/mUC who have not previously received a CPI. The study has 2 parts: dose escalation (EV + pembrolizumab) and dose expansion (EV + CPI [pembrolizumab or atezolizumab]). Pts must have la/m transitional cell carcinoma of the urothelium, be eligible for treatment with a CPI, and be either ineligible for first-line cisplatin-based chemotherapy or have disease progression during or following treatment with ≥1 platinum-containing regimen. The primary objective is to assess the safety/tolerability of EV + CPI. Secondary objectives include determining a recommended dose of EV + CPI in pts with la/mUC, antitumor activity as measured by ORR, disease control rate, duration of response, PFS, and OS. Response is assessed per RECIST v1.1 and iRECIST. Study enrollment began in Oct 2017. Clinical trial information: NCT03288545