Phase I/II study of ipilimumab plus nivolumab combined with sacituzumab govitecan in patients with metastatic cisplatin-ineligible urothelial carcinoma.

521 Background: Sacituzumab govitecan (SG) demonstrated an objective response rate (ORR) of 27% and median overall survival (OS) of 10.5 months (Mo) in metastatic urothelial carcinoma (mUC) patients (pts) progressing after platinum-based chemotherapy and PD1/L1 inhibitor, which led to accelerated US FDA approval in this setting. The combination of SG and pembrolizumab is safe and active following platinum-based chemotherapy. Nivolumab (NIVO) 1mg/kg plus Ipilimumab (IPI) 3mg/kg has shown promising activity in post-platinum mUC pts. Given the potential synergism between immunogenic cell death induced by SG and IPI-NIVO, we hypothesized that the combination of SG and IPI-NIVO would be safe and active as a frontline treatment for cisplatin ineligible mUC. Methods: 3+ 3 design was used for the phase I dose escalation of SG at 8 mg/kg and 10 mg/kg dose levels. IPI and NIVO were given at 3mg/kg and1mg/kg (I3+N1) intravenously (IV) every 3 weeks x 4 cycles followed by NIVO 360 mg IV day 1 every 3 weeks. SG was given IV at days 1,8 every 3 weeks The primary endpoint was safety and recommended phase 2 dose (RP2D) based on dose limiting toxicity (DLTs) observed in cycle 1; key secondary endpoints include ORR, DOR, PFS and OS. Key inclusion criteria were ECOG-PS 0-1, cisplatin-ineligibility, treatment naïve, no prior PD1/L1 inhibitor except >3 months earlier for non-metastatic disease. Results: The study has completed the phase I dose escalation after enrolling a total of 9 patients (8 men, 1-woman, median age: 74 years). 6 patients were enrolled at SG 8 mg/kg with 1 DLT, and 3 patients at 10 mg/kg with 2 DLTs. DLTs included grade 3 skin rash (n=2) and grade 3 pneumonitis (n=1). The RP2D of SG was determined to be 8 mg/kg with I3+N1. The most common treatment related adverse events (TRAE) included anemia (66.6%) neutropenia (66.6%), pruritus (66.6%), fatigue (66.6%), diarrhea (66.6%) and lymphopenia (55.5%). 2 patients developed grade 2 infusion reactions to SG. Other grade ≥ 3 TRAE included neutropenia (55.5%), anemia (33.3%), arthralgia (11.1%), and elevated amylase/lipase (11.1%). Both grade 2 pneumonitis and myositis were seen in 1 patient. Of the 9 pts, 6 pts (4 pts at SG dose of 8mg/kg and 2 pts at 10 mg/kg) were considered evaluable for response of whom 4 responded (ORR 66.6%) with 1 complete response and 3 partial responses. Median DOR was 9.2 Mo (range 4.6-12.0); mPFS was 8.8 Mo (95% CI 3.8-NR) and mOS was not reached. Conclusions: The RP2D of SG was identified as 8mg/kg in combination with Ipilimumab 3 mg/kg+ Nivolumab 1 mg/kg as first-line therapy for cisplatin-ineligible mUC. Early signals of promising activity were observed in a small cohort of evaluable pts. The Phase 2 trial is ongoing coupled with exploratory biomarker analyses. Clinical trial information: NCT04863885 .