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.
Petros Grivas, Damien Pouessel, Chandler H. Park, Philippe Barthélémy, Manojkumar Bupathi, Daniel P. Petrylak, Neeraj Agarwal, Sumati Gupta, Aude Fléchon, Chethan Ramamurthy, Nancy B. Davis, Alejandro Recio‐Boiles, Cora N. Sternberg, Astha Bhatia, Cabilia Pichardo, Mitch Sierecki, Julia Tonelli, Huafeng Zhou, Scott T. Tagawa, Yohann Loriot
Abstract
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 .