Primary analysis of TROPHY-U-01 cohort 3, a phase 2 study of sacituzumab govitecan (SG) in combination with pembrolizumab (Pembro) in patients (pts) with metastatic urothelial cancer (mUC) that progressed after platinum (PT)-based therapy.

518 Background: Pembro is standard of care for pts with mUC who progress after 1L PT therapy but only ~21% of pts respond, highlighting an unmet need (Bellmunt, et al. NEJM. 2017). SG is an antibody-drug conjugate composed of an anti-Trop-2 antibody coupled to SN-38 via a hydrolyzable linker. In Cohort 1 of the TROPHY-U-01 study, SG demonstrated a 27% objective response rate (ORR) with manageable safety in 113 pts with locally advanced or mUC who previously received PT and a checkpoint inhibitor (CPI; Tagawa, et al. J Clin Oncol. 2021), leading to accelerated FDA approval in this pt population. Preliminary results of the phase 2 TROPHY-U-01 Cohort 3 study showed that SG plus Pembro demonstrated a high ORR (34%) as a 2L therapy in 41 CPI-naive pts with mUC who progressed after PT (Grivas et al. J Clin Oncol. 2021). Here we present the primary analysis of Cohort 3. Methods: Cohort 3 pts (≥18 y) had progression of mUC following PT in the metastatic setting or following ≤12 mo of PT in the (neo)adjuvant setting and ECOG PS 0-1. Pts received 10 mg/kg of SG on D1 and D8 and 200 mg of Pembro on D1 of a 21-D cycle for ≤2 y. The primary endpoint was ORR [complete response (CR) + partial response (PR)] per central review by RECIST 1.1. Secondary endpoints include clinical benefit rate [CBR; CR + PR + stable disease for at least 6 mo], duration of response (DOR) and progression-free survival (PFS) per central review; and safety. Target enrollment was approximately 41 pts based on a Simon two-stage design for 90% power at one-sided α of 0.05 to demonstrate 21% improvement in ORR, with a null hypothesis of historical ORR ≤20% and an alternate hypothesis of ORR ≥41%. Results: As of July 26, 2022, median follow-up was 12.5 mo (range, 0.9-24.6) for treated pts (N=41); median age, 67 y (range, 46-86), 83% male, 61% ECOG PS 1, 76% ≥1 Bellmunt risk factors, and 78% visceral metastases (29% liver). Median duration of last prior anti-cancer therapy was 2.7 mo (range, 0-13). Per central review, ORR was 41% (95% CI, 26.3-57.9; 20% CR); CBR was 46% (95% CI, 30.7-62.6); median DOR was 11.1 mo (95% CI, 4.8-NE [not estimable]; n=17); and median PFS was 5.3 mo (95% CI, 3.4-10.2). Median time to response was 1.4 mo (95% CI, 1.3-2.7) and median OS was 12.7 mo (95% CI, 10.7-NE). Grade ≥3 treatment-related adverse events (TRAEs) occurred in 61% of pts; most common Grade ≥3 TRAEs were neutropenia (37%; 10% febrile neutropenia), leukopenia (20%), and diarrhea (20%). TRAEs led to a 15% discontinuation rate. Systemic steroid and G-CSF use were both 34%. No treatment-related death occurred. Conclusions: SG plus Pembro demonstrated a high ORR and CBR with a manageable safety profile in 2L mUC in CPI-naive pts who progressed after PT-based therapy. No new safety signals were observed with the combination. These data support further evaluation of SG plus CPI in mUC. Clinical trial information: NCT03547973 .